Intrinsic Epigenetic Regulation of the D4Z4 Macrosatellite Repeat in a Transgenic Mouse Model for FSHD

English version České info

Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat. Unaffected individuals generally have more than 10 repeats arrayed in the subtelomeric region of chromosome 4, whereas the most common form of FSHD (FSHD1) is caused by a contraction of the array to fewer than 10 repeats, associated with decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle. We have generated transgenic mice carrying D4Z4 arrays from an FSHD1 allele and from a control allele. These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD–specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation. In addition we show that DUX4 is able to activate similar functional gene groups in mouse muscle cells as it does in human muscle cells. These transgenic mice therefore represent a valuable animal model for FSHD and will be a useful resource to study the molecular mechanisms underlying FSHD and to test new therapeutic intervention strategies.

Vyšlo v časopise: Intrinsic Epigenetic Regulation of the D4Z4 Macrosatellite Repeat in a Transgenic Mouse Model for FSHD. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003415
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003415

Souhrn

Zdroje

1. ClappJ, MitchellLM, BollandDJ, FantesJ, CorcoranAE, et al. (2007) Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 81: 264–279 S0002-9297(07)61193-8 [pii];10.1086/519311 [doi].

2. DixitM, AnsseauE, TassinA, WinokurS, ShiR, et al. (2007) DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc Natl Acad Sci U S A 104: 18157–18162.

3. GabrielsJ, BeckersMC, DingH, De VrieseA, PlaisanceS, et al. (1999) Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236: 25–32.

4. LyleR, WrightTJ, ClarkLN, HewittJE (1995) The FSHD-associated repeat, D4Z4, is a member of a dispersed family of homeobox-containing repeats, subsets of which are clustered on the short arms of the acrocentric chromosomes. Genomics 28: 389–397.

5. GengLN, YaoZ, SniderL, FongAP, CechJN, et al. (2012) DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22: 38–51 S1534-5807(11)00523-5 [pii];10.1016/j.devcel.2011.11.013 [doi].

6. SniderL, GengLN, LemmersRJ, KybaM, WareCB, et al. (2010) Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6: e1001181 doi:10.1371/journal.pgen.1001181.

7. TawilR, Van Der MaarelSrM (2006) Facioscapulohumeral muscular dystrophy. Muscle & Nerve 34: 1–15.

8. de GreefJC, LemmersRJ, van EngelenBG, SacconiS, VenanceSL, et al. (2009) Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat 30: 1449–1459 10.1002/humu.21091 [doi].

9. JonesTI, ChenJC, RahimovF, HommaS, ArashiroP, et al. (2012) Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum Mol Genet 21: 4419–4430 dds284 [pii];10.1093/hmg/dds284 [doi].

10. LemmersRJ, TawilR, PetekLM, BalogJ, BlockGJ, S, etal (2012) Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44: 1370–1374 ng.2454 [pii];10.1038/ng.2454 [doi].

11. van DeutekomJC, WijmengaC, van TienhovenEA, GruterAM, HewittJE, et al. (1993) FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 2: 2037–2042.

12. van OverveldPG, LemmersRJ, SandkuijlLA, EnthovenL, WinokurST, et al. (2003) Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet 35: 315–317.

13. WijmengaC, HewittJE, SandkuijlLA, ClarkLN, WrightTJ, et al. (1992) Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 2: 26–30.

14. TassinA, Laoudj-ChenivesseD, VanderplanckC, BarroM, CharronS, et al. (2012) DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy? J Cell Mol Med 10.1111/j.1582-4934.2012.01647.x [doi].

15. LemmersRJ, WohlgemuthM, van der GaagKJ, van der VlietPJ, van TeijlingenCM, et al. (2007) Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet 81: 884–894.

16. LemmersRJ, van der VlietPJ, KloosterR, SacconiS, CamanoP, et al. (2010) A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329: 1650–1653 science.1189044 [pii];10.1126/science.1189044 [doi].

17. van der MaarelSM, TawilR, TapscottSJ (2011) Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 17: 252–258 S1471-4914(11)00002-5 [pii];10.1016/j.molmed.2011.01.001 [doi].

18. LeidenrothA, HewittJE (2010) A family history of DUX4: phylogenetic analysis of DUXA, B, C and Duxbl reveals the ancestral DUX gene. BMC Evol Biol 10: 364 1471-2148-10-364 [pii];10.1186/1471-2148-10-364 [doi].

19. FurstDO, OsbornM, WeberK (1989) Myogenesis in the mouse embryo: differential onset of expression of myogenic proteins and the involvement of titin in myofibril assembly. J Cell Biol 109: 517–527.

20. Cusella-De AngelisMG, LyonsG, SonninoC, DeAL, VivarelliE, FarmerK, et al. (1992) MyoD, myogenin independent differentiation of primordial myoblasts in mouse somites. J Cell Biol 116: 1243–1255.

