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Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity


Autoři: Lewin Small aff001;  Lars R. Ingerslev aff001;  Eleonora Manitta aff001;  Rhianna C. Laker aff001;  Ann N. Hansen aff001;  Brendan Deeney aff001;  Alain Carrié aff002;  Philippe Couvert aff002;  Romain Barrès aff001
Působiště autorů: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark aff001;  Sorbonne Université-INSERM UMR_S 1166 ICAN, Pitié-Salpêtrière Hospital, Paris, France aff002
Vyšlo v časopise: Ablation of DNA-methyltransferase 3A in skeletal muscle does not affect energy metabolism or exercise capacity. PLoS Genet 17(1): e1009325. doi:10.1371/journal.pgen.1009325
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009325

Souhrn

In response to physical exercise and diet, skeletal muscle adapts to energetic demands through large transcriptional changes. This remodelling is associated with changes in skeletal muscle DNA methylation which may participate in the metabolic adaptation to extracellular stimuli. Yet, the mechanisms by which muscle-borne DNA methylation machinery responds to diet and exercise and impacts muscle function are unknown. Here, we investigated the function of de novo DNA methylation in fully differentiated skeletal muscle. We generated muscle-specific DNA methyltransferase 3A (DNMT3A) knockout mice (mD3AKO) and investigated the impact of DNMT3A ablation on skeletal muscle DNA methylation, exercise capacity and energy metabolism. Loss of DNMT3A reduced DNA methylation in skeletal muscle over multiple genomic contexts and altered the transcription of genes known to be influenced by DNA methylation, but did not affect exercise capacity and whole-body energy metabolism compared to wild type mice. Loss of DNMT3A did not alter skeletal muscle mitochondrial function or the transcriptional response to exercise however did influence the expression of genes involved in muscle development. These data suggest that DNMT3A does not have a large role in the function of mature skeletal muscle although a role in muscle development and differentiation is likely.

Klíčová slova:

Diet – DNA methylation – DNA transcription – Gene expression – Muscle differentiation – Running – Skeletal muscles – Soleus muscles


Zdroje

1. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet. 2000;1: 11–19. doi: 10.1038/35049533 11262868

2. Pillon NJ, Gabriel BM, Dollet L, Smith JAB, Puig LS, Botella J, et al. Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity. Nat Commun. 2020;11: 470. doi: 10.1038/s41467-019-13869-w 31980607

3. Barrès R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell metabolism. 2012;15: 405–411. doi: 10.1016/j.cmet.2012.01.001 22405075

4. Bajpeyi S, Covington JD, Taylor EM, Stewart LK, Galgani JE, Henagan TM. Skeletal Muscle PGC1α -1 Nucleosome Position and -260nt DNA Methylation Determine Exercise Response and Prevent Ectopic Lipid Accumulation in Men. Endocrinology. 2017;158: 2190–2199. doi: 10.1210/en.2017-00051 28398573

5. Seaborne RA, Strauss J, Cocks M, Shepherd S, O’Brien TD, Someren KA van, et al. Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy. Sci Rep-uk. 2018;8: 1898. doi: 10.1038/s41598-018-20287-3 29382913

6. Kanzleiter T, Jähnert M, Schulze G, Selbig J, Hallahan N, Schwenk RW, et al. Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice. Am J Physiology Endocrinol Metabolism. 2015;308: E912–20. doi: 10.1152/ajpendo.00289.2014 25805191

7. Laker RC, Garde C, Camera DM, Smiles WJ, Zierath JR, Hawley JA, et al. Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. Scientific reports. 2017;7: 15134. doi: 10.1038/s41598-017-15420-7 29123172

8. Barrès R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, et al. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell metabolism. 2009;10: 189–198. doi: 10.1016/j.cmet.2009.07.011 19723495

9. Gillberg L, Rönn T, Jørgensen SW, Perfilyev A, Hjort L, Nilsson E, et al. Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men. Ebiomedicine. 2019;47: 341–351. doi: 10.1016/j.ebiom.2019.08.017 31439477

10. Barres R, Kirchner H, Rasmussen M, Yan J, Kantor FR, Krook A, et al. Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Reports. 2013;3: 1020–7. doi: 10.1016/j.celrep.2013.03.018 23583180

11. Jacobsen SC, Brøns C, Bork-Jensen J, Ribel-Madsen R, Yang B, Lara E, et al. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men. Diabetologia. 2012;55: 3341–9. doi: 10.1007/s00125-012-2717-8 22961225

12. Jacques M, Hiam D, Craig J, Barrès R, Eynon N, Voisin S. Epigenetic changes in healthy human skeletal muscle following exercise- a systematic review. Epigenetics. 2019;14: 633–648. doi: 10.1080/15592294.2019.1614416 31046576

13. Sharples AP, Stewart CE, Seaborne RA. Does skeletal muscle have an ‘epi’-memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise. Aging Cell. 2016;15: 603–16. doi: 10.1111/acel.12486 27102569

14. Jeltsch A, Jurkowska RZ. New concepts in DNA methylation. Trends Biochem Sci. 2014;39: 310–318. doi: 10.1016/j.tibs.2014.05.002 24947342

15. Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 1999;27: 2291–2298. doi: 10.1093/nar/27.11.2291 10325416

16. Bi P, Yue F, Sato Y, Wirbisky S, Liu W, Shan T, et al. Stage-specific effects of Notch activation during skeletal myogenesis. eLife. 2016;5. doi: 10.7554/eLife.17355 27644105

