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The Roles of Jumonji-Type Oxygenases in Human Disease

Catrine Johansson, Anthony Tumber, KaHing Che and 4 more

Epigenomics · 2014 · Review · CC BY

doi:10.2217/epi.13.79

Abstract

The iron- and 2-oxoglutarate-dependent oxygenases constitute a phylogenetically conserved class of enzymes that catalyze hydroxylation reactions in humans by acting on various types of substrates, including metabolic intermediates, amino acid residues in different proteins and various types of nucleic acids. The discovery of jumonji (Jmj), the founding member of a class of Jmj-type chromatin modifying enzymes and transcriptional regulators, has culminated in the discovery of several branches of histone lysine demethylases, with essential functions in regulating the epigenetic landscape of the chromatin environment. This work has now been considerably expanded into other aspects of epigenetic biology and includes the discovery of enzymatic steps required for methyl-cytosine demethylation as well as modification of RNA and ribosomal proteins. This overview aims to summarize the current knowledge on the human Jmj-type enzymes and their involvement in human pathological processes, including development, cancer, inflammation and metabolic diseases.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

Several landmark discoveries have defined the Jumonji (Jmj) oxygenase protein family and provided important connections to chromatin and human biology. This family of iron (Fe2+)- and 2-oxoglutarate (2-OG)-dependent enzymes has its phylogenetic roots in prokaryotes, thus highlighting the functional versatility and critical importance of this protein class for life in an oxygen atmosphere. Regarding their roles in chromatin biology, the first breakthrough discovery was a gene trap approach to identify novel factors involved in mouse embryonic development – this study defined the jmj gene (named JARID2 in humans) as a novel class of transcriptional regulators. The gene was given the Japanese name jumonji, literally translated as ‘cruciform’, based on the cross-like shape found during neural groove development of jmj mutant mice. Analysis of the domain arrangements and primary structure of this gene identified an ARID/Bright domain, found in many DNA-binding proteins, immediately suggesting chromatin association of the gene product, as well as novel, so-called Jmj N and C domains (JmjN and JmjC, respectively). Further bioinformatic analysis of the JmjC domain revealed this to be an evolutionarily conserved protein fold belonging to the cupin family.

Mechanistic features of Jmj enzymes

Cupins are ancient protein domains, found in archaea, bacteria and eukarya, and are often metalloenzymes with metal ion-containing active sites based around a histidine cluster – hence the jumonji C (JmjC) enzymes belong to a large family of metalloproteins that, despite low sequence similarities, share a common Fe2+- and 2-OG-dependent catalytic core. The human 2-OG oxygenase family consists of over 60 members, to which the different Jmj-type lysine demethylases contribute significantly (Figure 1). All members of this family share few conserved sequence motifs necessary for iron and cofactor binding (with exceptions discussed below), and are mechanistically defined by their ability to hydroxylate their specific substrates using an activated oxo-ferryl intermediate. In brief, the catalytic sequence proceeds through distinct steps of 2-OG cofactor and molecular oxygen binding and activation, resulting in a highly reactive oxo-ferryl intermediate that reacts with the specific substrate atom, usually resulting in a hydroxylated substrate and concomitant CO2 and succinate formation. In terms of lysine demethylase reactions, the hydroxylated substrate is an unstable hemiaminal intermediate derived from the lysine methyl hydroxylation of the Nε -side-chain. This intermediate then fragments into formaldehyde and a lysine side-chain decreased by a methyl group. Importantly, this mechanism allows to demethylate all possible Nε-methyl states (mono-, di- and tri-) found in methylated histone lysine residues and thus differs significantly from the mechanism of monoamine oxidases such as LSD1 and LSD2 (KDM 1A and B) which are important mediators of chromatin function, and which can only demethylate mono- or di-methyl lysine states. Other important functions found in the human 2-OG family comprise hydroxylation of metabolic intermediates (e.g., phytanoic acid degradation [PHYH], or involvement in carnitine synthesis [BBOX, TMLH]), amino acids found, for example, in collagen (e.g., PLOD enzymes (Figure 1)), or transcription factors (e.g., HIFα by 2-OG oxygenases such as FIH and PHD enzymes).

Structural features of 2-OG enzymes

The JmjC domain is a double-stranded β-helical (DSBH) fold also called the jelly-roll fold or double Greek motif. The DSBH fold is composed of eight β-strands that form a β-sandwich structure comprised of two four-stranded antiparallel β-sheets (Figure 2). Most 2-OG oxygenases also contain additional secondary structure elements that surround the DSBH and define the different subfamilies. This includes additional β-strands that extend the DSBH, at least one helix on the C-terminal side of the DSBH, and inserts between the fourth and fifth β-strand. This DSBH core fold provides a rigid scaffold for the cosubstrates 2-OG and Fe2+, which are located in the more open end of the barrel (Figure 2). The iron is coordinated by two histidinyl residues together with a glutamyl or aspartyl residue in a conserved HxE/DxH motif found among 2-OG oxygenases. The 2-OG binding is less well conserved, and the cofactor coordinates the iron in a bidentate manner via its 2-oxo group and one of its 1-carboxylate oxygens, whereas the 5-carboxylate is usually bound to the side-chain of a basic residue (Arg/Lys) and to a hydroxyl group from a Ser/Thr or Tyr residue. The substrate binding varies considerably among the different subfamilies of 2-OG oxygenases/demethylases and the specific interactions identified thus far are beyond the scope of this review. However, crystallographic studies have revealed that it often involves residues from the first and second β-strand, together with strands and loops that extend the DSBH. Other protein domain modules, such as a plant homeodomain (PHD), Tudor, AT-rich interaction domain (ARID) or CxxC zinc finger motifs that vary between the different subfamilies, are usually also required for interaction with DNA/RNA or chromatin protein substrates. An overview of the different protein domains as well as annotation of substrate specificities found in Jmj enzymes with defined or hypothetical roles in chromatin biology is given in Table 1.

Jmj-enzymes as transcriptional regulators

Paradoxically, the founding member of the Jmj family, JARID2, lacks essential residues necessary for catalytic activity but nevertheless has been shown in various studies to be a key factor in mammalian development. JARID2 shows sequence homology with the JARID1 (KDM 5) family which is defined by the presence of JmjC/JmjN and ARID domains. The molecular mechanism by which JARID2 modulates mammalian development is not well understood, however it is now established that it associates with Polycomb group (PcG) proteins in several cell types, including embryonic stem (ES) cells, and is also critical for ES cell differentiation. PcG proteins were identified more than 30 years ago as regulators of homeobox (Hox) genes and development in Drosophila melanogaster and also have a critical role in mammalian adult tissue homeostasis and cancer.

Importantly, these studies highlight the fact that most, if not all Jmj-type chromatin enzymes function as parts of transcriptional or chromatin protein complexes and in addition to their catalytic roles exert their function as scaffold proteins. The second major breakthrough in Jmj enzyme biochemistry and understanding as transcriptional regulators was therefore the discovery that members of the Jmj family indeed possess catalytic activity towards methyl-lysine histone substrates. This effort was spawned by the discovery of the first lysine demethylase, LSD1 (which belongs to the amine oxidase family) followed by the characterization of distinct members of the Jmj family displaying methyl-lysine demethylase activity. These chronological discoveries led to the current and systematic nomenclature system of lysine demethylases (KDM).

Identification of methyl-lysine demethylases was important, because post-translational modifications of N-terminal, unstructured tails of histone proteins had been previously recognized as key-components in the regulation and signaling of functional states of the epigenomic landscape. Accordingly, reversal of these modifications has important consequences in processes such as gene regulation or genome stability; for example, trimethylated lysine 9 of histone 3 (H3K9me3) indicates heterochromatic or repetitive regions, whereas H3K4me3 marks regulatory elements associated with active promoters or transcription start sites, and H3K27me3 often specifies developmentally repressed genes. With the discovery of histone demethylation, lysine methylation of histone residues is now considered reversible and to respond dynamically to changes in metabolism or chromatin environment. At present several classes of histone modifications and their respective enzymatic modification systems have been identified and amongst their epigenetic substrate marks, lysine and arginine modifications are probably the best studied: acetylation and methylation of lysine residues, as well as methylation of arginine. Whereas acetylation of histone tails is correlated with gene activation, the influence of histone methylation on regulating gene transcription depends on the exact residue methylated and the number of added methyl groups, both for arginine and lysine residues.

This review focuses on the description of Jmj-type chromatin hydroxylases and their involvement in human chromatin biology and associated pathologies. We will focus our description on the different KDM subfamilies, but also include the nucleotide hydroxylases as well as several further subfamily members with suspected nuclear or chromatin functions (Figure 1). For completeness, we will also briefly describe the monoamine oxidases of the KDM1 family despite being mechanistically distinct. It is worth noting that since the discovery of Jmj enzymes as mediators of histone demethylation with its important consequences in chromatin biology and transcriptional regulation, not in every case have sufficiently stringent methods (e.g., product identification through mass spectrometry) been employed to properly characterize these enzymes. Therefore in several instances it remains to be established what their true endogenous substrates and inferred biological functions are.

KDM1 subfamily

Starting with the groundbreaking discovery of LSD1 (KDM1A) as methyl-lysine demethylase, a series of studies revealed the enzymatic and biological roles of this amine oxidase that was able to demethylate histone methyl-lysine residues H3K4me2/1 and H3K9me2/1 in an FADH-dependent reaction (summarized in). Following this work, the paralog LSD2 (KDM1B) with activity towards H3Kme2/1 was discovered. Analyses of mice with targeted deletion of LSD1 or LSD2 revealed their essential roles in development, and other studies highlight the essential role of LSD1 in embryonic and cancer stem cell biology. Several investigations found that both KDM1 forms are aberrantly expressed in a variety of human tumor types (see) and, taken together, provide the rationale for current inhibitor development. LSD1 is found in a variety of chromatin complexes, which include components such as HDAC/CoREST, BRAF35, BHC80 and noncoding RNA, and possibly the NuRD remodeling complex; in these cases LSD1 functions as a repressor through its H3K4me2 demethylase activity. In contrast, LSD1 can associate with nuclear hormone receptors such as the androgen or estrogen receptor, and in these situations LSD1 shows H3K9me2 demethylase activity, thereby promoting target gene transcription. Taken together, the KDM1 enzymes are involved in various context-specific functions (e.g., in transcription initiation, enhancer modification or chromatin remodeling). Interestingly, LSD1 is able to demethylate other nonhistone, chromatin-associated factors such as p53 or DNA methyltransferase 1 (DNMT1), indicating that lysine demethylase substrates are not restricted to histone molecules.

KDM2 subfamily

Soon after the breakthrough discovery of histone lysine demethylation mediated by LSD1, mechanistically different members of the Jmj family were shown to catalyze removal of methyl-lysine histone marks. The first enzymes characterized within this family were human FBXL10 and FBXL11 (KDM2B and KDM2A, respectively), catalyzing the demethylation of H3K36me2/1 histone chromatin marks, an activity that orthologous forms display as well. The full-length proteins show a domain organization comprising JmjC, CxxC, PHD, Fbox and leucine-rich repeats (Table 1). Fbox-containing domains are involved in formation of cullin-Fbox protein-E3 ubiquitin ligase complexes, which suggests a link between KDM2, histone ubiquitination and proteasomal degradation. The CxxC zinc finger domains are modules that recognize unmethylated cytosine residues in a CpG dinucleotide context. Usually unmethylated, contiguous stretches of CpG elements are often found overlapping with a large fraction (up to 70%) of promoter and transcriptional start sites (so-called CpG islands [CGIs]), enforcing the notion that they contribute to gene regulation by providing a suitable environment for chromatin complexes. Elegant work has provided evidence that FBXL10 and FBXL11 are recruited to the majority of mammalian unmethylated CGIs through their CxxC-Zn finger domains. KDM2 enzymes thereby contribute to a specific chromatin environment surrounding CpG sites, independent of the transcriptional states of the particular gene. For example, FBXL11 is bound to 90% of annotated CpG sites in murine ES cells, creates a unique H3K36me2 depleted signature that distinguishes CpG/promoter structures from bulk chromatin, and possibly provides a permissive environment allowing subsequently chromatin elements such as regulatory and transcription factors to bind. Interestingly, FBXL10 shows a largely overlapping occupancy of binding sites when compared to FBXL11 and, in addition, defines a CGI subset through binding to Polycomb repressive complex 1 (PRC1), which mediates histone 2A (H2A K119) ubiquitylation through the RING1B component of this noncanonical PRC1 complex. This is in line with data about the activity of CGI1033, the Drosophila KDM2 ortholog that regulates PRC1-mediated H2A monoubiquitylation, independent of its demethylase function and, collectively, provides novel insights how PRC1 is directed to its target genes. The localization of KDM2 enzymes to unmethylated DNA regions is consistent with mass spectrometry studies using nucleosome preparations, demonstrating enrichment at H3K9me3/unmethylated DNA nucleosomes. Other chromatin functions of KDM2 forms may be related to heterochromatin formation and ribosomal gene transcription.

These studies give evidence for the essential role of KDM2 genes during development and in general for an emerging picture of chromatin architecture and function. The general targeting of KDM2 enzyme forms to CpG-containing promoter regions can explain many of the various phenotypes observed in several biological systems. For example, by being part of the Oct4/Sox2 regulatory axis, KDM2 enzymes can regulate reprogramming, pluripotency and stem cell properties, associate with corepressors such as BCL-6 corepressor (BCOR), or control senescence and proliferation through repression of the Ink4b locus and hence KDM2 involvement in oncogenic processes has been analyzed. From these studies, it is apparent that KDM2 enzymes exert their critical importance through enzymatic (i.e., H3K36me demethylase activity) and nonenzymatic scaffolding functions (i.e., as being part of chromatin protein complexes). In addition, it has been shown that FBXL11 regulates the activity of the transcription factor NF-κB through direct demethylation of methylated Lys218 and Lys221 in NF-κB, a modification that is installed through the methyltransferase NSD1.

KDM3 subfamily

In humans the evolutionarily conserved KDM3 subfamily comprises four proteins, JmjD1A-C and the related hairless (HR) gene product. These proteins differ considerably in amino acid chain-length but have two regions in common that are both required for demethylase activity: a C2HC4-zinc finger-like domain followed by a C-terminal ~220-residue-long JmjC-domain that shares approximately 65% overall similarities. Both full-length and truncated versions of JmjD1A and B specifically demethylate H3K9me2/me1 substrates while no demethylase activity has been described for human JmjD1C or HR yet. The demethylase activity of JmjD1A is inhibited by iron chelators and divalent metals (Co2+ and Ni2+) that replace the ferrous iron at the catalytic site, as well as by NO that forms a nitrosyl-iron complex in the catalytic pocket. JmjD1A-C enzymes are expressed in many cell lines or tissues and are primarily localized to the nucleus. Several phosphorylation sites have been reported for all members in the KDM3 subfamily that could be important for substrate recognition and signaling, but the impact of these modifications is unknown at present.

