Runx1 Transcription Factor Is Required for Myoblasts Proliferation during Muscle Regeneration

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In response to muscle injury, the muscle initiates a repair process that calls for the proliferation of muscle stem cells, which differentiate and fuse to create the myofibers that regenerate the tissue. Maintaining the balance between myoblast proliferation and differentiation is crucial for proper regeneration, with disruption leading to impaired regeneration characteristic of muscle-wasting diseases. Our study highlights the important role the Runx1 transcription factor plays in muscle regeneration and in regulating the balance between muscle stem cell proliferation and differentiation. While not expressed in healthy muscle tissue, Runx1 level significantly increases in response to various types of muscle damage. This aligns with our finding that mice lacking Runx1 in their muscles suffer from impaired muscle regeneration. Their muscles contained a significantly low number of regenerating myofibers, which were also relatively smaller in size, resulting in loss of muscle mass and motor capabilities. Our results indicate that Runx1 regulates muscle regeneration by preventing premature differentiation of proliferating myoblasts, thereby facilitating the buildup of the myoblast pool required for proper regeneration. Through genome-wide gene-expression analysis we identify a set of Runx1-regulated genes responsible for muscle regeneration thereby implicating Runx1 in the pathology of muscle wasting diseases such as Duchenne muscular dystrophy.

Vyšlo v časopise: Runx1 Transcription Factor Is Required for Myoblasts Proliferation during Muscle Regeneration. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005457
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005457

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Zdroje

1. Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS (2005) Robbins and Cotran pathologic basis of disease. Philadelphia: Elsevier Saunders. xv, 1525 p. p.

2. Zammit PS, Partridge TA, Yablonka-Reuveni Z (2006) The skeletal muscle satellite cell: the stem cell that came in from the cold. J Histochem Cytochem 54 : 1177–1191. 16899758

3. Braun T, Gautel M (2011) Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. Nat Rev Mol Cell Biol 12 : 349–361. doi: 10.1038/nrm3118 21602905

4. Swiers G, de Bruijn M, Speck NA (2010) Hematopoietic stem cell emergence in the conceptus and the role of Runx1. Int J Dev Biol 54 : 1151–1163. doi: 10.1387/ijdb.103106gs 20711992

5. Levanon D, Brenner O., Negreanu V., Bettoun D., Woolf E., Eilam R., Lotem J., Gat U., Otto F., Speck N., Groner Y. (2001) Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis. Mech Dev 109, 109 : 413–417.

6. Simeone A, Daga A., Calabi F. (1995) Expression of runt in the mouse embryo. Dev Dyn 203 : 61–70. 7647375

7. Zhu X, Yeadon JE, Burden SJ (1994) AML1 is expressed in skeletal muscle and is regulated by innervation. Mol Cell Biol 14 : 8051–8057. 7969143

8. Porter JD, Merriam AP, Leahy P, Gong B, Khanna S (2003) Dissection of temporal gene expression signatures of affected and spared muscle groups in dystrophin-deficient (mdx) mice. Hum Mol Genet 12 : 1813–1821. 12874102

9. Gonzalez de Aguilar JL, Niederhauser-Wiederkehr C, Halter B, De Tapia M, Di Scala F, et al. (2008) Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Physiol Genomics 32 : 207–218. 18000159

10. Bakay M, Wang Z, Melcon G, Schiltz L, Xuan J, et al. (2006) Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain 129 : 996–1013. 16478798

11. Zhao P, Iezzi S, Carver E, Dressman D, Gridley T, et al. (2002) Slug is a novel downstream target of MyoD. Temporal profiling in muscle regeneration. J Biol Chem 277 : 30091–30101. 12023284

12. Cao Y, Yao Z, Sarkar D, Lawrence M, Sanchez GJ, et al. (2010) Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell 18 : 662–674. doi: 10.1016/j.devcel.2010.02.014 20412780

13. Blum R, Vethantham V, Bowman C, Rudnicki M, Dynlacht BD (2012) Genome-wide identification of enhancers in skeletal muscle: the role of MyoD1. Genes Dev 26 : 2763–2779. doi: 10.1101/gad.200113.112 23249738

14. Philipot O, Joliot V, Ait-Mohamed O, Pellentz C, Robin P, et al. (2010) The core binding factor CBF negatively regulates skeletal muscle terminal differentiation. PLoS One 5: e9425. doi: 10.1371/journal.pone.0009425 20195544

15. Macquarrie KL, Yao Z, Young JM, Cao Y, Tapscott SJ (2012) miR-206 integrates multiple components of differentiation pathways to control the transition from growth to differentiation in rhabdomyosarcoma cells. Skelet Muscle 2 : 7. doi: 10.1186/2044-5040-2-7 22541669