21. MessinaG, CossuG (2009) The origin of embryonic and fetal myoblasts: a role of Pax3 and Pax7. Genes Dev 23: 902–905 23/8/902 [pii];10.1101/gad.1797009 [doi].

22. BuckinghamM, BajardL, ChangT, DaubasP, HadchouelJ, et al. (2003) The formation of skeletal muscle: from somite to limb. J Anat 202: 59–68.

23. YamanakaG, GotoK, MatsumuraT, FunakoshiM, KomoriT, et al. (2001) Tongue atrophy in facioscapulohumeral muscular dystrophy. Neurology 57: 733–5.

24. SniderL, AsawachaicharnA, TylerAE, GengLN, PetekLM, et al. (2009) RNA Transcripts, miRNA-sized Fragments, and Proteins Produced from D4Z4 Units: New Candidates for the Pathophysiology of Facioscapulohumeral Dystrophy. Hum Mol Genet 18: 2414–2430.

25. de GreefJC, FrantsRR, van der MaarelSM (2008) Epigenetic mechanisms of facioscapulohumeral muscular dystrophy. Mutat Res 647: 94–102.

26. van OverveldPG, EnthovenL, RicciE, RossiM, FelicettiL, J, etal (2005) Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann Neurol 58: 569–576.

27. ZengW, de GreefJC, ChienR, KongX, GregsonHC, WinokurST, et al. (2009) Specific loss of histone H3 lysine 9 trimethylation and HP1g/cohesin binding at D4Z4 repeats in facioscapulohumeral dystrophy (FSHD). PLoS Genet 7: e1000559 doi:10.1371/journal.pgen.1000559.

28. BalogJ, ThijssenPE, de GreefJC, ShahB, van EngelenBG, et al. (2012) Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. Epigenetics 7: 579–584 20001 [pii];10.4161/epi.20001 [doi].

29. HagiwaraK, KikuchiT, EndoY, Huqun, UsuiK, et al. (2003) Mouse SWAM1 and SWAM2 are antibacterial proteins composed of a single whey acidic protein motif. J Immunol 170: 1973–1979.

30. StatlandJM, TawilR (2011) Facioscapulohumeral muscular dystrophy: molecular pathological advances and future directions. Curr Opin Neurol 24: 423–428 10.1097/WCO.0b013e32834959af [doi].

31. TurkR, SterrenburgE, van der WeesCG, de MeijerEJ, de MenezesRX, et al. (2006) Common pathological mechanisms in mouse models for muscular dystrophies. FASEB J 20: 127–129.

32. BosnakovskiD, XuZ, GangEJ, GalindoCL, LiuM, et al. (2008) An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. Embo J 27: 2766–2779.

33. KowaljowV, MarcowyczA, AnsseauE, CondeCB, SauvageS, et al. (2007) The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord 17: 611–623.

34. GabelliniD, GreenM, TuplerR (2002) Inappropriate Gene Activation in FSHD. A Repressor Complex Binds a Chromosomal Repeat Deleted in Dystrophic Muscle. Cell 110: 339–248.

35. van DeutekomJCT, LemmersRJLF, GrewalPK, van GeelM, RombergS, et al. (1996) Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. Hum Mol Genet 5: 581–590.

36. GabelliniD, D'AntonaG, MoggioM, PrelleA, ZeccaC, et al. (2005) Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature

37. WuebblesRD, LongSW, HanelML, JonesPL (2010) Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol 3: 386–400.

38. WuebblesRD, HanelML, JonesPL (2009) FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy. Dis Model Mech 2: 267–274 dmm.002261 [pii];10.1242/dmm.002261 [doi].

39. JiangG, YangF, van OverveldPG, VedanarayananV, van derMS, et al. (2003) Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum Mol Genet 12: 2909–2921.

40. KloosterR, StraasheijmK, ShahB, SowdenJ, FrantsR, et al. (2009) Comprehensive expression analysis of FSHD candidate genes at the mRNA and protein level. Eur J Hum Genet 17: 1615–1624 ejhg200962 [pii];10.1038/ejhg.2009.62 [doi].

41. OsborneRJ, WelleS, VenanceSL, ThorntonCA, TawilR (2007) Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy. Neurology 68: 569–577 01.wnl.0000251269.31442.d9 [pii];10.1212/01.wnl.0000251269.31442.d9 [doi].

42. HommaS, ChenJC, RahimovF, BeermannML, HangerK, et al. (2012) A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function. Eur J Hum Genet 20: 404–410 ejhg2011213 [pii];10.1038/ejhg.2011.213 [doi].

43. BosnakovskiD, DaughtersRS, XuZ, SlackJM, KybaM (2009) Biphasic myopathic phenotype of mouse DUX, an ORF within conserved FSHD-related repeats. PLoS ONE 4: e7003 doi:10.1371/journal.pone.0007003.