JmjD1A was identified by its interaction with the androgen receptor (AR) and acts as a coactivator of AR-mediated transcription. The protein is also known as KDM3A, JHDM2 or testis-specific gene A (TSGA) since it is highly and dynamically expressed during spermatogenesis. Male knockout mice are infertile with small testes and a severe reduction in sperm count, which suggests that JmjD1A positively regulates the expression of genes involved in sperm chromatin condensation and maturation. JmjD1A-knockout mice also exhibit an adult obesity phenotype, which implies an important role in transcriptional control of metabolic genes in muscle and adipose tissue. The protein is upregulated in human cells exposed to hypoxia and its expression is regulated by HIF-1α that binds to a specific hypoxia responsive element in the JmjD1A promoter. The hypoxia signaling pathway plays an important role in tumor progression, and JmjD1A has recently been associated with many types of cancers. Significantly elevated levels have been reported in several human cancer cells including bladder, lung, hepatocellular, prostate, colorectal and renal cell carcinoma, and treatment of cancer cell lines with siRNA targeting JmjD1A results in significant suppression of proliferation, tumor angiogenesis and macrophage infiltration into tumor tissues. Although the exact role of JmjD1A in tumor progression remains to be elucidated it is considered a potential therapeutic target in the treatment of cancer.

JmjD1B also has the synonyms KDM3B/JHDM2B/5qNCA. In humans, the gene is located in the 5q31 chromosomal region, which is frequently deleted in myeloid leukemias and in breast cancer. JmjD1B is a suggested tumor suppressor that regulates the expression of the leukemic oncogene lmo2 and it is also found to specifically interact with the transcriptional repressor suppressor of cancer cell invasion (SCAI). JmjD1C/JHDM2C was originally referred to as TRIP8. Two transcripts have been reported for this gene where the major transcript (variant 2) consists of a TRI8H1 domain with the zinc finger motif, a TRI8H2 domain with a thyroid hormone receptor β-binding region, and a C-terminal JmjC domain. JmjD1C is similar to JmjD1A, an AR-interacting coactivator (see above), that is suggested to perform a transcriptional regulatory function in testes development by regulating the expression of the steroidogenesis marker p450c17, via SF-1-mediated interactions. JmjD1C is expressed in a variety of human tissues and its reduced expression in human breast cancer tumors compared to normal breast tissues suggests a putative role in tumor suppression. No H3K9me2/1 demethylase activity has thus far been detected for the human protein, although all the conserved residues known to be important for enzymatic activity are conserved. A recent report that used both mutational analysis of single residues and domain swapping of both the JmjC- and the Zn-finger domain with JmjD1A/B revealed that both the sequence identity within the JmjC domain and in the sequence N-terminal of the JmjC domain are important for enzyme activity. In other KDMs it has been shown that single amino acid substitutions are sufficient to completely abrogate enzymatic activity and it is possible that thus far unidentified residues involved in substrate binding differ between the different KDM3 homologs. Further studies are needed to elucidate whether JmjD1C utilizes other substrates or cofactors, or if it has a predominant scaffolding function.

The HR protein plays a critical role in the maintenance of hair growth but the underlying mechanisms are still unclear. The protein is expressed in the skin but also the CNS where it is suggested to function as a corepressor for multiple nuclear receptors including the thyroid hormone receptor, the retinoic acid receptor-related orphan receptors and the vitamin D receptor. HR also interacts with histone deacetylases, including HDACs 1, 3 and 5, and this interaction supposedly is responsible for the corepressor activity observed for HR. Mutations in the HR protein (C622G, N970S, D1012N, V1136D) are associated with congenital alopecia or atrichia with papular lesions. These pathogenic mutants occur primarily within the JmjC and the Zn-finger domain and appear to be essential for its co-repressor activity.

KDM4 subfamily

The KDM4 subfamily of histone demethylases comprises four members, JmjD2A-D. The proteins are defined by an N-terminal JmjN and JmjC domain that in JmjD2A-C is followed by two tandem PHD and tudor domains (Table 1). These enzymes catalyze the demethylation of H3K9me3/me2 with a preference for the tri-methyl state, a histone mark associated with gene repression and found in heterochromatin. In addition, JmjD2A-C catalyze the demethylation of H3K36me3 albeit at a lower rate. A less well-studied repressive histone mark, H1.4K27me, is also reported to be demethylated by all KDM4 members. JmjD2A-C isoforms are also found to catalyze demethylation of trimethyl-lysine peptides of chromatin repressors WIZ, CDYL1, CSB and G9a proteins, indicating that KDM4 members can antagonize chromatin repressive marks and regulate gene transcription. A further two members of the human KDM4 subfamily (JmjD2E and JmjD2F) are known to exist but are currently considered to be pseudogenes due to lack of intronic sequences in their genes. However, in vitro studies demonstrate that at least the catalytic domain of human JmjD2E is highly active and shows similar substrate specificities as JmjD2D.

The involvement of JmjD2A, B and C in cancer is now unequivocally established, highlighting the importance of these enzymes as potential targets for drug discovery (reviewed recently). Many studies over the past 6 years have focused on the role of JmjD2 demethylases in progression of hormone responsive and hormone non-responsive cancers in both prostate and breast, underpinning the coregulation with nuclear hormone receptors. For example, Cloos et al. showed that JmjD2A, B and C are increased in prostate cancer tissues followed by studies demonstrating KDM4 enzymes to be coactivators of the androgen receptor, in addition to roles in androgen independent proliferation of prostate cancer cells. More recently it was demonstrated by siRNA approaches that JmjD2B regulates AR transcriptional activity and controls stability of AR by prevention of proteosomal degradation of the receptor. JmjD2C (GASC1) has been shown to be amplified in triple-negative (estrogen, progesterone and HER2 receptor-negative) breast cancers. Gene silencing studies demonstrate clear antiproliferative effects of JmjD2A knockdown in (estrogen receptor [ER]-negative breast cancer cells, and downregulation of JmjD2A in ER-positive breast cancer cells leads to reduced cell proliferation associated with decreased levels of cyclin D1. Yang et al. showed that JmjD2B is highly expressed in ER-positive primary breast cancer and that JmjD2B is a target gene for ER itself, underlining the evidence for the importance of JmjD2B in the etiology of ER-positive breast cancers. JmjD2B and JmjD2C are targets for the hypoxia inducible transcription factor HIF1α in cancer cell lines, and hence are of possible importance in regulating transcriptional responses in a hypoxic tumor environment. A role for the lipopolysaccharide (LPS)- and TNF-inducible enzyme JmjD2D in regulating H3K9me3 levels, and hence activity of upstream enhancer elements in a variety of cell types, was recently demonstrated.

Given the wealth of publications on the KDM4 family and cancer, relatively little has been published on their role in epigenetic control of other key processes such as embryonic development or normal tissue remodeling. Recent studies revealed a function for JmjD2A in specification of neural crest cells in the early mouse embryo. Conditional gene ablation studies and transgenic studies in mice provide further insights into the function of KDM4 enzymes in development, for example, the generation of mice with a knockout or overexpression of JmjD2A in the heart shows a role for JmjD2A in cardiac hypertrophy in response to cardiac stresses. More recent studies provide insights into how KDM4 enzymes regulate cell fate determination. In vitro and in vivo studies have demonstrated a role for JmjD2B in commitment of mesenchymal stem cells (MSC) to the osteogenic lineage by removing the repressive H3K9me3 marks from osteogenic lineage-selective genes such as DLX5, thus favoring osteoblas-togenesis over adipogenesis. JmjD2B has also been shown to be a target gene for the transcription factor C/EBPβ, a transcription factor that is involved in preadipocyte proliferation and differentiation. In this study, a knockdown of JmjD2B inhibited mitotic cell expansion and terminal differentiation of the preadipocyte cell line, 3T3-L1.

More recently, several studies demonstrated a role for the H3K9me3 demethylase JmjD2D (KDM4D) in oncology, inflammation and drug metabolism. In mice, JmjD2D assists the nuclear receptor constitutive androstane receptor (CAR), a key regulator of drug metabolizing enzymes in induction of a neonatal metabolic gene program persisting through adult life. JmjD2D also interacts with the tumor suppressor p53 and controls proliferation, and activity of cell-type specific enhancer regions in immune cells through H3K9me3 demethylation.

KDM5 subfamily

As with many of the JmjC lysine demethylases, the KDM5 family is composed of multidomain members. These are defined by the presence of both JmjC and JmjN domains but also a DNA-binding, ARID domain and a C5HC2 zinc finger motif as well as methyllysine- or methyl-arginine-binding PHD domains involved in histone-substrate recognition (Table 1). There are four genes described within the human family, namely JARID1A (KDM5A/RBP2), JARID1B (KDM5B/PLU1), JARID1C (KDM5C/SMCX) and JARID1D (KDM5D/SMCY). All KDM5 members demethylate the H3K4me3 histone mark, a signature indicative of transcriptional activation, and hence KDM5 are considered transcriptional corepressors. One important function appears to be as members of chromatin complexes, for example, JARID1A is found associated to the PRC2 Polycomb complex, important in establishing repressive chromatin marks during development, and JARID1C can be identified in complexes with other repressive chromatin modulators such as HDAC1/2/REST, or the H3K9 methyltransferase G9a. KDM5 enzymes are found around the transcriptional start sites of a large set of target genes, where they are thought to fine-tune the transcriptional output, as indicated by modest transcriptional responses upon depletion of, for example, JARID1B – effects, which nevertheless are critical for cellular responses in development and disease.

JARID1A was discovered as an interaction partner of the retinoblastoma protein (Rb), a key regulator of cell cycle control and differentiation, hence its alias as Rb-binding protein (RBP2). Interactions between the two proteins can promote cellular differentiation, in addition to a role for JARID1A and demethylation of H3K4 in the control of cellular senescence. JARID1A regulates HOX gene activity during development, underlining the importance of KDM5 enzymes in stem cell biology. The role of JARID1A also extends to other areas of cellular control, with an example being modification of the circadian clock period. In cancer, the NUP98/JARID1A gene fusion has been described as a cryptic translocation involved in pediatric acute megakaryoblastic leukemia, and additionally the JARID1A locus was identified in a recent GWAS analysis as a susceptibility gene in ankylosing spondylitis. Importantly, JARID1A has been implicated in facilitating an altered chromatin state that promotes drug-tolerant subpopulations of cancer cells.

JARID1B displays an important yet complex role in stem cell biology by blocking differentiation in embryonic and hematopoietic stem cells, however in a different study it was found to be dispensable for embryonic stem cell maintenance and critical for neural differentiation. JARID1B is also implicated in the control of cellular senescence. It is a deregulated factor in several cancer types, for example, it can suppress tumor progression in breast cancer cells, and is specifically expressed in melanoma, as well as breast cancer. The involvement of JARID1B in cancer stem cell maintenance highlights its role in tumorigenesis.

JARID1C and JARID1D are located on the X- and Y-chromosomes respectively and may well have diverged from a single ancestral sex chromosome. Intriguingly, this segregation to the gonosomes offers some interesting prospects regarding sex-specific gene regulation, however, it should be noted that JARID1C is not subject to X-inactivation. The ubiquitously transcribed JARID1C is known for its role in X-linked intellectual disability (XLID). It is highly expressed in brain tissue and the gene is found to be frequently mutated in this condition of male cognitive impairment. There is also a potential role for JARID1C variants in autism spectrum disorder. Taken together, these data present evidence for an important role for JARID1C in normal brain function, by regulating expression of important neuronal genes. In tumor biology, JARID1C interacts with the von-Hippel–Lindau protein and has been shown to regulate gene expression and to suppress tumor growth.

JARID1D transcripts are detected in a wide range of male tissues and a JARID1D-derived peptide has been identified as the male-specific histocompatibility antigen (H-Y). The JARID1D genomic locus is associated with a region of the Y-chromosome designated azoospermia factor region; a region involved in spermatogenesis. It is thought that JARID1D interacts with the meiosis-regulatory protein MSH5 during this process. Furthermore, deletion of this gene has been detected in prostate cancer. It has been shown that PCGF6/MBLR can directly interact with JARID1D to enhance its demethylase activity via a C-terminal domain.

KDM6 subfamily

Since the identification of JmjD3 and UTX as H3K27 demethylases in 2007, numerous publications have emerged describing the functions of H3K27 demethylase enzymes in various biological contexts such as development, inflammation and oncology. The human KDM6 subfamily consists of three distinct members, namely JmjD3, UTX and UTY with documented histone lysine demethylase activities for UTX and JmjD3 (KDM6A and B). Whereas UTX and UTY are located on X and Y chromosomes, respectively, JmjD3 is found on chromosome 17. All KDM6 members have a JmjC domain followed by a GATA-like DNA-binding domain, whereas UTX and UTY also have N-terminal located protein interaction (tetratricopeptide repeat [TPR]) domains (Table 1). Whereas the catalytic role of JmjD3 and UTX is undisputed, critical scaffolding and protein interaction functions of all KDM6 members have been recognized. For example, Sola et al. reported that during mouse neural stem cell differentiation, the N-terminal region of JmjD3 stabilizes the key transcription factor p53 in a demethylase-independent manner and contributes to nuclear localization of p53, or during T-cell development JmjD3 associates with Tbox proteins independent of its catalytic role. However, a key mechanism of JmjD3 and UTX appears to be their ability to remove H3K27me3 chromatin marks which anchor Polycomb repressive complexes and are often found in ‘bivalent’ chromatin domains thought to be in a transcriptionally ‘poised’ state.