16. Growney JD, Shigematsu H, Li Z, Lee BH, Adelsperger J, et al. (2005) Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106 : 494–504. 15784726

17. Tallquist MD, Weismann KE, Hellstrom M, Soriano P (2000) Early myotome specification regulates PDGFA expression and axial skeleton development. Development 127 : 5059–5070. 11060232

18. Emery AE (2002) The muscular dystrophies. Lancet 359 : 687–695. 11879882

19. Partridge TA (2013) The mdx mouse model as a surrogate for Duchenne muscular dystrophy. FEBS J 280 : 4177–4186. doi: 10.1111/febs.12267 23551987

20. Muntoni F, Mateddu A, Marchei F, Clerk A, Serra G (1993) Muscular weakness in the mdx mouse. J Neurol Sci 120 : 71–77. 8289081

21. Wang X, Blagden C, Fan J, Nowak SJ, Taniuchi I, et al. (2005) Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle. Genes Dev 19 : 1715–1722. 16024660

22. Pencovich N, Jaschek R, Tanay A, Groner Y (2010) Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models. Blood 117: e1–14. doi: 10.1182/blood-2010-07-295113 20959602

23. Lichtinger M, Ingram R, Hannah R, Muller D, Clarke D, et al. (2012) RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis. EMBO J 31 : 4318–4333. doi: 10.1038/emboj.2012.275 23064151

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

25. Alli NS, Yang EC, Miyake T, Aziz A, Collins-Hooper H, et al. (2013) Signal-dependent fra-2 regulation in skeletal muscle reserve and satellite cells. Cell Death Dis 4: e692. doi: 10.1038/cddis.2013.221 23807221

26. Bengal E, Ransone L, Scharfmann R, Dwarki VJ, Tapscott SJ, et al. (1992) Functional antagonism between c-Jun and MyoD proteins: a direct physical association. Cell 68 : 507–519. 1310896

27. Thinakaran G, Ojala J, Bag J (1993) Expression of c-jun/AP-1 during myogenic differentiation in mouse C2C12 myoblasts. FEBS Lett 319 : 271–276. 8458421

28. Bulger M, Groudine M (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144 : 327–339. doi: 10.1016/j.cell.2011.01.024 21295696

29. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10 : 1213–1218. doi: 10.1038/nmeth.2688 24097267

30. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, et al. (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A 107 : 21931–21936. doi: 10.1073/pnas.1016071107 21106759

31. Rada-Iglesias A, Bajpai R, Swigut T, Brugmann SA, Flynn RA, et al. (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470 : 279–283. doi: 10.1038/nature09692 21160473

32. McIntosh LM, Anderson JE (1995) Hypothyroidism prolongs and increases mdx muscle precursor proliferation and delays myotube formation in normal and dystrophic limb muscle. Biochem Cell Biol 73 : 181–190. 7576492

33. Perie S, Mamchaoui K, Mouly V, Blot S, Bouazza B, et al. (2006) Premature proliferative arrest of cricopharyngeal myoblasts in oculo-pharyngeal muscular dystrophy: Therapeutic perspectives of autologous myoblast transplantation. Neuromuscul Disord 16 : 770–781. 17005403

34. Zhang L, Wang XH, Wang H, Du J, Mitch WE (2010) Satellite cell dysfunction and impaired IGF-1 signaling cause CKD-induced muscle atrophy. J Am Soc Nephrol 21 : 419–427. doi: 10.1681/ASN.2009060571 20056750

35. Krause MP, Moradi J, Coleman SK, D'Souza DM, Liu C, et al. (2013) A novel GFP reporter mouse reveals Mustn1 expression in adult regenerating skeletal muscle, activated satellite cells and differentiating myoblasts. Acta Physiol (Oxf) 208 : 180–190.

36. Liu C, Gersch RP, Hawke TJ, Hadjiargyrou M (2010) Silencing of Mustn1 inhibits myogenic fusion and differentiation. Am J Physiol Cell Physiol 298: C1100–1108. doi: 10.1152/ajpcell.00553.2009 20130207

37. Buas MF, Kadesch T (2010) Regulation of skeletal myogenesis by Notch. Exp Cell Res 316 : 3028–3033. doi: 10.1016/j.yexcr.2010.05.002 20452344

38. Laborda J, Sausville EA, Hoffman T, Notario V (1993) dlk, a putative mammalian homeotic gene differentially expressed in small cell lung carcinoma and neuroendocrine tumor cell line. J Biol Chem 268 : 3817–3820. 8095043

39. Shin S, Choi YM, Suh Y, Lee K (2014) Delta-like 1 homolog (DLK1) inhibits proliferation and myotube formation of avian QM7 myoblasts. Comp Biochem Physiol B Biochem Mol Biol 179C: 37–43.

