Epigenetic Regulation of Skeletal Muscle Development and Differentiation

  • Narendra Bharathy
  • Belinda Mei Tze Ling
  • Reshma TanejaEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 61)


Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. Formation of skeletal muscle involves a series of steps in which cells are commited towards the myogenic lineage, undergo expansion to give rise to myoblasts that differentiate into multinucleated myotubes, and mature to form adult muscle fibers. The commitment, proliferation, and differentiation of progenitor cells involve both genetic and epigenetic changes that culminate in alterations in gene expression. Members of the Myogenic regulatory factor (MRF), as well as the Myocyte Enhancer Factor (MEF2) families control distinct steps of skeletal muscle proliferation and differentiation. In addition, ­growing evidence indicates that chromatin modifying enzymes and remodeling complexes epigenetically reprogram muscle promoters at various stages that preclude or promote MRF and MEF2 activites. Among these, histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs) and SWI/SNF complexes alter chromatin structure through post-translational modifications to impact MRF and MEF2 activities. With such new and emerging knowledge, we are beginning to develop a true molecular understanding of the mechanisms by which skeletal muscle development and differentiation is regulated. Elucidation of the mechanisms by which epigenetic regulators control myogenesis will likely provide a new foundation for the development of novel therapeutic drugs for muscle dystrophies, ageing-related regeneration defects that occur due to altered proliferation and differentiation, and other malignancies.


Satellite Cell HDAC Inhibitor Anacardic Acid Myogenic Regulatory Factor MyoD Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ait-Si-Ali S, Guasconi V, Fritsch L, Yahi H, Sekhri R, Naguibneva I, Robin P, Cabon F, Polesskaya A, Harel-Bellan A (2004) A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells. EMBO J 23:605–615PubMedCrossRefGoogle Scholar
  2. Albini S, Puri PL (2010) SWI/SNF complexes, chromatin remodeling and skeletal myogenesis: it’s time to exchange! Exp Cell Res 316:3073–3080PubMedCrossRefGoogle Scholar
  3. Azmi S, Ozog A, Taneja R (2004) Sharp-1 inhibits skeletal muscle differentiation through repression of myogenic transcription factors. J Biol Chem 279:52643–52652PubMedCrossRefGoogle Scholar
  4. Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H (1990) Cell 61:49–59PubMedCrossRefGoogle Scholar
  5. Black BL, Olson EN (1998) Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol 14:167–196PubMedCrossRefGoogle Scholar
  6. Blais A, van Oevelen CJ, Margueron R, Acosta-Alvear D, Dynlacht BD (2007) Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit. J Cell Biol 179:1399–1412PubMedCrossRefGoogle Scholar
  7. Braun T, Rudnicki MA, Arnold HH, Jaenisch R (1992) Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death. Cell 7:369–382CrossRefGoogle Scholar
  8. Buckingham M (1992) Making muscle in mammals. Trends Genet 8:144–149PubMedGoogle Scholar
  9. Buckingham M (2001) Skeletal muscle formation in vertebrates. Curr Opin Genet Dev 11:440–448PubMedCrossRefGoogle Scholar
  10. Caretti G, Di Padova M, Micales B, Lyons GE, Sartorelli V (2004) The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev 18:2627–2638PubMedCrossRefGoogle Scholar
  11. Chen SL, Loffler KA, Chen D, Stallcup MR, Muscat GE (2002) The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2. J Biol Chem 277:4324–4333PubMedCrossRefGoogle Scholar
  12. Colussi C, Rosati J, Straino S, Spallotta F, Berni R, Stilli D, Rossi S, Musso E, Macchi E, Mai A, Sbardella G, Castellano S, Chimenti C, Frustaci A, Nebbioso A, Altucci L, Capogrossi MC, Gaetano C (2011) Nε-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart. Proc Natl Acad Sci USA 108:2795–2800PubMedCrossRefGoogle Scholar
  13. Cossu G, Tajbakhsh S, Buckingham M (1996a) How is myogenesis initiated in the embryo? Trends Genet 12:218–223PubMedCrossRefGoogle Scholar
  14. Cossu G, Kelly R, Tajbakhsh S, Di Donna S, Vivarelli E, Buckingham M (1996b) Activation of different myogenic pathways: myf-5 is induced by the neural tube and MyoD by the dorsal ectoderm in mouse paraxial mesoderm. Development 122:429–437PubMedGoogle Scholar
  15. Cserjesi P, Olson EN (1991) Myogenin induces the myocyte-specific enhancer binding factor MEF-2 independently of other muscle-specific gene products. Mol Cell Biol 11:4854–4862PubMedGoogle Scholar