JmjD3 is expressed in human, rhesus monkey and mouse oocytes during metaphase, and plays a role in oocyte preimplantation (e.g., in bovine fertilization), since knockdown of JmjD3 in oocytes inhibited H3K27me3 demethylation and impacted blastocyst, and later endoderm and mesoderm development. This is accomplished through methylation of bivalent chromatin domains and their poised transcriptional states, by removal of H3K27me3 marks, thus enabling expression of key developmental genes such as WNT3, DKK1 or FOXH1 involved in Wnt and Nodal pathways. Multiple studies highlight the key role of H3K27 demethylases in cellular differentiation, for example, in later stages of embryo development, JmjD3 is largely involved in regulation of genes responsible for body and limb morphogenesis, including HOX and T-box transcription factors. However, here the enzymatic function of JmjD3 appears to be at least in part dispensable. The importance of H3K27 demethylases is further underpinned by their roles in induced pluripotent stem cell (iPS) biology. Silencing of JmjD3 in mouse embryonic fibroblasts (MEFs) during iPS reprogramming enhanced iPS formation, whereas ectopic expression of JmjD3 inhibited reprogramming, an effect that is mediated through both demethylase-dependent and -independent pathways. Where as the demethylase-dependent function mediates removal of H3K27me3 repressive marks on genes involved in reprogramming such as Ink4/Arf, the demethylase-independent pathway involves PHF20 for ubiquitination, thereby leading to degradation. Other work has shown that JmjD3 is involved in bone cell differentiation, for example, knockdown of JmjD3 caused significantly reduced osteogenic differentiation of mesenchymal stem cells to osteoblasts. Osteoclast development is partly regulated by H3K27 demethylation, by controlling H3K27me3 levels at the promoter of the key osteoclastogenic transcription factor NFATc1. A number of studies indicated that JmjD3 also plays an important role in neural differentiation and commitment. Here, JmjD3 is one of the early neural differentiation regulators modulated by BMP4 in neural stem cells and is crucial to activate TGFβ-responsive genes. In retinoic acid (RA)-induced neural differentiation, an increased expression level of JmjD3 was shown to remove H3K27me3 at the HOX gene regulatory elements. Mash1, a key gene in RA neuronal differentiation, is also regulated by a similar mechanism, whereas silencing of an RNA binding protein induces expression levels of JmjD3 in RA neurogenesis. Importantly, a JmjD3-knockout in mouse resulted in perinatal lethality, affecting the pre-Botzinger complex (PBC) complex, which is the pace-maker of the CNS respiratory rhythm generator. The critical role of UTX in developmental effects is underscored by the discovery of mutations in the human gene associated with Kabuki syndrome, an intellectual disability syndrome also associated with mutations in the H3K4 MLL methyltransferase.

A role in inflammation was found for KDM6 enzymes, since JmjD3 expression in macrophages is regulated through the NF-κB signalling pathway in LPS-stimulated macrophages. It was found that JmjD3 associates with 70% of LPS-inducible genes, though it is unclear whether JmjD3 is directly involved in transcription of these genes. A direct effect on regulating TNF promoter K27 methylation and transcription was demonstrated in a study using a H3K27 demethylase inhibitor. Stimulation of mouse macrophages by IL-4 induces JmjD3 via the STAT6 pathway and leads to activation of several anti-inflammatory genes. In addition, in mice, the polarization of anti-inflammatory macrophages during helminth infection is modulated by JmjD3. In T cells, JmjD3 is involved in T-helper cell lineage commitment, through interaction with T-box transcription factors. Expression of HPK1/MAP4K1, a kinase that negatively regulates T-cell immune response, is influenced by JmjD3-mediated demethylation of H3K27. Overexpression of JmjD3 causes upregulation of HPK1, which in turn suppresses T-cell responses. Hence, blocking of JmjD3 activity could be a potential therapeutic approach for the treatment of systemic lupus erythematosus. During wound healing, JmjD3 and UTX are upregulated at the wound site and control epidermal differentiation. JmjD3 is also overexpressed in vasculitis where it regulates expression of Itaga2b and Mpl in megakaryocytes.

Unsurprisingly, the critical function of H3K27 demethylases (KDM6 enzymes) in controlling key developmental factors is reflected also through their involvement in oncology. Importantly, the particular role (either as tumor suppressor or oncogene) depends on the particular cellular context. Numerous studies have demonstrated overexpression of JmjD3 in cancer cell lines or tumor biopsies, also associated with increased proliferation or control of anti-apoptotic genes such as Bcl-2, or for example aberrant repressive PcG methylation patterns in medulloblastoma.

However, in several instances KDM6 enzymes can also be regarded as tumor suppressor genes by counteracting the oncogenic function of PcG proteins, for example by controlling the INK4A/ARF locus that comprises tumor suppressor genes p16INK4A and p14ARF involved in cellular senescence. For example, in cells undergoing oncogenic stress, JmjD3 is induced by RAS/RAF signaling pathways and activates P16/INK4a and p14/ARF, causing p53-dependent cell cycle arrest.

JmjD3 is involved in the epithelial–mesenchymal transition (EMT), and is overexpressed in invasive breast carcinoma. Knockdown of JmjD3 prevented breast cancer infiltration, and overexpression of JmjD3 affected the expression of a range of adhesion molecules, including downregulation of E-cadherin and upregulation of N-cadherin and fibronectin. Detailed analysis revealed that during TGFβ stimulated EMT, JmjD3 removes H3K27me3 at the promoter of an EMT-inducer gene, SNAI1, thus allowing transcription of the gene. In SW480-ADH colon cancer cells, calcitrol (vitamin D3, 1,25-(OH)2D3 induces JmjD3 expression thus controlling critical target genes. Knockdown of JmjD3 induced SNAI1-mediated EMT, upregulation of mesenchymal markers and downregulation of epithelial proteins. Expression of JmjD3 correlates with expression of vitamin D receptor but is inversely correlated with expression of SNAI1 in 96 human colon tumors. Lastly, mutations found in the UTX or JmjD3 genes suggest a possible role in the oncogenic process.

Little is currently known about the function of UTY, a gene showing a large number of splice variants, but encodes a minor HLA-B8 HY-antigen, implicated in graft/host interactions. A recent genetic study identified downregulation of UTY in the predisposing haplogroup I of the Y chromosome in coronary artery disease.

KDM7 subfamily

The human KDM7 subfamily consists of three members: KIAA1718 (KDM7A), PHF8 (KDM7B) and PHF2 (KDM7C), showing a characteristic domain organization with an N-terminal PHD domain, and a catalytic Jmj domain (Figure 1 & Table 1). The C-termini are comprised of coiled–coiled domains and structurally undetermined amino acid stretches. These C-terminal regions have been shown to be important for association with RNA polymerase or transcription factors such as the retinoic acid receptor (RAR) and possibly cell cycle regulators such as E2F1, and contain nuclear localization signals or phosphorylation sites. Several reports unequivocally demonstrate a catalytic role of KDM7 members in demethylation of repressive histone marks such as H3K9me1/2, H3K27me1/2 or H4K20me1 (summarized in) with distinct differences in substrate specificities among the various enzymes. The critical importance of these activities in mediating transcriptional coactivation is highlighted through association with H3K4me3 marks (through the conserved PHD modules), and oxidative removal of repressive histone marks. This creates a permissive chromatin environment by facilitating transcription through subsequent acetylation of lysine residues after methyl mark removal which is accomplished through KDM7 enzymes. The cooperative role of histone marks in KDM7 mediated coactivation is further emphasized through phosphorylation of Ser 3 of histone 3 (H3S3), an important histone mark during mitotic progression, which also prevents KDM7 binding to mitotic chromosomes, in addition to the cell cycle-dependent phosphorylation of, for example, PHF8, a critical event in cell-cycle progression. The importance of KDM7 members in gene transcription is demonstrated through chromatin immunoprecipitation followed by next-generation sequencing, showing promoter occupancy at a large fraction of transcriptionally active genes. Besides their roles in RNA polymerase II (RNA Pol II)-mediated transcription, at least PHF8 and PHF2 are also involved in RNA Pol I-mediated RNA gene transcription. The pathophysiological roles of KDM7 members include involvement in cancer, such as RARα coactivation in pro-myelocytic leukemia, regulation of proinflammatory responses and development (e.g., of neural tissues). PHF2, a H3K9me2 demethylase, has been shown to play a role in breast cancer. Several mutations described in PHF8 are causative of Hamel–Siderius syndrome, an X-linked mental retardation often accompanied by developmental malformation such as cleft lip/cleft palate or microdeletions in autism disorders, in line with observations on the critical roles of KDM7 enzymes during neuronal development. Interestingly, another 2-OG enzyme, trimethyllysine hydroxylase found within the small molecule branch (TMLHE, Figure 1), was identified along with PHF8 in an X-chromosome exome sequencing study of autism and intellectual disability cases.

Other putative Jmj-type demethylases & amino acid hydroxylases

This group (see Figure 1) of human 2-OG oxygenases comprises a functionally diverse group of enzymes several of which have well-described roles, such as factor inhibiting HIF (FIH), or which have been rarely studied to date (e.g., JmjD8). These enzymes have, beside the Jmj core domains, few predicted or structurally verified additional domains, the lack of chromatin-binding domains especially suggests potential functions other than histone modification. Indeed, with few studies conducted thus far, the role in histone modification appears, in most instances, secondary at best. Nevertheless, for several of these 2-OG enzymes, hydroxylation of amino acids (e.g., asparagine or histidine residues) in nonhistone proteins has been clearly shown by using mass spectrometry techniques.

Among the best-studied members of the Jmj family is FIH, an asparaginyl hydroxylase that modifies an asparagine residue (Asp803) in the C-terminal transactivation domain of HIFα proteins. These transcription factors regulate key programs involved in metabolic adaptation to low O2 tension, such as energy metabolism, redox and pH homeostasis, and O2 supply, as well as many other functions. FIH-mediated HIFα hydroxylation is important to regulate interaction with the transcriptional coactivator p300, a function that is impaired under low oxygen levels. HIFα activity is regulated by FIH in concert with prolyl hydroxylases (see Figure 1) such as PHD1 and PHD2, which regulate proteasomal degradation of HIFα under normoxic conditions. In normoxia, PHD and FIH enzymes act synergistically to degrade and inactivate HIF-1α. Under hypoxic conditions, the PHD enzymes no longer hydroxylate HIFα, leading to stabilization and accumulation of the HIF-1α subunit. FIH remains active at this stage and continues to repress HIFα activity until conditions of severe hypoxia occur, where FIH ceases to hydroxylate the asparagine residue in the C-terminal domain and releases HIFα repression. FIH-null mice do not display a phenotype related to increased HIF or hypoxia responses, but show significant metabolic changes such as reduced body weight, elevated metabolic rate and resistance to effects of high-fat diet. FIH is important in several cancer types, for example, FIH expression is regulated by miRNA-31 in head and neck squamous cell carcinoma. Low nuclear expression of FIH is a prognostic factor for poor overall survival in clear cell renal cell carcinoma. Inhibition of FIH-1 in cell cultures of cell renal cell carcinoma decreases cells expansion and increases apoptosis by regulating HIFα. Over expression of FIH and PHD HIF hydroxylases in non-small-cell lung cancer is indicative of a poor prognosis. FIH is also expressed in invasive breast carcinomas, and is found to be inhibited by gankyrin, an oncoprotein expressed in hepatocellular carcinomas, causing an increased HIF and VEGF expression resulting in hemangioma.

More recently, it has been demonstrated that FIH can also modify asparagine, aspartate and histidine residues in ankyrin repeat proteins such as NF-κB or Notch indicating hydroxylation of amino acid residues as a widespread function that awaits further investigations.

MINA53 is closely linked to expression of the transcription factor c-Myc, a gene associated with cell growth, proliferation, loss of differentiation and apoptosis. MINA53 has been reported to demethylate H3K9me3, but this activity is controversial since a lack of demethylase activity has been reported by several groups. More recently it was shown that MINA53 catalyses histidyl hydroxylation of ribosomal protein L27a, suggesting a function in ribosomal assembly and function. A series of papers have confirmed MINA53 effects on cell differentiation, and overexpression of MINA53 in various cancers appears to be linked to oncogenesis. The role of MINA53 has been especially well characterized in lung cancer, making it a potential prognostic biomarker for the disease. MINA53 expression was also found to be induced by silica particles, and the protein plays a key regulatory role in immunity, for example, in allergen-induced inflammatory response and, importantly, in differentiation of proinflammatory TH17 cells. Taken together these studies conclude that MINA53 is an important regulator in inflammation and oncology, however the mechanistic link between its enzymatic activity and those cellular phenotypes awaits clarification.

The closely related oxygenase NO66 (also known as MAPJD) was first identified and characterized in 2004 by Eilbracht et al. in purified nucleoli from Xenopus laevis oocytes. NO66 shows significant sequence homology to MINA53 (34% sequence identity) and is reported to demethylate H3K4 and H3K36, and similar to MINA53, to catalyse ribosomal histidinyl hydroxylation, in this case on ribosomal protein L8. During mouse embryonic stem cell differentiation NO66 is recruited by PHF19, a component of the Polycomb repressive complex PRC2, to stem cell genes resulting in loss of H3K36me3, transcriptional silencing and PRC2-dependent methylation of H3K27. NO66 regulates osteoblast differentiation and bone formation by inhibiting Osterix (Osx), a key transcription factor essential at later stages of bone development, accordingly Osx-null mice have a normal cartilage development, but lack bone formation. Conversely, knockdown of NO66 in differentiating osteoblasts derived from mesenchymal stem cells causes accelerated differentiation and mineralization of osteoblasts. The interaction between NO66 and Osx was recently mapped to a conserved hinge domain, that links the N-terminal JmjC domain and C-terminal wHTH domain of NO66 (Table 1). The protein is overexpressed in non-small-cell lung cancer, and postulated to be a potential drug target.

JmjD4 is a poorly characterized oxygenase whose enzymatic activity has not been characterized, and shows approximately 30% sequence similarity to JmjD6. JmjD5 (also classified as KDM8) plays a critical role in the regulation of cell cycle by inhibition of HDAC recruitment and by activating the cyclin A1 locus, postulated through demethylation of histone H3K36me2, although this activity needs further investigation. Instead, a hydroxylase activity of JmjD5 appears to control the half-life of transcriptional regulators such as NFATc1 through promotion of E3-ligase association and proteasomal degradation of the transcription factor. JmjD5 deficiency results in a short-period circadian phenotype both in mammalian cell cultures and Arabidopsis plants. JmjD5 is widely overexpressed in several types of tumors (e.g., in leukemia and breast cancer) and a knockout in a MCF7 breast cancer cell line resulted in reduced proliferation, and its function appears to be interrelated with the tumor suppressor p53. Ablation of murine JmjD5 causes severe growth retardation and ends in embryonic lethality.

JmjD6, initially characterized as phosphatidyl serine receptor, a function that together with its postulated methyl arginine demethylase activity has not yet been confirmed, catalyzes the hydroxylation on the carbon side-chain of lysyl residues located in arginine–serine rich regions of, for example, splicing factors or might modify single-stranded RNA, indicating involvement in RNA modification and function. In mice, the gene is indispensable for normal development of many tissues such as brain, eyes, lung, kidney, liver and intestine at different stages of embryogenesis. Furthermore, JmjD6 plays an important role during heart development since ablation of its function is associated with complex cardiopulmonary malformations that resemble the human congenital heart syndrome tetralogy of Fallot. Overexpression of JmjD6 protein has now been strongly linked to poor prognosis in breast cancer and in lung adenocarcinoma. JmjD7 is a poorly characterized enzyme located on chromosome 15; a fusion with phospholipase represents a novel isoform of this lipid metabolizing enzyme. JmjD8 is linked to cell proliferation and cancer but its enzymatic and cellular functions remain unknown. JmjD8 siRNA knockdown in SCC23/MET cells, a cellular model for squamous cell carcinoma, inhibited invasion of the cells by 80%, suggesting an inhibitory effect on cell proliferation. The rat ortholog of human HSPBAP1 (named PASS1) was identified in 2000 by Liu et al., associated with the heat shock protein hsp27. PASS1 is expressed in various tissues, but shows high expression in the testis and kidney, whereas human HSPBAP1 is abundant in the thymus and pancreas, as indicated by reverse transcription-PCR analysis. HSPBAP1 inhibits the function of hsp27, which has been shown to be neuroprotective in animal models of motor neuron disease and peripheral nerve injury. HSPBAP1 is expressed in neuronal and glial cells in the temporal lobe of patients with IE, with no brain expression in control tissues. A follow-up study tested samples from the temporal neocortex taken from intractable epilepsy patients showing significant expression of HSPBAP gene over the controls, however the enzymatic role of HSPBAP1 remains unclear. TYW5 acts as a tRNA hydroxylase and at present a biological function has not been reported.

