Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer’s Disease

Abstract

Cognitive impairment in Alzheimer’s disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, N 6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is perturbed in AD. To address this, we investigated the expression profile of known m6A-regulatory genes using a public RNA-seq dataset and identified a subset of genes which were significantly dysregulated in the human AD brain. Among these, genes encoding the m6A methyltransferase, METTL3 , and a member of the m6A methyltransferase complex (MACOM), RBM15B , were downregulated and upregulated in the hippocampus, respectively. These findings were validated at the protein level using an independent cohort of postmortem human brain samples. Unexpectedly, we observed an accumulation of methyltransferase-like 3 (METTL3), but not RBM15B, in the insoluble fractions, which positively correlated with the levels of insoluble Tau protein in the postmortem human AD samples. Aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may therefore represent an epitranscriptomic mechanism underlying the altered gene expression patterns associated with disease pathogenesis.

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References 54

1. 1.

   Anggono V, Koç-Schmitz Y, Widagdo J, Kormann J, Quan A, Chen CM, Robinson PJ, Choi SY, Linden DJ, Plomann M, Huganir RL (2013 ) PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression. Proc Natl Acad Sci USA 110:13976–13981.

   Not in our library10.1073/pnas.1312467110

2. 2.

   Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, Iritani S, Onaya M, Akiyama H (2009 ) Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136.

   Not in our library10.1007/s00401-008-0480-1

3. 3.

   Conlon EG, Manley JL (2017 ) RNA-binding proteins in neurodegeneration: mechanisms in aggregate. Genes Dev 31:1509–1528.

   Not in our library10.1101/gad.304055.117

4. 4.

   De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT, Ernst J, McCabe C, Tang A, Raj T, Replogle J, Brodeur W, Gabriel S, Chai HS, Younkin C, Younkin SG, Zou F, Szyf M, et al. (2014 ) Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17:1156–1163.

   Not in our library10.1038/nn.3786

5. 5.

   Du Y, Hou G, Zhang H, Dou J, He J, Guo Y, Li L, Chen R, Wang Y, Deng R, Huang J, Jiang B, Xu M, Cheng J, Chen GQ, Zhao X, Yu J (2018 ) SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. Nucleic Acids Res 46:5195–5208.

   Not in our library10.1093/nar/gky156

6. 6.

   Engel M, Chen A (2018 ) The emerging role of mRNA methylation in normal and pathological behavior. Genes Brain Behav 17:e12428.

   Not in our library10.1111/gbb.12428

7. 7.

   Engel M, Eggert C, Kaplick PM, Eder M, Röh S, Tietze L, Namendorf C, Arloth J, Weber P, Rex-Haffner M, Geula S, Jakovcevski M, Hanna JH, Leshkowitz D, Uhr M, Wotjak CT, Schmidt MV, Deussing JM, Binder EB, Chen A (2018 ) The role of m(6)A/m-RNA methylation in stress response regulation. Neuron 99:389–403.

   Not in our library10.1016/j.neuron.2018.07.009

8. 8.

   Flamand MN, Meyer KD (2019 ) The epitranscriptome and synaptic plasticity. Curr Opin Neurobiol 59:41–48.

   Not in our library10.1016/j.conb.2019.04.007

9. 9.
   Abnormality of m6A mRNA Methylation Is Involved in Alzheimer’s Disease · 2020

   No notice
10. 10.

    Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, et al. (2010 ) A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci USA 107:8404–8409.

    Not in our library10.1073/pnas.0910878107

11. 11.

    Ho J, Tumkaya T, Aryal S, Choi H, Claridge-Chang A (2019 ) Moving beyond P values: data analysis with estimation graphics. Nat Methods 16:565–566.

    Not in our library10.1038/s41592-019-0470-3

12. 12.

    Huang H, Weng H, Chen J (2020a ) m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell 37:270–288.

    Not in our library10.1016/j.ccell.2020.02.004

13. 13.

    Huang H, Weng H, Chen J (2020b ) The biogenesis and precise control of RNA m(6)A methylation. Trends Genet 36:44–52.

    Not in our library10.1016/j.tig.2019.10.011

14. 14.

    Huang YS, Lu WH (2018 ) Decoding hidden messages in neurons: insights from epitranscriptome-controlled and specialized ribosome-controlled translation. Curr Opin Neurobiol 48:64–70.

    Not in our library10.1016/j.conb.2017.10.018

15. 15.

    Ihara Y, Morishima-Kawashima M, Nixon R (2012 ) The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006361

    Not in our library10.1101/cshperspect.a006361

16. 16.

    Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C (2011 ) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887.

    Not in our library10.1038/nchembio.687

17. 17.

    Kadumuri RV, Janga SC (2018 ) Epitranscriptomic code and its alterations in human disease. Trends Mol Med 24:886–903.

    Not in our library10.1016/j.molmed.2018.07.010

18. 18.

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

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

19. 19.

    Klein HU, McCabe C, Gjoneska E, Sullivan SE, Kaskow BJ, Tang A, Smith RV, Xu J, Pfenning AR, Bernstein BE, Meissner A, Schneider JA, Mostafavi S, Tsai LH, Young-Pearse TL, Bennett DA, De Jager PL (2019 ) Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer's human brains. Nat Neurosci 22:37–46.

    Not in our library10.1038/s41593-018-0291-1

20. 20.

    Koranda JL, Dore L, Shi H, Patel MJ, Vaasjo LO, Rao MN, Chen K, Lu Z, Yi Y, Chi W, He C, Zhuang X (2018 ) Mettl14 is essential for epitranscriptomic regulation of striatal function and learning. Neuron 99:283–292.