44. WallaceLM, GarwickSE, MeiW, BelayewA, CoppeeF, et al. (2011) DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann Neurol 69: 540–552 10.1002/ana.22275 [doi].

45. MitsuhashiH, MitsuhashiS, Lynn-JonesT, KawaharaG, KunkelLM (2012) Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Hum Mol Genet dds467 [pii];10.1093/hmg/dds467 [doi].

46. WallaceLM, LiuJ, DomireJS, Garwick-CoppensSE, GuckesSM, et al. (2012) RNA Interference Inhibits DUX4-induced Muscle Toxicity In Vivo: Implications for a Targeted FSHD Therapy. Mol Ther 20: 1417–1423 mt201268 [pii];10.1038/mt.2012.68 [doi].

47. de GreefJC, WohlgemuthM, ChanOA, HanssonKB, SmeetsD, et al. (2007) Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD. Neurology 69: 1018–1026.

48. CabiancaDS, CasaV, BodegaB, XynosA, GinelliE, et al. (2012) A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell 149: 819–831 S0092-8674(12)00463-1 [pii];10.1016/j.cell.2012.03.035 [doi].

49. FitzsimonsRB (2011) Retinal vascular disease and the pathogenesis of facioscapulohumeral muscular dystrophy. A signalling message from Wnt? Neuromuscul Disord 21: 263–271 S0960-8966(11)00027-7 [pii];10.1016/j.nmd.2011.02.002 [doi].

50. van DeutekomJC, WijmengaC, van TienhovenEA, GruterAM, HewittJE, P, etal (1993) FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 2: 2037–2042.

51. van GeelM, HeatherLJ, LyleR, HewittJE, FrantsRR, et al. (1999) The FSHD region on human chromosome 4q35 contains potential coding regions among pseudogenes and a high density of repeat elements. Genomics 61: 55–65.

52. SzuhaiK, TankeHJ (2006) COBRA: combined binary ratio labeling of nucleic-acid probes for multi-color fluorescence in situ hybridization karyotyping. Nat Protoc 1: 264–275 nprot.2006.41 [pii];10.1038/nprot.2006.41 [doi].

53. WhiteSJ, BreuningMH, den DunnenJT (2004) Detecting copy number changes in genomic DNA: MAPH and MLPA. Methods Cell Biol 75: 751–768.

54. SchoutenJP, McElgunnCJ, WaaijerR, ZwijnenburgD, DiepvensF, et al. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30: e57.

55. CollinsCA, ZammitPS (2009) Isolation and grafting of single muscle fibres. Methods Mol Biol 482: 319–330 10.1007/978-1-59745-060-7_20 [doi].

56. GengLN, TylerAE, TapscottSJ (2011) Immunodetection of human double homeobox 4. Hybridoma (Larchmt) 30: 125–130 10.1089/hyb.2010.0094 [doi].

57. LiLC, DahiyaR (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18: 1427–1431.

58. LewinJ, SchmittAO, AdorjanP, HildmannT, PiepenbrockC (2004) Quantitative DNA methylation analysis based on four-dye trace data from direct sequencing of PCR amplificates. Bioinformatics 20: 3005–3012 10.1093/bioinformatics/bth346 [doi];bth346 [pii].

59. NelsonJD, DenisenkoO, BomsztykK (2006) Protocol for the fast chromatin immunoprecipitation (ChIP) method. Nat Protoc 1: 179–185 nprot.2006.27 [pii];10.1038/nprot.2006.27 [doi].

60. DuP, KibbeWA, LinSM (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24: 1547–1548 btn224 [pii];10.1093/bioinformatics/btn224 [doi].

61. WettenhallJM, SmythGK (2004) limmaGUI: a graphical user interface for linear modeling of microarray data. Bioinformatics 20: 3705–3706 10.1093/bioinformatics/bth449 [doi];bth449 [pii].

62. BenjaminiY, HochbergY (1995) Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological) 57: 289–300.

63. FongAP, YaoZ, ZhongJW, CaoY, RuzzoWL, et al. (2012) Genetic and epigenetic determinants of neurogenesis and myogenesis. Dev Cell 22: 721–735 S1534-5807(12)00049-4 [pii];10.1016/j.devcel.2012.01.015 [doi].

64. CaoY, YaoZ, SarkarD, LawrenceM, SanchezGJ, et al. (2010) Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell 18: 662–674 S1534-5807(10)00112-7 [pii];10.1016/j.devcel.2010.02.014 [doi].

65. PaliiCG, Perez-IratxetaC, YaoZ, CaoY, DaiF, et al. (2011) Differential genomic targeting of the transcription factor TAL1 in alternate haematopoietic lineages. EMBO J 30: 494–509 emboj2010342 [pii];10.1038/emboj.2010.342 [doi].