Nucleotide hydroxylases

The distantly related group of nucleotide hydroxylases comprises, in humans, the ALKBH members (ALKBH 1–8) and the TET 1–3 and FTO enzymes (see Figure 1). Despite low sequence identities they share the conserved sequence and structural elements found within the 2-OG oxygenase family (Figure 2). ALKBH enzymes were initially identified as mammalian orthologs of the E. coli AlkB DNA repair enzyme, important in the adaptive repair response to alkylated DNA residues such as 1-methyladenosine and 3-methylcytosine in single-stranded DNA. However, more recent investigations have demonstrated that their physiological role in humans extends well beyond DNA damage repair (see below).

ALKBH 1–3 have been studied extensively and their role in DNA and RNA damage repair has been established. Although they display distinct but overlapping subcellular distribution and substrate specificities, they are critically involved in various types of cancer and indicative of cancer drug responses. Human ALKBH4 supposedly interacts with chromatin-binding proteins such as the histone acetyltransferase p300, however, no enzymatic function with nucleotide substrates has been demonstrated yet. Recently, it was found that demethylation of a monomethylated lysine residue in actin by ALKBH4 regulates actin-myosin interactions, of importance in cytokinesis and cell migration.

The landmark discoveries of two Jmj members as RNA demethylases have opened new avenues in under-standing the relationships between RNA metabolism, gene regulation and human physiology and disease. Initially found in FTO and later extended to ALKBH5, demethylation of N6-methyladenosine (m6A) residues found in several types of RNA species was identified, with a reaction sequence analogous to Nε demethylation of lysine residues. The discovery of reversible methylation of m6A, a prevalent methyl modification found in mRNA and noncoding RNA, the effects of chemical inhibition of RNA methylation on transcription, processing, translation and the analysis of animal or clinical phenotypes therefore suggest a fundamental role of m6A demethylation in human physiology. The critical role of these enzymes was already suggested by the identification of FTO variants as risk alleles for BMI and obesity. Subsequently, the in vitro activity as demethylase for 3-methylthymine and 3-methyluracil found in single-stranded DNA and RNA was established, indicating the distant relationship with the ALKBH-type nucleotide hydroxylases. Although the subject of in vivo activity is still a matter of debate, data indicate that m6A is a physiological substrate of FTO, as evidenced from knockdown studies. The role of FTO in maintenance and regulation of energy homeostasis and food intake has been demonstrated in animal models and through GWAS relationships to insulin resistance and obesity, Alzheimer’s disease, cardiovascular disease and renal failure, as well as breast and colorectal cancer have been established. A loss-of-function homozygous mutation in the FTO gene shows a defect in normal brain and cardiac development, in line with previous observations in animal studies.

Other currently uncharacterized members of the ALKBH subfamily comprise members ALKBH6 and 7. Human ALKBH8 has been recently identified as a methyltransferase acting upon 5-carboxymethyl-uridine and catalyzes an important step in tRNA synthesis, is involved in survival after DNA damage, and may contribute to cancer progression.

The subgroup of TET enzymes (Figure 1) was named after the ten-eleven translocation (t10;11)(q22;q23) found in rare cases of acute myeloid and lymphocytic leukemias. The translocation fuses the mixed-lineage leukemia (MLL) gene on chromosome 10 with the TET1 gene on chromosome 11. Subsequently the relationship to the 2-OG family and the activity as hydroxylases of 5-methylcytosine with the consecutive formation of 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine was established in a series of elegant studies. Identification of TET enzymes as 2-OG members was a challenging task, due to the large insertions found with the catalytic domains (Table 1), that made correct assignment challenging. Oxidized methylcytosine marks are found at promoters, enhancers and gene bodies, depending on the tissue examined. The chemical modification sequence of oxidation of methylcytosine forms the basis for an enzymatic mechanism to remove the DNA methylcytosine modification, shown to be critical for epigenetic regulation of gene transcription. Several mechanisms of methylcytosine demethylation might apply, including passive demethylation during cell division, or active enzymatic mechanisms acting on the oxidized intermediates. The TET-modified cytosine residues can be actively removed through a base-excision mechanism using DNA glycosylases, or might involve activation-induced cytidine deaminase (AID) and APOBEC constituting a deamination reaction of 5-hydroxymethylcytosine to 5-hydroxyuracil, followed by glycosylase and cytosine replacement. Other mechanisms might involve enzymatic decarboxylation by a yet unidentified decarboxylase, or dehydroxy-methylation by DNA methyltransferases. The importance of the TET enzymes in stem cell biology and development (summarized in) is at present not completely understood, however, especially in myeloproliferative types of cancers, their critical roles have been now established.

Conclusion & future perspective

Over the last decade we have witnessed significant progress in understanding the function that many members of the Jmj family have in human physiology and disease. This advancement went hand-in-hand with technological improvements in, for example, allowing interrogation of epigenomic changes at single base-pair resolution, providing unprecedented details and mechanisms how chromatin marks sculpt and regulate cellular phenotypes and features such as proliferation, differentiation, metabolism and genomic stability, among others. Undoubtedly, the discovery of hydroxylation as a mechanism to revert N-methylation found in nucleic acids or proteins is a milestone that has triggered substantial progress in identifying the role of this post-translational modification in chromatin biology, and defining epigenomic elements in genome biology in general.

We have here attempted to summarize the current knowledge of human Jmj enzymes with particular emphasis on histone lysine modification and their roles in human disease. It is apparent from this body of research literature that the involvement of Nε-methyl lysine demethylases in disease is partially related to putative functions of the epigenomic elements they modify, however, recent data suggest that several histone demethylases bind to a large number of genes, but display only modest effects on target gene expression when depleted, suggesting a ‘fine-tuning’ effect of these enzymes. Moreover, they are often found bound to chromatin without their substrate mark present, suggesting a ‘guardian’ function to ‘protect’ chromatin against aberrant modifications. This indicates that the KDM-Jmj hydroxylases are not necessarily involved as on-off switches (as found, for example, in the kinase-phosphatase paradigm of signal transduction), but support other roles, highlighted by the fact that a scaffolding function is of critical importance in various settings, (e.g., as observed for JARID2 or the KDM6 enzymes). However, a substantial fraction of the Jmj enzymes (Figure 1) remains enigmatic in terms of substrate specificity or enzymatic activity, calling for further systematic screening activities, including non-histone substrates. In fact, the discovery of Jmj-mediated oxidation of nucleic acids or nonhistone proteins suggests that the substrate spectrum is much larger than anticipated. Furthermore, there might have been substantial misleads in identifying substrate specificities by employing inappropriate assays, so it appears mandatory to stringently evaluate those biochemical parameters to deduce cellular functions. Laudable efforts to map the cellular ‘lysine-methylome’ have recently demonstrated that nuclear lysine methylation constitutes approximately 40% of cellular Nε-lysine methylation, including transcription factors and chromatin modifiers besides histone proteins, thus providing a wealth of testable novel substrate hypotheses for Jmj enzymes.

An important aspect deserving further research efforts is to understand the regulation of Jmj enzymes themselves. Intriguingly, some of the KDM enzymes are inducible by extracellular stimuli (e.g., LPS or inflammatory cytokines and growth factors) exemplified by JmjD3 or JmjD2D, and post-translational modifications or domain arrangements of the enzymes have an impact on enzyme activity as seen with PHF2, indicating that substrate analyses need evaluation in the context of cellular expression and specific growth conditions. It is also becoming increasingly clear, that regulation of Jmj activity through levels (normoxic vs hypoxic) of the cosubstrate O2, or indirectly through HIFα-mediated responses, reactive oxygen species or metabolic intermediates is of importance. Taken together, these research lines will undoubtedly reveal novel facets in regulation of the epigenetic landscape and its impact on human disease. However, to evaluate and harness the potential of Jmj-enzymes as potential drug targets, chemical biology efforts to provide tools for better understanding of biology are mandatory; fortunately recent efforts from several laboratories reveal that this class of enzymes indeed is chemically tractable, expanding the chemical toolbox of epigenetic inhibitors and possibly allowing to modulate disease outcome by targeting Jmj-type oxygenases.

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    Not in our library10.1074/jbc.m807818200

  23. 23.

    Christensen J, Agger K, Cloos PA, et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007;128(6):1063-1076.

    Not in our library10.1016/j.cell.2007.02.003

  24. 24.

    Iwase S, Lan F, Bayliss P, et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 2007;128(6):1077-1088.

    Not in our library10.1016/j.cell.2007.02.017

  25. 25.

    Klose RJ, Yan Q, Tothova Z, et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007;128(5):889-900.

    Not in our library10.1016/j.cell.2007.02.013

  26. 26.

    Lee MG, Norman J, Shilatifard A, Shiekhattar R. Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell. 2007;128(5):877-887.

    Not in our library10.1016/j.cell.2007.02.004

  27. 27.

    Seward DJ, Cubberley G, Kim S, et al. Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins. Nat. Struct. Mol. Biol. 2007;14(3):240-242.

    Not in our library10.1038/nsmb1200

  28. 28.

    De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007;130(6):1083-1094.

    Not in our library10.1016/j.cell.2007.08.019

  29. 29.

    Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc. Natl Acad. Sci. USA. 2007;104(47):18439-18444.

    Not in our library10.1073/pnas.0707292104

  30. 30.

    Lan F, Bayliss PE, Rinn JL, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449(7163):689-694.

    Not in our library10.1038/nature06192

  31. 31.

    Lee MG, Villa R, Trojer P, et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science. 2007;318(5849):447-450.

    Not in our library10.1126/science.1149042

  32. 32.

    Xiang Y, Zhu Z, Han G, Lin H, Xu L, Chen CD. JMJD3 is a histone H3K27 demethylase. Cell Res. 2007;17(10):850-857.

    Not in our library10.1038/cr.2007.83

  33. 33.

    Wen H, Li J, Song T, et al. Recognition of histone H3K4 trimethylation by the plant homeodomain of PHF2 modulates histone demethylation. J. Biol. Chem. 2010;285(13):9322-9326.

    Not in our library10.1074/jbc.c109.097667

  34. 34.

    Horton JR, Upadhyay AK, Qi HH, Zhang X, Shi Y, Cheng X. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat. Struct. Mol. Biol. 2010;17(1):38-43.

    Not in our library10.1038/nsmb.1753

  35. 35.

    Zhu Z, Wang Y, Li X, et al. PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis. Cell Res. 2010;20(7):794-801.

    Not in our library10.1038/cr.2010.75

  36. 36.

    Qi HH, Sarkissian M, Hu GG, et al. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature. 2010;466(7305):503-507.

    Not in our library10.1038/nature09261

  37. 37.

    Tsukada Y, Ishitani T, Nakayama KI. KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development. Genes Dev. 2010;24(5):432-437.

    Not in our library10.1101/gad.1864410

  38. 38.

    Yue Ww, Hozjan V, Ge W, et al. Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase. FEBS Lett. 2010;584(4):825-830.

    Not in our library10.1016/j.febslet.2009.12.055

  39. 39.

    Ge W, Wolf A, Feng T, et al. Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. Nat. Chem. Biol. 2012;8(12):960-962.

    Not in our library10.1038/nchembio.1093

  40. 40.

    Sinha KM, Yasuda H, Coombes MM, Dent SY, De Crombrugghe B. Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase. EMBO J. 2010;29(1):68-79.

    Not in our library10.1038/emboj.2009.332

  41. 41.

    Lu Y, Beezhold K, Chang Q, et al. Lung cancer-associated JmjC domain protein mdig suppresses formation of trimethyl lysine 9 of histone H3. Cell Cycle. 2009;8(13):2101-2109.

    Not in our library10.4161/cc.8.13.8927

  42. 42.

    Hsia DA, Tepper CG, Pochampalli MR, et al. KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc. Natl Acad. Sci. USA. 2010;107(21):9671-9676.

    Not in our library10.1073/pnas.1000401107

  43. 43.

    Youn M-Y, Yokoyama A, Fujiyama-Nakamura S, et al. JMJD5, a Jumonji C (JmjC) domain-containing protein, negatively regulates osteoclastogenesis by facilitating NFATc1 protein degradation. J. Biol. Chem. 2012;287(16):12994-13004.

    Not in our library10.1074/jbc.m111.323105

  44. 44.

    Chang B, Chen Y, Zhao Y, Bruick RK. JMJD6 is a histone arginine demethylase. Science. 2007;318(5849):444-447.

    Not in our library10.1126/science.1145801

  45. 45.

    Webby Cj, Wolf A, Gromak N, et al. Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science. 2009;325(5936):90-93.

    Not in our library10.1126/science.1175865

  46. 46.

    Mantri M, Loik ND, Hamed RB, Claridge TDW, Mccullagh JSO, Schofield CJ. The 2-oxoglutarate-dependent oxygenase JMJD6 catalyses oxidation of lysine residues to give 5S-hydroxylysine residues. ChemBioChem. 2011;12(4):531-534.

    Not in our library10.1002/cbic.201000641

  47. 47.

    Unoki M, Masuda A, Dohmae N, et al. Lysyl 5-hydroxylation, a novel hstone modification, by Jumonji domain containing 6 (JMJD6). J. Biol. Chem. 2013;288(9):6053-6062.

    Not in our library10.1074/jbc.m112.433284

  48. 48.

    Yang M, Chowdhury R, Ge W, et al. Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains. FEBS J. 2011;278(7):1086-1097.

    Not in our library10.1111/j.1742-4658.2011.08022.x

  49. 49.

    Yang M, Ge W, Chowdhury R, et al. Asparagine and aspartate hydroxylation of the cytoskeletal ankyrin family is catalyzed by factor-inhibiting hypoxia-inducible factor. J. Biol. Chem. 2011;286(9):7648-7660.

    Not in our library10.1074/jbc.m110.193540

  50. 50.

    Cockman ME, Lancaster DE, Stolze IP, et al. Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc. Natl Acad. Sci. USA. 2006;103(40):14767-14772.

    Not in our library10.1073/pnas.0606877103

  51. 51.