  16. Dacwag CS, Bedford MT, Sif S, Imbalzano AN (2009) Distinct protein arginine methyltransferases promote ATP-dependent chromatin remodeling function at different stages of skeletal muscle differentiation. Mol Cell Biol 29:1909–1921PubMedCrossRefGoogle Scholar
  17. Davis RL, Weintraub H, Lassar AB (1987) Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000PubMedCrossRefGoogle Scholar
  18. de la Serna IL, Ohkawa Y, Berkes CA, Bergstrom DA, Dacwag CS, Tapscott SJ, Imbalzano AN (2005) MyoD targets chromatin remodeling complexes to the myogenin locus prior to forming a stable DNA-bound complex. Mol Cell Biol 25:3997–4009PubMedCrossRefGoogle Scholar
  19. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749PubMedCrossRefGoogle Scholar
  20. Dilworth FJ, Seaver KJ, Fishburn AL, Htet SL, Tapscott SJ (2004) In vitro transcription system delineates the distinct roles of the coactivators PCAF and p300 during MyoD/E47-dependent transactivation. Proc Natl Acad Sci USA 101:11593–11598PubMedCrossRefGoogle Scholar
  21. Dodou E, Xu SM, Black BL (2003) mef2c is activated directly by myogenic basic helix–loop–helix proteins during skeletal muscle development in vivo. Mech Dev 120:1021–1103PubMedCrossRefGoogle Scholar
  22. Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, Sartorelli V (2003) Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12:51–62PubMedCrossRefGoogle Scholar
  23. Gros J, Manceau M, Thomé V, Marcelle C (2005) A common somitic origin for embryonic muscle progenitors and satellite cells. Nature 435:954–958PubMedCrossRefGoogle Scholar
  24. Guasconi V, Puri PL (2009) Chromatin: the interface between extrinsic cues and the epigenetic regulation of muscle regeneration. Trends Cell Biol 19:286–294PubMedCrossRefGoogle Scholar
  25. Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB (1995) Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267:1018–1021PubMedCrossRefGoogle Scholar
  26. Hasty P, Bradley A, Morris JH, Edmondsnon DG, Venuti JM, Olson EN, Klein WH (1993) Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364:501–506PubMedCrossRefGoogle Scholar
  27. Huh MS, Parker MH, Scimè A, Parks R, Rudnicki MA (2004) Rb is required for progression through myogenic differentiation but not maintenance of terminal differentiation. J Cell Biol 166:865–876PubMedCrossRefGoogle Scholar
  28. Iezzi S, Di Padova M, Serra C, Caretti G, Simone C, Maklan E, Minetti G, Zhao P, Hoffman EP, Puri PL, Sartorelli V (2004) Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin. Dev Cell 6:673–684PubMedCrossRefGoogle Scholar
  29. Kuang S, Chargé SB, Seale P, Huh M, Rudnicki MA (2006) Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis. J Cell Biol 172:103–113PubMedCrossRefGoogle Scholar
  30. Lassar AB, Paterson BM, Weintraub H (1986) Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 47:649–656PubMedCrossRefGoogle Scholar
  31. Lemercier C, To RQ, Carrasco RA, Konieczny SF (1998) The basic helix-loop-helix transcription factor Mist1 functions as a transcriptional repressor of myoD. EMBO J 17:1412–1422PubMedCrossRefGoogle Scholar
  32. Ling BM, Bharathy N, Chung TK, Kok WK, Li S, Tan YH, Rao VK, Gopinadhan S, Sartorelli V, Walsh MJ, Taneja R (2012) Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation. Proc Natl Acad Sci USA 109:841–846Google Scholar
  33. Lu J, Webb R, Richardson JA, Olson EN (1999) MyoR: a muscle-restricted basic helix-loop-helix transcription factor that antagonizes the actions of MyoD. Proc Natl Acad Sci USA 96:552–557PubMedCrossRefGoogle Scholar
  34. Lu J, McKinsey TA, Zhang CL, Olson EN (2000) Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6:233–244PubMedCrossRefGoogle Scholar
  35. Mal AK (2006) Histone methyltransferase Suv39h1 represses MyoD-stimulated myogenic differentiation. EMBO J 25:3323–3334PubMedCrossRefGoogle Scholar
  36. Mal A, Harter ML (2003) MyoD is functionally linked to the silencing of a muscle-specific regulatory gene prior to skeletal myogenesis. Proc Natl Acad Sci USA 100:1735–1739PubMedCrossRefGoogle Scholar
  37. Mal A, Sturniolo M, Schiltz RL, Ghosh MK, Harter ML (2001) A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program. EMBO J 20:1739–1753PubMedCrossRefGoogle Scholar
  38. McKinnell IW, Ishibashi J, Le Grand F, Punch VG, Addicks GC, Greenblatt JF, Dilworth FJ, Rudnicki MA (2008) Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nat Cell Biol 10:77–84PubMedCrossRefGoogle Scholar
  39. McKinsey TA, Zhang CL, Olson EN (2001) Control of muscle development by dueling HATs and HDACs. Curr Opin Genet Dev 11:497–504PubMedCrossRefGoogle Scholar
