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Macrosatellite epigenetics: the two faces of DXZ4 and D4Z4

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Abstract

Almost half of the human genome consists of repetitive DNA. Understanding what role these elements have in setting up chromatin states that underlie gene and chromosome function in complex genomes is paramount. The function of some types of repetitive DNA is obvious by virtue of their location, such as the alphoid arrays that define active centromeres. However, there are many other types of repetitive DNA whose evolutionary origins and current roles in genome biology remain unknown. One type of repetitive DNA that falls into this class is the macrosatellites. The relevance of these sequences to disease is clearly demonstrated by the 4q macrosatellite (D4Z4), whereupon contraction in the size of the array is associated with the onset of facioscapulohumeral muscular dystrophy. Here, I describe recent findings relating to the chromatin organization of D4Z4 and that of the X-linked macrosatellite DXZ4, highlighting the fact that these enigmatic sequences share more than a similar name.

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References

  • Boggs BA, Cheung P, Heard E, Spector DL, Chinault AC, Allis CD (2002) Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes. Nat Genet 30:73–76

    Article  PubMed  CAS  Google Scholar 

  • Cao F, Li X, Hiew S, Brady H, Liu Y, Dou Y (2009) Dicer independent small RNAs associate with telomeric heterochromatin. RNA 15:1274–1281

    Article  PubMed  CAS  Google Scholar 

  • Chadwick BP (2007) Variation in Xi chromatin organization and correlation of the H3K27me3 chromatin territories to transcribed sequences by microarray analysis. Chromosoma 116:147–157

    Article  PubMed  CAS  Google Scholar 

  • Chadwick BP (2008) DXZ4 chromatin adopts an opposing conformation to that of the surrounding chromosome and acquires a novel inactive X-specific role involving CTCF and antisense transcripts. Genome Res 18:1259–1269

    Article  PubMed  CAS  Google Scholar 

  • Chadwick BP, Willard HF (2002) Cell cycle-dependent localization of macroH2A in chromatin of the inactive X chromosome. J Cell Biol 157:1113–1123

    Article  PubMed  CAS  Google Scholar 

  • Chadwick BP, Willard HF (2003) Chromatin of the Barr body: histone and non-histone proteins associated with or excluded from the inactive X chromosome. Hum Mol Genet 12:2167–2178

    Article  PubMed  CAS  Google Scholar 

  • Chadwick BP, Willard HF (2004) Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. Proc Natl Acad Sci USA 101:17450–17455

    Article  PubMed  CAS  Google Scholar 

  • Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT (2002) CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295:345–347

    Article  PubMed  CAS  Google Scholar 

  • Chen YT, Iseli C, Venditti CA, Old LJ, Simpson AJ, Jongeneel CV (2006) Identification of a new cancer/testis gene family, CT47, among expressed multicopy genes on the human X chromosome. Genes Chromosomes Cancer 45:392–400

    Article  PubMed  CAS  Google Scholar 

  • Chung JH, Whiteley M, Felsenfeld G (1993) A 5' element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell 74:505–514

    Article  PubMed  CAS  Google Scholar 

  • Clapp J, Mitchell LM, Bolland DJ, Fantes J, Corcoran AE, Scotting PJ, Armour JA, Hewitt JE (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

    Article  PubMed  CAS  Google Scholar 

  • de Greef JC, Frants RR, van der Maarel SM (2008) Epigenetic mechanisms of facioscapulohumeral muscular dystrophy. Mutat Res 647:94–102

    PubMed  Google Scholar 

  • de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL, Frants RR, Tawil R, van der Maarel SM (2009) Common epigenetic changes of D4Z4 in contraction-dependent and contraction independent FSHD. Hum Mutat (in press)

  • de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M, Koseki H, Brockdorff N (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 7:663–676