    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16(12):1466-1471.

    Not in our library10.1101/gad.991402

  52. 52.

    Noma A, Ishitani R, Kato M, Nagao A, Nureki O, Suzuki T. Expanding role of the jumonji C domain as an RNA hydroxylase. J. Biol. Chem. 2010;285(45):34503-34507.

    Not in our library10.1074/jbc.m110.156398

  53. 53.

    Sedgwick B. Repairing DNA-methylation damage. Nat. Rev. Mol. Cell Biol. 2004;5(2):148-157.

    Not in our library10.1038/nrm1312

  54. 54.

    Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B. Reversal of DNA alkylation damage by two human dioxygenases. Proc. Natl Acad. Sci. USA. 2002;99(26):16660-16665.

    Not in our library10.1073/pnas.262589799

  55. 55.

    Li Mm, Nilsen A, Shi Y, et al. ALKBH4-dependent demethylation of actin regulates actomyosin dynamics. Nat. Commun. 2013;4:1832.

    Not in our library10.1038/ncomms2863

  56. 56.

    Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell. 2012;49(1):18-29.

    Not in our library10.1016/j.molcel.2012.10.015

  57. 57.

    Fu D, Brophy JA, Chan CT, et al. Human AlkB homolog ABH8 Is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival. Mol. Cell Biol. 2010;30(10):2449-2459.

    Not in our library10.1128/mcb.01604-09

  58. 58.

    Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930-935.

    Not in our library10.1126/science.1170116

  59. 59.

    Ito S, Shen L, Dai Q, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300-1303.

    Not in our library10.1126/science.1210597

  60. 60.

    Gerken T, Girard CA, Tung YC, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318(5855):1469-1472.

    Not in our library10.1126/science.1151710

  61. 61.

    Jia G, Yang Cg, Yang S, et al. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 2008;582(23-24):3313-3319.

    Not in our library10.1016/j.febslet.2008.08.019

  62. 62.

    Landeira D, Sauer S, Poot R, et al. Jarid2 is a PRC2 component in embryonic stem cells required for multi-lineage differentiation and recruitment of PRC1 and RNA Polymerase II to developmental regulators. Nat. Cell. Biol. 2010;12(6):618-624.

    Not in our library10.1038/ncb2065

  63. 63.

    Pasini D, Cloos PA, Walfridsson J, et al. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature. 2010;464(7286):306-310.

    Not in our library10.1038/nature08788

  64. 64.

    Peng JC, Valouev A, Swigut T, et al. Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell. 2009;139(7):1290-1302.

    Not in our library10.1016/j.cell.2009.12.002

  65. 65.

    Shen X, Kim W, Fujiwara Y, et al. Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell. 2009;139(7):1303-1314.

    Not in our library10.1016/j.cell.2009.12.003

  66. 66.

    Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978;276(5688):565-570.

    Not in our library10.1038/276565a0

  67. 67.

    Struhl G. A gene product required for correct initiation of segmental determination in Drosophila. Nature. 1981;293(5827):36-41.

    Not in our library10.1038/293036a0

  68. 68.

    Bracken AP, Helin K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat. Rev. Cancer. 2009;9(11):773-784.

    Not in our library10.1038/nrc2736

  69. 69.

    Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437(7057):436-439.

    Not in our library10.1038/nature04020

  70. 70.

    Allis CD, Berger SL, Cote J, et al. New nomenclature for chromatin-modifying enzymes. Cell. 2007;131(4):633-636.

    Not in our library10.1016/j.cell.2007.10.039

  71. 71.

    Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57-74.

    Not in our library10.1038/nature11247

  72. 72.

    Ng SS, Yue WW, Oppermann U, Klose RJ. Dynamic protein methylation in chromatin biology. Cell. Mol. Life Sci. 2009;66(3):407-422.

    Not in our library10.1007/s00018-008-8303-z

  73. 73.

    Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 2012;13(5):297-311.

    Not in our library10.1038/nrm3327

  74. 74.

    Pedersen MT, Helin K. Histone demethylases in development and disease. Trends Cell Biol. 2010;20(11):662-671.

    Not in our library10.1016/j.tcb.2010.08.011

  75. 75.

    Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12-27.

    Not in our library10.1016/j.cell.2012.06.013

  76. 76.

    Greer El, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 2012;13(5):343-357.

    Not in our library10.1038/nrg3173

  77. 77.

    Mosammaparast N, Shi Y. Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu. Rev. Biochem. 2010;79:155-179.

    Not in our library10.1146/annurev.biochem.78.070907.103946

  78. 78.

    Ciccone DN, Su H, Hevi S, et al. KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature. 2009;461(7262):415-418.

    Not in our library10.1038/nature08315

  79. 79.

    Karytinos A, Forneris F, Profumo A, et al. A novel mammalian flavin-dependent histone demethylase. J. Biol. Chem. 2009;284(26):17775-17782.

    Not in our library10.1074/jbc.m109.003087

  80. 80.

    Wang J, Hevi S, Kurash JK, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat. Genet. 2009;41(1):125-129.

    Not in our library10.1038/ng.268

  81. 81.
    Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation · 2013
    No notice
  82. 82.

    Sprussel A, Schulte JH, Weber S, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26(9):2039-2051.

    Not in our library10.1038/leu.2012.157

  83. 83.

    Schenk T, Chen Wc, Gollner S, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 2012;18(4):605-611.

    Not in our library10.1038/nm.2661

  84. 84.

    Wang J, Lu F, Ren Q, et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res. 2011;71(23):7238-7249.

    Not in our library10.1158/0008-5472.can-11-0896

  85. 85.

    Tsai Mc, Manor O, Wan Y, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329(5992):689-693.

    Not in our library10.1126/science.1192002

  86. 86.

    Wang Y, Zhang H, Chen Y, et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell. 2009;138(4):660-672.

    Not in our library10.1016/j.cell.2009.05.050

  87. 87.

    Garcia-Bassets I, Kwon Ys, Telese F, et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell. 2007;128(3):505-518.

    Not in our library10.1016/j.cell.2006.12.038

  88. 88.

    Huang J, Sengupta R, Espejo AB, et al. p53 is regulated by the lysine demethylase LSD1. Nature. 2007;449(7158):105-108.

    Not in our library10.1038/nature06092

  89. 89.

    Deaton Am, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25(10):1010-1022.

    Not in our library10.1101/gad.2037511

  90. 90.
    CpG Islands Recruit a Histone H3 Lysine 36 Demethylase · 2010
    No notice
  91. 91.
    KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands · 2012
    No notice
  92. 92.

    He J, Shen L, Wan M, Taranova O, Wu H, Zhang Y. Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat. Cell Biol. 2013;15(4):373-384.

    Not in our library10.1038/ncb2702

  93. 93.

    Wu X, Johansen JV, Helin K. Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol. Cell. 2013;49(6):1134-1146.

    Not in our library10.1016/j.molcel.2013.01.016

  94. 94.

    Lagarou A, Mohd-Sarip A, Moshkin YM, et al. dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing. Genes Dev. 2008;22(20):2799-2810.

    Not in our library10.1101/gad.484208

  95. 95.

    Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T. Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell. 2010;143(3):470-484.

    Not in our library10.1016/j.cell.2010.10.012

  96. 96.

    Tanaka Y, Okamoto K, Teye K, et al. JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation. EMBO J. 2010;29(9):1510-1522.

    Not in our library10.1038/emboj.2010.56

  97. 97.

    Barrero MJ, Izpisua Belmonte JC. Polycomb complex recruitment in pluripotent stem cells. Nat. Cell Biol. 2013;15(4):348-350.

    Not in our library10.1038/ncb2723

  98. 98.

    Du J, Ma Y, Ma P, Wang S, Fan Z. Demethylation of epiregulin gene by histone demethylase FBXL11 and BCL6 corepressor inhibits osteo/dentinogenic differentiation. Stem Cells. 2013;31(1):126-136.

    Not in our library10.1002/stem.1255

  99. 99.

    Gao R, Dong R, Du J, Ma P, Wang S, Fan Z. Depletion of histone demethylase KDM2A inhibited cell proliferation of stem cells from apical papilla by de-repression of p15(INK4B) and p27 (Kip1.). Mol. Cell. Biochem. 2013;379(1-2):115-122.

    Not in our library10.1007/s11010-013-1633-7

  100. 100.

    Iuchi S, Green H. Lysine-specific demethylase 2A (KDM2A) normalizes human embryonic stem cell derived keratinocytes. Proc. Natl Acad. Sci. USA. 2012;109(24):9442-9447.

    Not in our library10.1073/pnas.1206176109

  101. 101.

    Liang G, He J, Zhang Y. Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat. Cell. Biol. 2012;14(5):457-466.

    Not in our library10.1038/ncb2483

  102. 102.

    Wang T, Chen K, Zeng X, et al. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell. 2011;9(6):575-587.

    Not in our library10.1016/j.stem.2011.10.005

  103. 103.

    Gearhart MD, Corcoran CM, Wamstad JA, Bardwell VJ. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol. Cell Biol. 2006;26(18):6880-6889.

    Not in our library10.1128/mcb.00630-06

  104. 104.

    He J, Kallin EM, Tsukada Y, Zhang Y. The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b). Nat. Struct. Mol. Biol. 2008;15(11):1169-1175.

    Not in our library10.1038/nsmb.1499

  105. 105.

    Tzatsos A, Pfau R, Kampranis SC, Tsichlis PN. Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc. Natl Acad. Sci. USA. 2009;106(8):2641-2646.

    Not in our library10.1073/pnas.0813139106

  106. 106.

    He J, Nguyen AT, Zhang Y. KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood. 2011;117(14):3869-3880.

    Not in our library10.1182/blood-2010-10-312736

  107. 107.

    Kottakis F, Polytarchou C, Foltopoulou P, Sanidas I, Kampranis SC, Tsichlis PN. FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol. Cell. 2011;43(2):285-298.

    Not in our library10.1016/j.molcel.2011.06.020

  108. 108.

    Tzatsos A, Paskaleva P, Ferrari F, et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 2013;123(2):727-739.

    Not in our library10.1172/jci64535

  109. 109.

    Chen H, Giri NC, Zhang R, et al. Nickel ions inhibit histone demethylase JMJD1A and DNA repair enzyme ABH2 by replacing the ferrous iron in the catalytic centers. J. Biol. Chem. 2010;285(10):7374-7383.

    Not in our library10.1074/jbc.m109.058503

  110. 110.

    Hickok JR, Vasudevan D, Antholine WE, Thomas DD. Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J. Biol. Chem. 2013;288(22):16004-16015.

    Not in our library10.1074/jbc.m112.432294

  111. 111.

    Yang F, Stenoien DL, Strittmatter EF, et al. Phosphoproteome profiling of human skin fibroblast cells in response to low- and high-dose irradiation. J. Proteome Res. 2006;5(5):1252-1260.

    Not in our library10.1021/pr060028v

  112. 112.

    Liu Z, Zhou S, Liao L, Chen X, Meistrich M, Xu J. Jmjd1a demethylase-regulated histone modification is essential for cAMP-response element modulator-regulated gene expression and spermatogenesis. J. Biol. Chem. 2010;285(4):2758-2770.

    Not in our library10.1074/jbc.m109.066845

  113. 113.

    Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature. 2007;450(7166):119-123.

    Not in our library10.1038/nature06236

  114. 114.

    Inagaki T, Tachibana M, Magoori K, et al. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes Cells. 2009;14(8):991-1001.

    Not in our library10.1111/j.1365-2443.2009.01326.x

  115. 115.

    Tateishi K, Okada Y, Kallin EM, Zhang Y. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature. 2009;458(7239):757-761.

    Not in our library10.1038/nature07777

  116. 116.

    Wellmann S, Bettkober M, Zelmer A, et al. Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. Biochem. Biophys. Res. Commun. 2008;372(4):892-897.

    Not in our library10.1016/j.bbrc.2008.05.150

  117. 117.

    Osawa T, Tsuchida R, Muramatsu M, et al. Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. Cancer Res. 2013;73(10):3019-3028.

    Not in our library10.1158/0008-5472.can-12-3231

  118. 118.

    Yamada D, Kobayashi S, Yamamoto H, et al. Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. Ann. Surg. Oncol. 2012;19(Suppl. 3):S355-S364.

    Not in our library10.1245/s10434-011-1797-x

  119. 119.

    Qi J, Nakayama K, Cardiff RD, et al. Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell. 2010;18(1):23-38.

    Not in our library10.1016/j.ccr.2010.05.024

  120. 120.

    Uemura M, Yamamoto H, Takemasa I, et al. Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells. Clin. Cancer Res. 2010;16(18):4636-4646.

    Not in our library10.1158/1078-0432.ccr-10-0407

  121. 121.

    Guo X, Shi M, Sun L, et al. The expression of histone demethylase JMJD1A in renal cell carcinoma. Neoplasma. 2011;58(2):153-157.

    Not in our library10.4149/neo_2011_02_153

  122. 122.

    Mackinnon RN, Kannourakis G, Wall M, Campbell LJ. A cryptic deletion in 5q31.2 provides further evidence for a minimally deleted region in myelodysplastic syndromes. Cancer Genet. 2011;204(4):187-194.

    Not in our library10.1016/j.cancergen.2011.02.001

  123. 123.

    Tang MH, Varadan V, Kamalakaran S, Zhang MG, Dimitrova N, Hicks J. Major chromosomal breakpoint intervals in breast cancer co-localize with differentially methylated regions. Front. Oncol. 2012;2:197.

    Not in our library10.3389/fonc.2012.00197

  124. 124.

    Hu Z, Gomes I, Horrigan SK, et al. A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene. 2001;20(47):6946-6954.

    Not in our library10.1038/sj.onc.1204850

  125. 125.

    Kim JY, Kim KB, Eom GH, et al. KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia. Mol. Cell Biol. 2012;32(14):2917-2933.

    Not in our library10.1128/mcb.00133-12

  126. 126.

    Lee JW, Choi HS, Gyuris J, Brent R, Moore DD. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol. Endocrinol. 1995;9(2):243-254.

    Not in our library10.1210/mend.9.2.7776974

  127. 127.

    Katoh M. Identification and characterization of TRIP8 gene in silico. Int. J. Mol. Med. 2003;12(5):817-821.

    Not in our library

  128. 128.

    Katoh M. Comparative integromics on JMJD1C gene encoding histone demethylase: conserved POU5F1 binding site elucidating mechanism of JMJD1C expression in undifferentiated ES cells and diffuse-type gastric cancer. Int. J. Oncol. 2007;31(1):219-223.

    Not in our library

  129. 129.

    Wolf SS, Patchev VK, Obendorf M. A novel variant of the putative demethylase gene, s-JMJD1C, is a coactivator of the AR. Arch. Biochem. Biophys. 2007;460(1):56-66.