40. Shin S, Suh Y, Zerby HN, Lee K (2014) Membrane-bound delta-like 1 homolog (Dlk1) promotes while soluble Dlk1 inhibits myogenesis in C2C12 cells. FEBS Lett 588 : 1100–1108. doi: 10.1016/j.febslet.2014.02.027 24582655

41. Waddell JN, Zhang P, Wen Y, Gupta SK, Yevtodiyenko A, et al. (2010) Dlk1 is necessary for proper skeletal muscle development and regeneration. PLoS One 5: e15055. doi: 10.1371/journal.pone.0015055 21124733

42. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, et al. (2004) The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14 : 395–403. 15125842

43. Duan C, Ren H, Gao S (2010) Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation. Gen Comp Endocrinol 167 : 344–351. doi: 10.1016/j.ygcen.2010.04.009 20403355

44. Czifra G, Toth IB, Marincsak R, Juhasz I, Kovacs I, et al. (2006) Insulin-like growth factor-I-coupled mitogenic signaling in primary cultured human skeletal muscle cells and in C2C12 myoblasts. A central role of protein kinase Cdelta. Cell Signal 18 : 1461–1472. 16403461

45. di Giacomo V, Rapino M, Sancilio S, Patruno A, Zara S, et al. (2010) PKC-delta signalling pathway is involved in H9c2 cells differentiation. Differentiation 80 : 204–212. doi: 10.1016/j.diff.2010.06.002 20817341

46. McPherron AC, Lawler AM, Lee SJ (1997) Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387 : 83–90. 9139826

47. Thomas M, Langley B, Berry C, Sharma M, Kirk S, et al. (2000) Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem 275 : 40235–40243. 10976104

48. McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R (2003) Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol 162 : 1135–1147. 12963705

49. McCroskery S, Thomas M, Platt L, Hennebry A, Nishimura T, et al. (2005) Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice. J Cell Sci 118 : 3531–3541. 16079293

50. Wagner KR, McPherron AC, Winik N, Lee SJ (2002) Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann Neurol 52 : 832–836. 12447939

51. Hoi CS, Lee SE, Lu SY, McDermitt DJ, Osorio KM, et al. (2010) Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol Cell Biol 30 : 2518–2536. doi: 10.1128/MCB.01308-09 20308320

52. Kim W, Barron DA, San Martin R, Chan KS, Tran LL, et al. (2014) RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc Natl Acad Sci U S A 111 : 16389–16394. doi: 10.1073/pnas.1407097111 25313057

53. MacQuarrie KL, Yao Z, Fong AP, Diede SJ, Rudzinski ER, et al. (2013) Comparison of genome-wide binding of MyoD in normal human myogenic cells and rhabdomyosarcomas identifies regional and local suppression of promyogenic transcription factors. Mol Cell Biol 33 : 773–784. doi: 10.1128/MCB.00916-12 23230269

54. Blum R (2014) Activation of Muscle Enhancers by MyoD and epigenetic modifiers. J Cell Biochem.

55. Pencovich N, Jaschek R, Dicken J, Amit A, Lotem J, et al. (2013) Cell-autonomous function of Runx1 transcriptionally regulates mouse megakaryocytic maturation. PLoS One 8: e64248. doi: 10.1371/journal.pone.0064248 23717578

56. Im WB, Phelps SF, Copen EH, Adams EG, Slightom JL, et al. (1996) Differential expression of dystrophin isoforms in strains of mdx mice with different mutations. Hum Mol Genet 5 : 1149–1153. 8842734

57. Gruenbaum-Cohen Y, Harel I, Umansky KB, Tzahor E, Snapper SB, et al. (2012) The actin regulator N-WASp is required for muscle-cell fusion in mice. Proc Natl Acad Sci U S A 109 : 11211–11216. doi: 10.1073/pnas.1116065109 22736793

58. Luo J, Deng ZL, Luo X, Tang N, Song WX, et al. (2007) A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc 2 : 1236–1247. 17546019

59. Schreiber E, Matthias P, Muller MM, Schaffner W (1989) Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res 17 : 6419. 2771659

60. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP (2003). Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics, 4(2):249–64. 12925520

61. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, et al. (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14: R36. doi: 10.1186/gb-2013-14-4-r36 23618408

62. Anders S, Pyl PT, Huber W (2014) HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics.

63. Love MI, Huber W, and Anders S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. bioRxiv, doi: 10.1101/002832,2014

64. Langmead B, Trapnell C, Pop M, Salzberg SL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10: R25. doi: 10.1186/gb-2009-10-3-r25 19261174

65. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, et al. (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9: R137. doi: 10.1186/gb-2008-9-9-r137 18798982