17. You D, Nilsson E, Tenen DE, Lyubetskaya A, Lo JC, Jiang R, et al. Dnmt3a is an epigenetic mediator of adipose insulin resistance. eLife. 2017;6: 205. doi: 10.7554/eLife.30766 29091029

18. Zurlo F, Larson K, Bogardus C, Ravussin E. Skeletal muscle metabolism is a major determinant of resting energy expenditure. Journal of Clinical Investigation. 1990;86: 1423–1427. doi: 10.1172/JCI114857 2243122

19. Dou X, Boyd-Kirkup JD, McDermott J, Zhang X, Li F, Rong B, et al. The strand-biased mitochondrial DNA methylome and its regulation by DNMT3A. Genome Res. 2019;29: 1622–1634. doi: 10.1101/gr.234021.117 31537639

20. Okano M, Bell DW, Haber DA, Li E. DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development. Cell. 1999;99: 247–257. doi: 10.1016/s0092-8674(00)81656-6 10555141

21. Jones PA, Liang G. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009;10: 805–811. doi: 10.1038/nrg2651 19789556

22. Ferrannini E, Bjorkman O, Reichard GA, Pilo A, Olsson M, Wahren J, et al. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes. 1985;34: 580–588. doi: 10.2337/diab.34.6.580 3891471

23. Hatazawa Y, Ono Y, Hirose Y, Kanai S, Fujii NL, Machida S, et al. Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. The FASEB Journal. 2018;32: 1452–1467. doi: 10.1096/fj.201700573R 29146735

24. Kamei Y, Suganami T, Ehara T, Kanai S, Hayashi K, Yamamoto Y, et al. Increased expression of DNA methyltransferase 3a in obese adipose tissue: studies with transgenic mice. Obes Silver Spring Md. 2009;18: 314–21. doi: 10.1038/oby.2009.246 19680236

25. Wong M, Gertz B, Chestnut BA, Martin LJ. Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front Cell Neurosci. 2013;7: 279. doi: 10.3389/fncel.2013.00279 24399935

26. Patil V, Cuenin C, Chung F, Aguilera JRR, Fernandez-Jimenez N, Romero-Garmendia I, et al. Human mitochondrial DNA is extensively methylated in a non-CpG context. Nucleic Acids Res. 2019;47: 10072–10085. doi: 10.1093/nar/gkz762 31665742

27. Mechta M, Ingerslev LR, Fabre O, Picard M, Barrès R. Evidence Suggesting Absence of Mitochondrial DNA Methylation. Frontiers Genetics. 2017;8: 166. doi: 10.3389/fgene.2017.00166 29163634

28. Lindholm ME, Marabita F, Gomez-Cabrero D, Rundqvist H, Ekström TJ, Tegnér J, et al. An integrative analysis reveals coordinated reprogramming of the epigenome and the transcriptome in human skeletal muscle after training. Epigenetics. 2015;9: 1557–1569. doi: 10.4161/15592294.2014.982445 25484259

29. García-Giménez JL, Romá-Mateo C, Pérez-Machado G, Peiró-Chova L, Pallardó FV. Role of glutathione in the regulation of epigenetic mechanisms in disease. Free Radic Biology Medicine. 2017;112: 36–48. doi: 10.1016/j.freeradbiomed.2017.07.008 28705657

30. Naito M, Mori M, Inagawa M, Miyata K, Hashimoto N, Tanaka S, et al. Dnmt3a Regulates Proliferation of Muscle Satellite Cells via p57Kip2. Tajbakhsh S, editor. PLoS genetics. 2016;12: e1006167. doi: 10.1371/journal.pgen.1006167 27415617

31. Gundersen K, Rabben I, Klocke BJ, Merlie JP. Overexpression of myogenin in muscles of transgenic mice: interaction with Id-1, negative crossregulation of myogenic factors, and induction of extrasynaptic acetylcholine receptor expression. Mol Cell Biol. 1995;15: 7127–7134. doi: 10.1128/mcb.15.12.7127 8524280

32. Olguin HC, Olwin BB. Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal. Dev Biol. 2004;275: 375–388. doi: 10.1016/j.ydbio.2004.08.015 15501225

33. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004;429: 900–903. doi: 10.1038/nature02633 15215868

34. Williams K, Ingerslev LR, Bork-Jensen J, Wohlwend M, Hansen AN, Small L, et al. Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism. Nat Commun. 2020;11: 2695. doi: 10.1038/s41467-020-16537-6 32483258

35. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. Embnet J. 2011;17: 10–12. doi: 10.14806/ej.17.1.200

36. Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinform Oxf Engl. 2011;27: 1571–2. doi: 10.1093/bioinformatics/btr167 21493656

37. Chen Y, Pal B, Visvader JE, Smyth GK. Differential methylation analysis of reduced representation bisulfite sequencing experiments using edgeR. F1000research. 2017;6: 2055. doi: 10.12688/f1000research.13196.2 29333247

38. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinform Oxf Engl. 2009;26: 139–40. doi: 10.1093/bioinformatics/btp616 19910308

39. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28: 495–501. doi: 10.1038/nbt.1630 20436461

40. Longchamps RJ, Castellani CA, Yang SY, Newcomb CE, Sumpter JA, Lane J, et al. Evaluation of mitochondrial DNA copy number estimation techniques. Plos One. 2020;15: e0228166. doi: 10.1371/journal.pone.0228166 32004343

41. Shahini A, Vydiam K, Choudhury D, Rajabian N, Nguyen T, Lei P, et al. Efficient and high yield isolation of myoblasts from skeletal muscle. Stem cell research. 2018;30: 122–129. doi: 10.1016/j.scr.2018.05.017 29879622


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