    Not in our library10.1016/j.abb.2007.01.017

  130. 130.

    Kim SM, Kim JY, Choe NW, et al. Regulation of mouse steroidogenesis by WHISTLE and JMJD1C through histone methylation balance. Nucleic Acids Res. 2010;38(19):6389-6403.

    Not in our library10.1093/nar/gkq491

  131. 131.

    Cachon-Gonzalez MB, Fenner S, Coffin JM, Moran C, Best S, Stoye JP. Structure and expression of the hairless gene of mice. Proc. Natl Acad. Sci. USA. 1994;91(16):7717-7721.

    Not in our library10.1073/pnas.91.16.7717

  132. 132.

    Thompson CC. Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. J. Neurosci. 1996;16(24):7832-7840.

    Not in our library10.1523/jneurosci.16-24-07832.1996

  133. 133.

    Hsieh JC, Sisk JM, Jurutka PW, et al. Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J. Biol. Chem. 2003;278(40):38665-38674.

    Not in our library10.1074/jbc.m304886200

  134. 134.

    Moraitis AN, Giguere V, Thompson CC. Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol. Cell Biol. 2002;22(19):6831-6841.

    Not in our library10.1128/mcb.22.19.6831-6841.2002

  135. 135.

    Potter GB, Beaudoin GM, Derenzo CL, Zarach JM, Chen SH, Thompson CC. The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor. Genes Dev. 2001;15(20):2687-2701.

    Not in our library10.1101/gad.916701

  136. 136.

    Mi Y, Zhang Y, Shen YF. Mechanism of JmjC-containing protein Hairless in the regulation of vitamin D receptor function. Biochim. Biophys. Acta. 2011;1812(12):1675-1680.

    Not in our library10.1016/j.bbadis.2011.09.015

  137. 137.

    Potter GB, Zarach JM, Sisk JM, Thompson CC. The thyroid hormone-regulated corepressor hairless associates with histone deacetylases in neonatal rat brain. Mol. Endocrinol. 2002;16(11):2547-2560.

    Not in our library10.1210/me.2002-0115

  138. 138.

    Ahmad W, Faiyaz UL, Haque M, et al. Alopecia universalis associated with a mutation in the human hairless gene. Science. 1998;279(5351):720-724.

    Not in our library10.1126/science.279.5351.720

  139. 139.

    Katoh Y, Katoh M. Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. Int. J. Mol. Med. 2007;20(2):269-273.

    Not in our library

  140. 140.

    Berry WL, Janknecht R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 2013;73(10):2936-2942.

    Not in our library10.1158/0008-5472.can-12-4300

  141. 141.

    Crea F, Sun L, Mai A, et al. The emerging role of histone lysine demethylases in prostate cancer. Mol. Cancer. 2012;11:52.

    Not in our library10.1186/1476-4598-11-52

  142. 142.

    Cloos PA, Christensen J, Agger K, et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature. 2006;442(7100):307-311.

    Not in our library10.1038/nature04837

  143. 143.

    Shin S, Janknecht R. Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochem. Biophys. Res. Commun. 2007;359(3):742-746.

    Not in our library10.1016/j.bbrc.2007.05.179

  144. 144.

    Wissmann M, Yin N, Muller JM, et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat. Cell. Biol. 2007;9(3):347-353.

    Not in our library10.1038/ncb1546

  145. 145.

    Suikki He, Kujala PM, Tammela TL, Van Weerden WM, Vessella RL, Visakorpi T. Genetic alterations and changes in expression of histone demethylases in prostate cancer. Prostate. 2010;70(8):889-898.

    Not in our library10.1002/pros.21123

  146. 146.

    Coffey K, Rogerson L, Ryan-Munden C, et al. The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover. Nucleic Acids Res. 2013;41(8):4433-4446.

    Not in our library10.1093/nar/gkt106

  147. 147.

    Gaughan L, Stockley J, Coffey K, et al. KDM4B is a master regulator of the estrogen receptor signalling cascade. Nucleic Acids Res. 2013;41(14):6892-6904.

    Not in our library10.1093/nar/gkt469

  148. 148.

    Liu G, Bollig-Fischer A, Kreike B, et al. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene. 2009;28(50):4491-4500.

    Not in our library10.1038/onc.2009.297

  149. 149.

    Li BX, Zhang MC, Luo CL, et al. Effects of RNA interference-mediated gene silencing of JMJD2A on human breast cancer cell line MDA-MB-231 in vitro. J. Exp. Clin. Cancer Res. 2011;30:90.

    Not in our library10.1186/1756-9966-30-90

  150. 150.

    Berry WL, Shin S, Lightfoot SA, Janknecht R. Oncogenic features of the JMJD2A histone demethylase in breast cancer. Int. J. Oncol. 2012;41(5):1701-1706.

    Not in our library10.3892/ijo.2012.1618

  151. 151.

    Yang J, Jubb AM, Pike L, et al. The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth. Cancer Res. 2010;70(16):6456-6466.

    Not in our library10.1158/0008-5472.can-10-0413

  152. 152.
    Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development · 2011
    Corrected
  153. 153.

    Shi L, Sun L, Li Q, et al. Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis. Proc. Natl Acad. Sci. USA. 2011;108(18):7541-7546.

    Not in our library10.1073/pnas.1017374108

  154. 154.

    Pollard PJ, Loenarz C, Mole DR, et al. Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. Biochem. J. 2008;416(3):387-394.

    Not in our library10.1042/bj20081238

  155. 155.

    Zhu Y, Van Essen D, Saccani S. Cell-type-specific control of enhancer activity by H3K9 trimethylation. Mol. Cell. 2012;46(4):408-423.

    Not in our library10.1016/j.molcel.2012.05.011

  156. 156.

    Strobl-Mazzulla PH, Sauka-Spengler T, Bronner-Fraser M. Histone demethylase JmjD2A regulates neural crest specification. Dev. Cell. 19(3);460-468.

    Not in our library10.1016/j.devcel.2010.08.009

  157. 157.

    Zhang QJ, Chen HZ, Wang L, Liu DP, Hill JA, Liu ZP. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J. Clin. Invest. 2011;121(6):2447-2456.

    Not in our library10.1172/jci46277

  158. 158.

    Ye L, Fan Z, Yu B, et al. Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell. 2012;11(1):50-61.

    Not in our library10.1016/j.stem.2012.04.009

  159. 159.

    Guo L, Li X, Huang JX, et al. Histone demethylase Kdm4b functions as a co-factor of C/EBPbeta to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes. Cell Death Differ. 2012;19(12):1917-1927.

    Not in our library10.1038/cdd.2012.75

  160. 160.

    Chen Wd, Fu X, Dong B, et al. Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver. Hepatology. 2012;56(4):1499-1509.

    Not in our library10.1002/hep.25766

  161. 161.

    Kim TD, Oh S, Shin S, Janknecht R. Regulation of tumor suppressor p53 and HCT116 cell physiology by histone demethylase JMJD2D/KDM4D. PLoS ONE. 2012;7(4):e34618.

    Not in our library10.1371/journal.pone.0034618

  162. 162.

    Wilsker D, Probst L, Wain HM, Maltais L, Tucker PW, Moran E. Nomenclature of the ARID family of DNA-binding proteins. Genomics. 2005;86(2):242-251.

    Not in our library10.1016/j.ygeno.2005.03.013

  163. 163.

    Wysocka J, Swigut T, Xiao H, et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature. 2006;442(7098):86-90.

    Not in our library10.1038/nature04815

  164. 164.

    Tahiliani M, Mei P, Fang R, et al. The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature. 2007;447(7144):601-605.

    Not in our library10.1038/nature05823

  165. 165.

    Defeo-Jones D, Huang PS, Jones RE, et al. Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature. 1991;352(6332):251-254.

    Not in our library10.1038/352251a0

  166. 166.

    Benevolenskaya EV, Murray HL, Branton P, Young RA, Kaelin WG. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol. Cell. 2005;18(6):623-635.

    Not in our library10.1016/j.molcel.2005.05.012

  167. 167.

    Chicas A, Kapoor A, Wang X, et al. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proc. Natl Acad. Sci. USA. 2012;109(23):8971-8976.

    Not in our library10.1073/pnas.1119836109

  168. 168.

    Ditacchio L, Le HD, Vollmers C, et al. Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science. 2011;333(6051):1881-1885.

    Not in our library10.1126/science.1206022

  169. 169.

    De Rooij JD, Hollink IH, Arentsen-Peters ST, et al. NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia. 2013;27(12):2280-2288.

    Not in our library10.1038/leu.2013.87

  170. 170.

    Pointon JJ, Harvey D, Karaderi T, Appleton LH, Farrar C, Wordsworth BP. The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis. Genes Immun. 2011;12(5):395-398.

    Not in our library10.1038/gene.2011.23

  171. 171.

    Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141(1):69-80.

    Not in our library10.1016/j.cell.2010.02.027

  172. 172.

    Cellot S, Hope KJ, Chagraoui J, et al. RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity. Blood. 2013;122(9):1545-1555.

    Not in our library10.1182/blood-2013-04-496281

  173. 173.

    Dey BK, Stalker L, Schnerch A, Bhatia M, Taylor-Papidimitriou J, Wynder C. The histone demethylase KDM5b/JARID1b plays a role in cell fate decisions by blocking terminal differentiation. Mol. Cell Biol. 2008;28(17):5312-5327.

    Not in our library10.1128/mcb.00128-08

  174. 174.

    Schmitz Su, Albert M, Malatesta M, et al. Jarid1b targets genes regulating development and is involved in neural differentiation. EMBO J. 2011;30(22):4586-4600.

    Not in our library10.1038/emboj.2011.383

  175. 175.

    Li Q, Shi L, Gui B, et al. Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14. Cancer Res. 2011;71(21):6899-6908.

    Not in our library10.1158/0008-5472.can-11-1523

  176. 176.

    Kuzbicki L, Lange D, Straczynska-Niemiec A, Chwirot BW. JARID1B expression in human melanoma and benign melanocytic skin lesions. Melanoma Res. 2013;23(1):8-12.

    Not in our library10.1097/cmr.0b013e32835d5d6f

  177. 177.

    Lu Pj, Sundquist K, Baeckstrom D, et al. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer. J. Biol. Chem. 1999;274(22):15633-15645.

    Not in our library10.1074/jbc.274.22.15633

  178. 178.

    Roesch A, Fukunaga-Kalabis M, Schmidt EC, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010;141(4):583-594.

    Not in our library10.1016/j.cell.2010.04.020

  179. 179.

    Wouters J, Stas M, Gremeaux L, et al. The human melanoma side population displays molecular and functional characteristics of enriched chemoresistance and tumorigenesis. PLoS ONE. 2013;8(10):e76550.

    Not in our library10.1371/journal.pone.0076550

  180. 180.

    Jensen LR, Amende M, Gurok U, et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am. J. Hum. Genet. 2005;76(2):227-236.

    Not in our library10.1086/427563

  181. 181.

    Agulnik Ai, Mitchell Mj, Mattei Mg, et al. A novel X gene with a widely transcribed Y-linked homologue escapes X-inactivation in mouse and human. Hum. Mol. Genet. 1994;3(6):879-884.

    Not in our library10.1093/hmg/3.6.879

  182. 182.

    Adegbola A, Gao H, Sommer S, Browning M. A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). Am. J. Med. Genet. Part A. 2008;146A(4):505-511.

    Not in our library10.1002/ajmg.a.32142

  183. 183.

    Niu X, Zhang T, Liao L, et al. The von Hippel-Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C. Oncogene. 2012;31(6):776-786.

    Not in our library10.1038/onc.2011.266

  184. 184.

    Agulnik AI, Mitchell MJ, Lerner JL, Woods DR, Bishop CE. A mouse Y chromosome gene encoded by a region essential for spermatogenesis and expression of male-specific minor histocompatibility antigens. Hum. Mol. Genet. 1994;3(6):873-878.

    Not in our library10.1093/hmg/3.6.873

  185. 185.

    Scott DM, Ehrmann IE, Ellis PS, et al. Identification of a mouse male-specific transplantation antigen, H-Y. Nature. 1995;376(6542):695-698.

    Not in our library10.1038/376695a0

  186. 186.

    Wang W, Meadows LR, Den Haan JM, et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science. 1995;269(5230):1588-1590.

    Not in our library10.1126/science.7667640

  187. 187.

    Akimoto C, Kitagawa H, Matsumoto T, Kato S. Spermatogenesis-specific association of SMCY and MSH5. Genes Cells. 2008;13(6):623-633.

    Not in our library10.1111/j.1365-2443.2008.01193.x

  188. 188.

    Perinchery G, Sasaki M, Angan A, Kumar V, Carroll P, Dahiya R. Deletion of Y-chromosome specific genes in human prostate cancer. J. Urol. 2000;163(4):1339-1342.

    Not in our library

  189. 189.

    Kruidenier L, Chung CW, Cheng Z, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488(7411):404-408.

    Not in our library10.1038/nature11262

  190. 190.

    Sola S, Xavier JM, Santos DM, et al. p53 interaction with JMJD3 results in its nuclear distribution during mouse neural stem cell differentiation. PLoS ONE. 2011;6(3):e18421.

    Not in our library10.1371/journal.pone.0018421

  191. 191.

    Miller SA, Mohn SE, Weinmann AS. Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol. Cell. 2010;40(4):594-605.

    Not in our library10.1016/j.molcel.2010.10.028

  192. 192.

    Miller SA, Weinmann AS. Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunol. Rev. 2010;238(1):233-246.

    Not in our library10.1111/j.1600-065x.2010.00952.x

  193. 193.

    Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125(2):315-326.

    Not in our library10.1016/j.cell.2006.02.041

  194. 194.

    Awe JP, Byrne JA. Identifying candidate oocyte reprogramming factors using cross-species global transcriptional analysis. Cell Reprogram. 2013;15(2):126-133.

    Not in our library10.1089/cell.2012.0060

  195. 195.

    Canovas S, Cibelli JB, Ross PJ. Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development. Proc. Natl Acad. Sci. USA. 2012;109(7):2400-2405.

    Not in our library10.1073/pnas.1119112109

  196. 196.

    Jiang W, Wang J, Zhang Y. Histone H3K27me3 demethylases KDM6A and KDM6B modulate definitive endoderm differentiation from human ESCs by regulating WNT signaling pathway. Cell Res. 2013;23(1):122-130.

    Not in our library10.1038/cr.2012.119

  197. 197.

    Kim SW, Yoon SJ, Chuong E, et al. Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. Dev. Biol. 2011;357(2):492-504.

    Not in our library10.1016/j.ydbio.2011.06.009

  198. 198.

    Agger K, Cloos PA, Christensen J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007;449(7163):731-734.

    Not in our library10.1038/nature06145

  199. 199.