    Not in our library10.1016/j.neuron.2018.06.007

21. 21.

    Li C, Götz J (2017 ) Somatodendritic accumulation of Tau in Alzheimer's disease is promoted by Fyn-mediated local protein translation. EMBO J 36:3120–3138.

    Not in our library10.15252/embj.201797724

22. 22.

    Li L, Zang L, Zhang F, Chen J, Shen H, Shu L, Liang F, Feng C, Chen D, Tao H, Xu T, Li Z, Kang Y, Wu H, Tang L, Zhang P, Jin P, Shu Q, Li X (2017 ) Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 26:2398–2411.

    Not in our library10.1093/hmg/ddx128

23. 23.
    Molecular characterization and clinical relevance of m6A regulators across 33 cancer types · 2019

    No notice
24. 24.

    Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C (2014 ) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 10:93–95.

    Not in our library10.1038/nchembio.1432

25. 25.

    Liu X, Liu J, Xiao W, Zeng Q, Bo H, Zhu Y, Gong L, He D, Xing X, Li R, Zhou M, Xiong W, Zhou Y, Zhou J, Li X, Guo F, Xu C, Chen X, Wang X, Wang F, Wang Q, Cao K (2020 ) SIRT1 regulates N(6) -methyladenosine RNA modification in hepatocarcinogenesis by inducing RANBP2-dependent FTO SUMOylation. Hepatology, in press.

    Not in our library10.1002/hep.31222

26. 26.

    Livneh I, Moshitch-Moshkovitz S, Amariglio N, Rechavi G, Dominissini D (2020 ) The m(6)A epitranscriptome: transcriptome plasticity in brain development and function. Nat Rev Neurosci 21:36–51.

    Not in our library10.1038/s41583-019-0244-z

27. 27.

    Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, Troakes C, Al-Sarraj S, Burrage J, Macdonald R, Condliffe D, Harries LW, Katsel P, Haroutunian V, Kaminsky Z, Joachim C, Powell J, Lovestone S, Bennett DA, Schalkwyk LC, et al. (2014 ) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci 17:1164–1170.

    Not in our library10.1038/nn.3782

28. 28.

    Marzi SJ, Leung SK, Ribarska T, Hannon E, Smith AR, Pishva E, Poschmann J, Moore K, Troakes C, Al-Sarraj S, Beck S, Newman S, Lunnon K, Schalkwyk LC, Mill J (2018 ) A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci 21:1618–1627.

    Not in our library10.1038/s41593-018-0253-7

29. 29.

    Medeiros R, Castello NA, Cheng D, Kitazawa M, Baglietto-Vargas D, Green KN, Esbenshade TA, Bitner RS, Decker MW, LaFerla FM (2014 ) α7 nicotinic receptor agonist enhances cognition in aged 3xTg-AD mice with robust plaques and tangles. Am J Pathol 184:520–529.

    Not in our library10.1016/j.ajpath.2013.10.010

30. 30.
    Neuropathological and transcriptomic characteristics of the aged brain · 2017

    No notice
31. 31.

    Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo JB, Gosai SJ, Gregory BD, Torres C, Trojanowski JQ, Wang LS, Johnson FB, Bonini NM, Berger SL (2018 ) Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease. Nat Neurosci 21:497–505.

    Not in our library10.1038/s41593-018-0101-9

32. 32.

    Neueder A (2019 ) RNA-mediated disease mechanisms in neurodegenerative disorders. J Mol Biol 431:1780–1791.

    Not in our library10.1016/j.jmb.2018.12.012

33. 33.

    Patil DP, Chen C-K, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR (2016 ) m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537:369–373.

    Not in our library10.1038/nature19342

34. 34.

    Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, et al. (2014 ) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24:177–189.

    Not in our library10.1038/cr.2014.3

35. 35.

    Polanco JC, Li C, Bodea L-G, Martinez-Marmol R, Meunier FA, Götz J (2018 ) Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies. Nat Rev Neurol 14:22–39.

    Not in our library10.1038/nrneurol.2017.162

36. 36.

    Saletore Y, Meyer K, Korlach J, Vilfan ID, Jaffrey S, Mason CE (2012 ) The birth of the epitranscriptome: deciphering the function of RNA modifications. Genome Biol 13:175.

    Not in our library10.1186/gb-2012-13-10-175

37. 37.
    Epigenetic Alterations in Alzheimer’s Disease · 2015

    No notice
38. 38.

    Schwartz S (2016 ) Cracking the epitranscriptome. RNA 22:169–174.

    Not in our library10.1261/rna.054502.115

39. 39.

    Shi H, Zhang X, Weng YL, Lu Z, Liu Y, Lu Z, Li J, Hao P, Zhang Y, Zhang F, Wu Y, Delgado JY, Su Y, Patel MJ, Cao X, Shen B, Huang X, Ming GL, Zhuang X, Song H, et al. (2018 ) m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563:249–253.

    Not in our library10.1038/s41586-018-0666-1

40. 40.

    Shi H, Wei J, He C (2019 ) Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell 74:640–650.

    Not in our library10.1016/j.molcel.2019.04.025

Cited by papers we hold 4

• Methylation across the central dogma in health and diseases: new therapeutic strategies · 2023
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• The Potential Role of m6A RNA Methylation in the Aging Process and Aging-Associated Diseases · 2022
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• N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer’s disease · 2021
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• METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer’s disease through aberrant cell cycle events · 2021
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