  40. Minetti GC, Colussi C, Adami R, Serra C, Mozzetta C, Parente V, Fortuni S, Straino S, Sampaolesi M, Di Padova M, Illi B, Gallinari P, Steinkühler C, Capogrossi MC, Sartorelli V, Bottinelli R, Gaetano C, Puri PL (2006) Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med 12:1147–1150PubMedCrossRefGoogle Scholar
  41. Molkentin JD, Olson EN (1996) Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors. Proc Natl Acad Sci USA 93:9366–9373PubMedCrossRefGoogle Scholar
  42. Molkentin JD, Black BL, Martin JF, Olson EN (1995) Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell 83:1125–1136PubMedCrossRefGoogle Scholar
  43. Nabeshima Y, Hanaoka K, Hayasaka M, Esumi E, Li S, Nonaka I, Nabeshima Y (1993) Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364:532–535PubMedCrossRefGoogle Scholar
  44. North BJ, Verdin E (2004) Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol 5:224PubMedCrossRefGoogle Scholar
  45. Olson EN, Arnold HH, Rigby PWJ, Wold BJ (1996) Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4. Cell 85:1–4PubMedCrossRefGoogle Scholar
  46. Ordahl CP, Le Douarin NM (1992) Two myogenic lineages within the developing somite. Development 114:339–353PubMedGoogle Scholar
  47. Pownall ME, Gustafsson MK, Emerson CP Jr (2002) Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos. Annu Rev Cell Dev Biol 18:747–783PubMedCrossRefGoogle Scholar
  48. Puri PL, Sartorelli V, Yang XJ, Hamamori Y, Ogryzko VV, Howard BH, Kedes L, Wang JY, Graessmann A, Nakatani Y, Levrero M (1997) Differential roles of p300 and PCAF acetyltransferases in muscle differentiation. Mol Cell 1:35–45PubMedCrossRefGoogle Scholar
  49. Puri PL, Iezzi S, Stiegler P, Chen TT, Schiltz RL, Muscat GE, Giordano A, Kedes L, Wang JY, Sartorelli V (2001) Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis. Mol Cell 8:885–897PubMedCrossRefGoogle Scholar
  50. Rampalli S, Li L, Mak E, Ge K, Brand M, Tapscott SJ, Dilworth FJ (2007) p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nat Struct Mol Biol 14:1150–1156PubMedCrossRefGoogle Scholar
  51. Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406:593–599PubMedCrossRefGoogle Scholar
  52. Relaix F, Rocancourt D, Mansouri A, Buckingham M (2005) A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature 435:948–953PubMedCrossRefGoogle Scholar
  53. Relaix F, Montarras D, Zaffran S, Gayraud-Morel B, Rocancourt D, Tajbakhsh S, Mansouri A, Cumano A, Buckingham M (2006) Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells. J Cell Biol 172:91–102PubMedCrossRefGoogle Scholar
  54. Rudnicki MA, Braun T, Hinuma S, Jaenisch R (1992) Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development. Cell 71:383–390PubMedCrossRefGoogle Scholar
  55. Rudnicki MA, Schnegelsberg PN, Stead RH, Braun T, Arnold HH, Jaenisch R (1993) MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75:1351–1359PubMedCrossRefGoogle Scholar
  56. Sartorelli V, Puri PL, Hamamori Y, Ogryzko V, Chung G, Nakatani Y, Wang JY, Kedes L (1999) Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. Mol Cell 4:725–734PubMedCrossRefGoogle Scholar
  57. Sebastian S, Sreenivas P, Sambasivan R, Cheedipudi S, Kandalla P, Pavlath GK, Dhawan J (2009) MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation. Proc Natl Acad Sci USA 106:4719–4724PubMedCrossRefGoogle Scholar
  58. Simone C, Forcales SV, Hill DA, Imbalzano AN, Latella L, Puri PL (2004) p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat Genet 36:738–743PubMedCrossRefGoogle Scholar
  59. Spicer DB, Rhee J, Cheung WL, Lassar AB (1996) Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein twist. Science 272:1476–1480PubMedCrossRefGoogle Scholar
  60. Tajbakhsh S, Cossu G (1997) Establishing myogenic identity during somitogenesis. Curr Opin Genet Dev 7:634–641PubMedCrossRefGoogle Scholar
  61. Venuti JM, Morris JH, Vivian JL, Olson EN, Klein WH (1995) Myogenin is required for late but not early aspects of myogenesis during mouse development. J Cell Biol 128:563–576PubMedCrossRefGoogle Scholar
  62. Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA, Beauchamp JR (2004) Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J Cell Biol 166:347–357PubMedCrossRefGoogle Scholar
  63. Zhang CL, McKinsey TA, Olson EN (2002) Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Mol Cell Biol 22:7302–7312PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Narendra Bharathy
    • 1
  • Belinda Mei Tze Ling
    • 1
  • Reshma Taneja
    • 1
    • 2
    Email author
  1. 1.Department of Physiology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.NUS Graduate School of Integrative Sciences and EngineeringSingaporeSingapore

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