    Shahhoseini M, Taghizadeh Z, Hatami M, Baharvand H. Retinoic acid dependent histone 3 demethylation of the clustered HOX genes during neural differentiation of human embryonic stem cells. Biochem. Cell Biol. 2013;91(2):116-122.

    Not in our library10.1139/bcb-2012-0049

  200. 200.

    Zhao W, Li Q, Ayers S, et al. Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. Cell. 2013;152(5):1037-1050.

    Not in our library10.1016/j.cell.2013.02.006

  201. 201.

    Yasui T, Hirose J, Tsutsumi S, Nakamura K, Aburatani H, Tanaka S. Epigenetic regulation of osteoclast differentiation: possible involvement of Jmjd3 in the histone demethylation of Nfatc1. J. Bone Miner. Res. 2011;26(11):2665-2671.

    Not in our library10.1002/jbmr.464

  202. 202.

    Burgold T, Voituron N, Caganova M, et al. The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival. Cell Rep. 2012;2(5):1244-1258.

    Not in our library10.1016/j.celrep.2012.09.013

  203. 203.

    Jepsen K, Solum D, Zhou T, et al. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature. 2007;450(7168):415-419.

    Not in our library10.1038/nature06270

  204. 204.

    Estaras C, Akizu N, Garcia A, Beltran S, De La Cruz X, Martinez-Balbas MA. Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program. Development. 2012;139(15):2681-2691.

    Not in our library10.1242/dev.078345

  205. 205.

    Fei T, Xia K, Li Z, et al. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination. Genome Res. 2010;20(1):36-44.

    Not in our library10.1101/gr.092114.109

  206. 206.

    Dai JP, Lu JY, Zhang Y, Shen YF. Jmjd3 activates Mash1 gene in RA-induced neuronal differentiation of P19 cells. J. Cell Biochem. 2010;110(6):1457-1463.

    Not in our library10.1002/jcb.22703

  207. 207.

    Giovarelli M, Bucci G, Pasero M, Gherzi R, Briata P. KSRP silencing favors neural differentiation of P19 teratocarcinoma cells. Biochim. Biophys. Acta. 2013;1829(5):469-479.

    Not in our library10.1016/j.bbagrm.2013.02.008

  208. 208.

    Lederer D, Grisart B, Digilio MC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am. J. Human Genet. 2011;90(1):119-124.

    Not in our library10.1016/j.ajhg.2011.11.021

  209. 209.

    Priolo M, Micale L, Augello B, et al. Absence of deletion and duplication of MLL2 and KDM6A genes in a large cohort of patients with Kabuki syndrome. Mol. Genet. Metab. 2012;107(3):627-629.

    Not in our library10.1016/j.ymgme.2012.06.019

  210. 210.

    Das ND, Jung KH, Choi MR, Yoon HS, Kim SH, Chai YG. Gene networking and inflammatory pathway analysis in a JMJD3 knockdown human monocytic cell line. Cell Biochem. Funct. 2012;30(3):224-232.

    Not in our library10.1002/cbf.1839

  211. 211.

    Wei Y, Chen R, Dimicoli S, et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia. 2013;27(11):2177-2186.

    Not in our library10.1038/leu.2013.91

  212. 212.

    De Santa F, Narang V, Yap ZH, et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 2009;28(21):3341-3352.

    Not in our library10.1038/emboj.2009.271

  213. 213.

    Ishii M, Wen H, Corsa CA, et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009;114(15):3244-3254.

    Not in our library10.1182/blood-2009-04-217620

  214. 214.

    Satoh T, Takeuchi O, Vandenbon A, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 2010;11(10):936-944.

    Not in our library10.1038/ni.1920

  215. 215.

    Zhang Q, Long H, Liao J, et al. Inhibited expression of hematopoietic progenitor kinase 1 associated with loss of jumonji domain containing 3 promoter binding contributes to autoimmunity in systemic lupus erythematosus. J. Autoimmun. 2011;37(3):180-189.

    Not in our library10.1016/j.jaut.2011.09.006

  216. 216.

    Sen Gl, Webster DE, Barragan DI, Chang HY, Khavari PA. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 2008;22(14):1865-1870.

    Not in our library10.1101/gad.1673508

  217. 217.

    Shaw T, Martin P. Epigenetic reprogramming during wound healing. loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep. 2009;10(8):881-886.

    Not in our library10.1038/embor.2009.102

  218. 218.

    Ciavatta DJ, Yang J, Preston GA, et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J. Clin. Invest. 2010;120(9):3209-3219.

    Not in our library10.1172/jci40034

  219. 219.

    Dumon S, Walton DS, Volpe G, et al. Itga2b regulation at the onset of definitive hematopoiesis and commitment to differentiation. PLoS ONE. 2012;7(8):e43300.

    Not in our library10.1371/journal.pone.0043300

  220. 220.

    Anderton JA, Bose S, Vockerodt M, et al. The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin’s lymphoma. Oncogene. 2011;30(17):2037-2043.

    Not in our library10.1038/onc.2010.579

  221. 221.

    Mclaughlin-Drubin ME, Crum CP, Munger K. Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc. Natl Acad. Sci. USA. 2011;108(5):2130-2135.

    Not in our library10.1073/pnas.1009933108

  222. 222.

    Shen Y, Guo X, Wang Y, et al. Expression and significance of histone H3K27 demethylases in renal cell carcinoma. BMC Cancer. 2012;12:470.

    Not in our library10.1186/1471-2407-12-470

  223. 223.

    Svotelis A, Bianco S, Madore J, et al. H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERalpha ligand dependency. EMBO J. 2011;30(19):3947-3961.

    Not in our library10.1038/emboj.2011.284

  224. 224.

    Bunt J, Hasselt NA, Zwijnenburg DA, Koster J, Versteeg R, Kool M. OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels. Acta Neuropathol. 2012;125(3):385-394.

    Not in our library10.1007/s00401-012-1069-2

  225. 225.

    Dubuc Am, Remke M, Korshunov A, et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 2012;125(3):373-384.

    Not in our library10.1007/s00401-012-1070-9

  226. 226.

    Agger K, Cloos PA, Rudkjaer L, et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009;23(10):1171-1176.

    Not in our library10.1101/gad.510809

  227. 227.

    Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M. Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence. PLoS ONE. 2009;4(5):e5622.

    Not in our library10.1371/journal.pone.0005622

  228. 228.

    Barradas M, Anderton E, Acosta JC, et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009;23(10):1177-1182.

    Not in our library10.1101/gad.511109

  229. 229.

    Ramadoss S, Chen X, Wang Cy. Histone demethylase KDM6B promotes epithelial-mesenchymal transition. J. Biol. Chem. 2012;287(53):44508-44517.

    Not in our library10.1074/jbc.m112.424903

  230. 230.

    Pereira F, Barbachano A, Silva J, et al. KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum. Mol. Genet. 2011;20(23):4655-4665.

    Not in our library10.1093/hmg/ddr399

  231. 231.

    Pereira F, Barbachano A, Singh PK, Campbell MJ, Munoz A, Larriba MJ. Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle. 2012;11(6):1081-1089.

    Not in our library10.4161/cc.11.6.19508

  232. 232.

    Chen C, Bartenhagen C, Gombert M, et al. Next-generation-sequencing-based risk stratification and identification of new genes involved in structural and sequence variations in near haploid lymphoblastic leukemia. Genes Chromosomes Cancer. 2013;52(6):564-579.

    Not in our library10.1002/gcc.22054

  233. 233.

    Van Haaften G, Dalgliesh GL, Davies H, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 2009;41(5):521-523.

    Not in our library10.1038/ng.349

  234. 234.

    Laaser I, Theis FJ, De Angelis MH, Kolb HJ, Adamski J. Huge splicing frequency in human Y chromosomal UTY gene. OMICS. 2011;15(3):141-154.

    Not in our library10.1089/omi.2010.0107

  235. 235.

    Warren EH, Gavin MA, Simpson E, et al. The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen. J. Immunol. 2000;164(5):2807-2814.

    Not in our library10.4049/jimmunol.164.5.2807

  236. 236.

    Bloomer LD, Nelson CP, Eales J, et al. Male-specific region of the Y chromosome and cardiovascular risk: phylogenetic analysis and gene expression studies. Arterioscler. Thromb. Vasc. Biol. 2013;33(7):1722-1727.

    Not in our library10.1161/atvbaha.113.301608

  237. 237.

    Fortschegger K, Shiekhattar R. Plant homeodomain fingers form a helping hand for transcription. Epigenetics. 2010;6(1):4-8.

    Not in our library10.4161/epi.6.1.13297

  238. 238.

    Dai J, Sultan S, Taylor SS, Higgins JM. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 2005;19(4):472-488.

    Not in our library10.1101/gad.1267105

  239. 239.

    Fortschegger K, De Graaf P, Outchkourov Ns, Van Schaik FM, Timmers HT, Shiekhattar R. PHF8 targets histone methylation and RNA polymerase II to activate transcription. Mol. Cell Biol. 2010;30(13):3286-3298.

    Not in our library10.1128/mcb.01520-09

  240. 240.

    Liu W, Tanasa B, Tyurina OV, et al. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature. 2010;466(7305):508-512.

    Not in our library10.1038/nature09272

  241. 241.
    A Functional Link between the Histone Demethylase PHF8 and the Transcription Factor ZNF711 in X-Linked Mental Retardation · 2010
    No notice
  242. 242.

    Feng W, Yonezawa M, Ye J, Jenuwein T, Grummt I. PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation. Nat. Struct. Mol. Biol. 2010;17(4):445-450.

    Not in our library10.1038/nsmb.1778

  243. 243.

    Arteaga MF, Mikesch JH, Qiu J, et al. The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia. Cancer Cell. 2013;23(3):376-389.

    Not in our library10.1016/j.ccr.2013.02.014

  244. 244.

    Stender Jd, Pascual G, Liu W, et al. Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20. Mol. Cell. 2012;48(1):28-38.

    Not in our library10.1016/j.molcel.2012.07.020

  245. 245.

    Huang C, Xiang Y, Wang Y, et al. Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell Res. 2010;20(2):154-165.

    Not in our library10.1038/cr.2010.5

  246. 246.

    Sinha S, Singh RK, Alam N, Roy A, Roychoudhury S, Panda CK. Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region. pathological significance in early- and late-onset breast carcinoma. Mol. Cancer. 2008;7:84.

    Not in our library10.1186/1476-4598-7-84

  247. 247.

    Abidi F, Miano M, Murray J, Schwartz C. A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin. Genet. 2007;72(1):19-22.

    Not in our library10.1111/j.1399-0004.2007.00817.x

  248. 248.

    Koivisto AM, Ala-Mello S, Lemmela S, Komu HA, Rautio J, Jarvela I. Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin. Genet. 2007;72(2):145-149.

    Not in our library10.1111/j.1399-0004.2007.00836.x

  249. 249.

    Laumonnier F, Holbert S, Ronce N, et al. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J. Med. Genet. 2005;42(10):780-786.

    Not in our library10.1136/jmg.2004.029439

  250. 250.

    Siderius LE, Hamel BC, Van Bokhoven H, et al. X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3. Am. J. Med. Genet. 1999;85(3):216-220.

    Not in our library

  251. 251.

    Qiao Y, Liu X, Harvard C, et al. Autism-associated familial microdeletion of Xp11.22. Clin. Genet. 2008;74(2):134-144.

    Not in our library10.1111/j.1399-0004.2008.01028.x

  252. 252.

    Nava C, Lamari F, Heron D, et al. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl Psychiatry. 2012;2:e179.

    Not in our library10.1038/tp.2012.102

  253. 253.

    Aragones J, Fraisl P, Baes M, Carmeliet P. Oxygen sensors at the crossroad of metabolism. Cell Metab. 2009;9(1):11-22.

    Not in our library10.1016/j.cmet.2008.10.001

  254. 254.

    Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 2004;5(5):343-354.

    Not in our library10.1038/nrm1366

  255. 255.

    Melvin A, Mudie S, Rocha S. The chromatin remodeler ISWI regulates the cellular response to hypoxia: role of FIH. Mol. Biol. 2011;22(21):4171-4181.

    Not in our library10.1091/mbc.e11-02-0163

  256. 256.

    Zhang N, Fu Z, Linke S, et al. The asparaginyl hydroxylase factor inhibiting HIF-1α is an essential regulator of metabolism. Cell Metab. 2010;11(5):364-378.

    Not in our library10.1016/j.cmet.2010.03.001

  257. 257.

    Liu C-J, Tsai M-M, Hung P-S, et al. miR-31 ablates expression of the HIF regulatory factor FIH to activate the HIF pathway in head and neck carcinoma. Cancer Res. 2010;70(4):1635-1644.

    Not in our library10.1158/0008-5472.can-09-2291

  258. 258.

    Kroeze SGC, Vermaat JS, Van Brussel A, et al. Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients. Eur. J. Cancer. 2010;46(18):3375-3382.

    Not in our library10.1016/j.ejca.2010.07.018

  259. 259.

    Khan MN, Bhattacharyya T, Andrikopoulos P, et al. Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1[alpha]-mediated apoptosis. Br. J. Cancer. 2011;104(7):1151-1159.

    Not in our library10.1038/bjc.2011.73

  260. 260.

    Andersen S, Donnem T, Stenvold H, et al. Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival. PLoS ONE. 2011;6(8):e23847.

    Not in our library10.1371/journal.pone.0023847

  261. 261.

    Hyseni A, Groep P, Wall E, Diest P. Subcellular FIH-1 expression patterns in invasive breast cancer in relation to HIF-1α expression. Cell Oncol. 2011;34(6):565-570.

    Not in our library10.1007/s13402-011-0053-5

  262. 262.

    Liu Y, Higashitsuji H, Higashitsuji H, et al. Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1. Biochem. Biophys. Res. Comm. 2013;432(1):22-27.

    Not in our library10.1016/j.bbrc.2013.01.093

  263. 263.

    Tsuneoka M, Koda Y, Soejima M, Teye K, Kimura H. A novel myc target gene, mina53, that is involved in cell proliferation. J. Biol. Chem. 2002;277(38):35450-35459.

    Not in our library10.1074/jbc.m204458200

  264. 264.

    Hoffman B, Liebermann DA. Apoptotic signaling by c-MYC. Oncogene. 2008;27(50):6462-6472.

    Not in our library10.1038/onc.2008.312

  265. 265.

    Lu Y, Chang Q, Zhang Y, et al. Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3. Cell Cycle. 2009;8(13):2101-2109.

    Not in our library10.4161/cc.8.13.8927

  266. 266.

    Fukahori S, Yano H, Tsuneoka M, et al. Immunohistochemical expressions of Cap43 and Mina53 proteins in neuroblastoma. J. Pediatric Surg. 2007;42(11):1831-1840.

    Not in our library10.1016/j.jpedsurg.2007.07.008

  267. 267.

    Ishizaki H, Yano H, Tsuneoka M, et al. Overexpression of the myc target gene Mina53 in advanced renal cell carcinoma. Pathol. Int. 2007;57(10):672-680.

    Not in our library10.1111/j.1440-1827.2007.02156.x

  268. 268.

    Komiya K, Sueoka-Aragane N, Sato A, et al. Expression of Mina53, a novel c-Myc target gene, is a favorable prognostic marker in early stage lung cancer. Lung Cancer. 2010;69(2):232-238.

    Not in our library10.1016/j.lungcan.2009.10.010

  269. 269.

    Tan XP, Zhang Q, Dong WG, Lei XW, Yang ZR. Upregulated expression of Mina53 in cholangiocarcinoma and its clinical significance. Oncol. Lett. 2012;3(5):1037-1041.

    Not in our library10.3892/ol.2012.620

  270. 270.

    Teye K, Tsuneoka M, Arima N, et al. Increased expression of a Myc target gene Mina53 in human colon cancer. Am. J. Pathol. 2004;164(1):205-216.

    Not in our library10.1016/s0002-9440(10)63111-2

  271. 271.

    Tsuneoka M, Fujita H, Arima N, et al. Mina53 as a potential prognostic factor for esophageal squamous cell carcinoma. Clin. Cancer Res. 2004;10(21):7347-7356.

    Not in our library10.1158/1078-0432.ccr-03-0543

  272. 272.

    Tsuneoka M, Nishimune Y, Ohta K, et al. Expression of Mina53, a product of a Myc target gene in mouse testis. Int. J. Androl. 2006;29(2):323-330.

    Not in our library10.1111/j.1365-2605.2005.00572.x

  273. 273.

    Zhang Y, Lu Y, Yuan BZ, et al. The human mineral dust-induced gene, mdig, is a cell growth regulating gene associated with lung cancer. Oncogene. 2005;24(31):4873-4882.

    Not in our library10.1038/sj.onc.1208668

  274. 274.

    Mori T, Okamoto K, Tanaka Y, et al. Ablation of mina53 in mice reduces allergic response in the airways. Cell Struct. Funct. 2013;38(2):155-167.

    Not in our library10.1247/csf.13006

  275. 275.

    Yosef N, Shalek AK, Gaublomme JT, et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature. 2013;496(7446):461-468.

    Not in our library10.1038/nature11981

  276. 276.

    Eilbracht J, Reichenzeller M, Hergt M, et al. NO66, a highly conserved dual location protein in the nucleolus and in a special type of synchronously replicating chromatin. Mol Biol Cell. 2004;15(4):1816-1832.

    Not in our library10.1091/mbc.e03-08-0623

  277. 277.

    Brien GL, Gambero G, O’Connell DJ, et al. Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nat. Struct. Mol. Biol. 2012;19(12):1273-1281.

    Not in our library10.1038/nsmb.2449

  278. 278.

    Tao Y, Wu M, Zhou X, et al. Structural insights into histone demethylase NO66 in interaction with osteoblast-specific transcription factor Osterix and gene repression. J. Biol. Chem. 2013;288(23):16430-16437.

    Not in our library10.1074/jbc.m112.446849

  279. 279.

    Suzuki C, Takahashi K, Hayama S, et al. Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer. Mol. Cancer Ther. 2007;6(2):542-551.

    Not in our library10.1158/1535-7163.mct-06-0659

  280. 280.

    Jones MA, Covington MF, Ditacchio L, Vollmers C, Panda S, Harmer SL. Jumonji domain protein JMJD5 functions in both the plant and human circadian systems. Proc. Natl Acad. Sci. USA. 2010;107(50):21623-21628.

    Not in our library10.1073/pnas.1014204108

  281. 281.

    Oh S, Janknecht R. Histone demethylase JMJD5 is essential for embryonic development. Biochem. Biophys. Res. Comm. 2012;420(1):61-65.

    Not in our library10.1016/j.bbrc.2012.02.115

  282. 282.

    Ishimura A, Minehata K-I, Terashima M, Kondoh G, Hara T, Suzuki T. Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression. Development. 2012;139(4):749-759.

    Not in our library10.1242/dev.074138

  283. 283.

    Cikala M, Alexandrova O, David CN, et al. The phosphatidylserine receptor from Hydra is a nuclear protein with potential Fe(II) dependent oxygenase activity. BMC Cell Biol. 2004;5:26.

    Not in our library10.1186/1471-2121-5-26

  284. 284.

    Mantri M, Krojer T, Bagg EA, et al. Crystal structure of the 2-oxoglutarate- and Fe(II)-dependent lysyl hydroxylase JMJD6. J. Mol. Biol. 2010;401(2):211-222.

    Not in our library

  285. 285.

    Hong X, Zang J, White J, et al. Interaction of JMJD6 with single-stranded RNA. Proc. Natl Acad. Sci. USA. 2010;107(33):14568-14572.

    Not in our library10.1073/pnas.1008832107

  286. 286.
    The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal · 2004
    No notice
  287. 287.

    Kunisaki Y, Masuko S, Noda M, et al. Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor. Blood. 2004;103(9):3362-3364.

    Not in our library10.1182/blood-2003-09-3245

  288. 288.
    Identification of cardiac malformations in mice lacking Ptdsrusing a novel high-throughput magnetic resonance imaging technique · 2004
    No notice
  289. 289.

    Hahn P, Wegener I, Burrells A, et al. Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation. PLoS ONE. 2010;5(10):e13769.

    Not in our library10.1371/journal.pone.0013769

  290. 290.

    Lee Y, Miller L, Chan X, et al. JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer. Breast Cancer Res. 2012;14(3):R85.

    Not in our library10.1186/bcr3200

  291. 291.

    Ghosh M, Loper R, Gelb MH, Leslie CC. Identification of the expressed form of human cytosolic phospholipase A2beta (cPLA2beta): cPLA2beta3 is a novel variant localized to mitochondria and early endosomes. J. Biol. Chem. 2006;281(24):16615-16624.

    Not in our library10.1074/jbc.m601770200

  292. 292.

    Ding X, Pan H, Li J, et al. Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis. Sci. Signal. 2013;6(273):ra28-13.

    Not in our library10.1126/scisignal.2003884

  293. 293.

    Liu C, Gilmont Rr, Benndorf R, Welsh MJ. Identification and characterization of a novel protein from Sertoli cells, PASS1, that associates with mammalian small stress protein hsp27. J. Biol. Chem. 2000;275(25):18724-18731.

    Not in our library10.1074/jbc.m001981200

  294. 294.

    Jiang M, Ma Y, Cheng H, et al. Molecular cloning and characterization of a novel human gene (HSPBAP1) from human fetal brain. Cytogenet. Cell Genet. 2001;95(1-2):48-51.

    Not in our library10.1159/000057016

  295. 295.

    Srivastava AK, Renusch SR, Naiman NE, et al. Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice. Neurobiol. Dis. 2012;47(2):163-173.

    Not in our library10.1016/j.nbd.2012.03.035

  296. 296.

    Xi ZQ, Sun JJ, Wang XF, et al. HSPBAP1 is found extensively in the anterior temporal neocortex of patients with intractable epilepsy. Synapse. 2007;61(9):741-747.

    Not in our library10.1002/syn.20417

  297. 297.

    Xi ZQ, Xiao F, Yuan J, et al. Gene expression analysis on anterior temporal neocortex of patients with intractable epilepsy. Synapse. 2009;63(11):1017-1028.

    Not in our library10.1002/syn.20681

  298. 298.

    Aas PA, Otterlei M, Falnes PO, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003;421(6925):859-863.

    Not in our library10.1038/nature01363

  299. 299.

    Dango S, Mosammaparast N, Sowa ME, et al. DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Mol. Cell. 2011;44(3):373-384.

    Not in our library10.1016/j.molcel.2011.08.039

  300. 300.

    Fu D, Samson LD. Direct repair of 3,N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase. DNA Repair (Amst.). 2012;11(1):46-52.

    Not in our library10.1016/j.dnarep.2011.10.004

  301. 301.

    Lee DH, Jin SG, Cai S, Chen Y, Pfeifer GP, O’connor TR. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues. J. Biol. Chem. 2005;280(47):39448-39459.

    Not in our library10.1074/jbc.m509881200

  302. 302.

    Muller TA, Meek K, Hausinger RP. Human AlkB homologue 1 (ABH1) exhibits DNA lyase activity at abasic sites. DNA Repair (Amst.). 2010;9(1):58-65.

    Not in our library10.1016/j.dnarep.2009.10.011

  303. 303.

    Westbye MP, Feyzi E, Aas PA, et al. Human AlkB homolog 1 is a mitochondrial protein that demethylates 3-methylcytosine in DNA and RNA. J. Biol. Chem. 2008;283(36):25046-25056.

    Not in our library10.1074/jbc.m803776200

  304. 304.

    Bethke L, Murray A, Webb E, et al. Comprehensive analysis of DNA repair gene variants and risk of meningioma. J. Natl Cancer Inst. 2008;100(4):270-276.

    Not in our library10.1093/jnci/djn004

  305. 305.

    Fujii T, Shimada K, Anai S, Fujimoto K, Konishi N. ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression. Cancer Sci. 2013;104(3):321-327.

    Not in our library10.1111/cas.12089

  306. 306.

    Hu L, Wu C, Zhao X, et al. Genome-wide association study of prognosis in advanced non-small cell lung cancer patients receiving platinum-based chemotherapy. Clin. Cancer Res. 2012;18(19):5507-5514.

    Not in our library10.1158/1078-0432.ccr-12-1202

  307. 307.

    Johannessen TC, Prestegarden L, Grudic A, Hegi ME, Tysnes BB, Bjerkvig R. The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells. Neuro. Oncol. 2013;15(3):269-278.

    Not in our library10.1093/neuonc/nos301

  308. 308.

    Koike K, Ueda Y, Hase H, et al. Anti-tumor effect of AlkB homolog 3 knockdown in hormone-independent prostate cancer cells. Curr. Cancer Drug Targets. 2012;12(7):847-856.

    Not in our library10.2174/156800912802429283

  309. 309.

    Shimada K, Fujii T, Tsujikawa K, Anai S, Fujimoto K, Konishi N. ALKBH3 contributes to survival and angiogenesis of human urothelial carcinoma cells through NADPH oxidase and tweak/Fn14/VEGF signals. Clin. Cancer Res. 2012;18(19):5247-5255.

    Not in our library10.1158/1078-0432.ccr-12-0955

  310. 310.

    Tasaki M, Shimada K, Kimura H, Tsujikawa K, Konishi N. ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer. Br. J. Cancer. 2011;104(4):700-706.

    Not in our library10.1038/sj.bjc.6606012

  311. 311.

    Yamato I, Sho M, Shimada K, et al. PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis. Cancer Res. 2012;72(18):4829-4839.

    Not in our library10.1158/0008-5472.can-12-0328

  312. 312.

    Bjornstad LG, Meza TJ, Otterlei M, Olafsrud SM, Meza-Zepeda LA, Falnes PO. Human ALKBH4 interacts with proteins associated with transcription. PLoS ONE. 2012;7(11):e49045.

    Not in our library10.1371/journal.pone.0049045

  313. 313.

    Fu Y, He C. Nucleic acid modifications with epigenetic significance. Curr. Opin. Chem. Biol. 2012;16(5-6):516-524.

    Not in our library10.1016/j.cbpa.2012.10.002

  314. 314.

    Jia G, Fu Y, He C. Reversible RNA adenosine methylation in biological regulation. Trends Genet. 2013;29(2):108-115.

    Not in our library10.1016/j.tig.2012.11.003

  315. 315.

    Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011;7(12):885-887.

    Not in our library10.1038/nchembio.687

  316. 316.

    Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889-894.

    Not in our library10.1126/science.1141634

  317. 317.
    The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice · 2010
    No notice
  318. 318.

    Do R, Bailey SD, Desbiens K, et al. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes. 2008;57(4):1147-1150.

    Not in our library10.2337/db07-1267

  319. 319.

    Jacobsson JA, Klovins J, Kapa I, et al. Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents. Int. J. Obes. (Lond.). 2008;32(11):1730-1735.

    Not in our library10.1038/ijo.2008.168

  320. 320.

    Keller L, Xu W, Wang Hx, Winblad B, Fratiglioni L, Graff C. The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer’s disease risk: a prospective cohort study. J. Alzheimers Dis. 2011;23(3):461-469.

    Not in our library10.3233/jad-2010-101068

  321. 321.

    Lappalainen T, Kolehmainen M, Schwab US, et al. Association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolism-the Finnish Diabetes Prevention Study. Nutr. Metab. Cardiovasc. Dis. 2011;21(9):691-698.

    Not in our library10.1016/j.numecd.2010.01.006

  322. 322.

    Hubacek JA, Viklicky O, Dlouha D, et al. The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population. Nephrol. Dial. Transplant. 2012;27(3):1030-1035.

    Not in our library10.1093/ndt/gfr418

  323. 323.
    The role of the fat mass and obesity associated gene (FTO) in breast cancer risk · 2011
    No notice
  324. 324.

    Tarabra E, Actis GC, Fadda M, et al. The obesity gene and colorectal cancer risk: a population study in Northern Italy. Eur. J. Intern. Med. 2012;23(1):65-69.

    Not in our library10.1016/j.ejim.2011.07.011

  325. 325.

    Boissel S, Reish O, Proulx K, et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 2009;85(1):106-111.

    Not in our library10.1016/j.ajhg.2009.06.002

  326. 326.

    Shimada K, Nakamura M, Anai S, et al. A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. Cancer Res. 2009;69(7):3157-3164.

    Not in our library10.1158/0008-5472.can-08-3530

  327. 327.

    Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia. 2003;17(3):637-641.

    Not in our library10.1038/sj.leu.2402834

  328. 328.

    Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y. LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res. 2002;62(14):4075-4080.

    Not in our library

  329. 329.

    Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 2013;14(6):341-356.

    Not in our library10.1038/nrm3589

  330. 330.

    Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114(1):144-147.

    Not in our library10.1182/blood-2009-03-210039

  331. 331.
    Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population · 2012
    No notice
  332. 332.

    Cao XJ, Arnaudo AM, Garcia BA. Large-scale global identification of protein lysine methylation in vivo. Epigenetics. 2013;8(5):477-485.

    Not in our library10.4161/epi.24547

  333. 333.

    Chowdhury R, Yeoh KK, Tian YM, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463-469.

    Not in our library10.1038/embor.2011.43

  334. 334.

    Watson JA, Watson CJ, McCann A, Baugh J. Epigenetics, the epicenter of the hypoxic response. Epigenetics. 2010;5(4):293-296.

    Not in our library10.4161/epi.5.4.11684

  335. 335.

    Edwards AM, Isserlin R, Bader GD, Frye SV, Willson TM, Yu FH. Too many roads not taken. Nature. 2011;470(7333):163-165.

    Not in our library10.1038/470163a

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