    Article  PubMed  Google Scholar 

  • Dixit M, Ansseau E, Tassin A, Winokur S, Shi R, Qian H, Sauvage S, Matteotti C, van Acker AM, Leo O, Figlewicz D, Barro M, Laoudj-Chenivesse D, Belayew A, Coppee F, Chen YW (2007) DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc Natl Acad Sci USA 104:18157–18162

    Article  PubMed  Google Scholar 

  • Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159

    Article  PubMed  CAS  Google Scholar 

  • Filippova GN (2008) Genetics and epigenetics of the multifunctional protein CTCF. Curr Top Dev Biol 80:337–360

    Article  PubMed  CAS  Google Scholar 

  • Gabriels J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A (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

    Article  PubMed  CAS  Google Scholar 

  • Giacalone J, Friedes J, Francke U (1992) A novel GC-rich human macrosatellite VNTR in Xq24 is differentially methylated on active and inactive X chromosomes. Nat Genet 1:137–143

    Article  PubMed  CAS  Google Scholar 

  • Gjerstorff MF, Ditzel HJ (2008) An overview of the GAGE cancer/testis antigen family with the inclusion of newly identified members. Tissue Antigens 71:187–192

    Article  PubMed  CAS  Google Scholar 

  • Grewal SI, Elgin SC (2007) Transcription and RNA interference in the formation of heterochromatin. Nature 447:399–406

    Article  PubMed  CAS  Google Scholar 

  • Grewal SI, Jia S (2007) Heterochromatin revisited. Nat Rev Genet 8:35–46

    Article  PubMed  CAS  Google Scholar 

  • Hewitt JE, Lyle R, Clark LN, Valleley EM, Wright TJ, Wijmenga C, van Deutekom JC, Francis F, Sharpe PT, Hofker M et al (1994) Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet 3:1287–1295

    Article  PubMed  CAS  Google Scholar 

  • Lemmers RJ, Wohlgemuth M, Frants RR, Padberg GW, Morava E, van der Maarel SM (2004) Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy. Am J Hum Genet 75:1124–1130

    Article  PubMed  CAS  Google Scholar 

  • Lemmers RJ, Wohlgemuth M, van der Gaag KJ, van der Vliet PJ, van Teijlingen CM, de Knijff P, Padberg GW, Frants RR, van der Maarel SM (2007) Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet 81:884–894

    Article  PubMed  CAS  Google Scholar 

  • Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373

    Article  PubMed  CAS  Google Scholar 

  • Martens JH, O'Sullivan RJ, Braunschweig U, Opravil S, Radolf M, Steinlein P, Jenuwein T (2005) The profile of repeat-associated histone lysine methylation states in the mouse epigenome. Embo J 24:800–812

    Article  PubMed  CAS  Google Scholar 

  • Mukhopadhyay R, Yu W, Whitehead J, Xu J, Lezcano M, Pack S, Kanduri C, Kanduri M, Ginjala V, Vostrov A, Quitschke W, Chernukhin I, Klenova E, Lobanenkov V, Ohlsson R (2004) The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Genome Res 14:1594–1602

    Article  PubMed  CAS  Google Scholar 

  • Ohno S (1972) So much "junk" DNA in our genome. Brookhaven Symp Biol 23:366–370

    PubMed  CAS  Google Scholar 

  • Orgel LE, Crick FH (1980) Selfish DNA: the ultimate parasite. Nature 284:604–607

    Article  PubMed  CAS  Google Scholar 

  • Ottaviani A, Rival-Gervier S, Boussouar A, Foerster AM, Rondier D, Sacconi S, Desnuelle C, Gilson E, Magdinier F (2009) The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy. PLoS Genet 5:e1000394

    Article  PubMed  CAS  Google Scholar 

  • Payer B, Lee JT (2008) X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet 42:733–772

    Article  PubMed  CAS  Google Scholar 

  • Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, de la Cruz CC, Otte AP, Panning B, Zhang Y (2003) Role of histone H3 lysine 27 methylation in X inactivation. Science 300:131–135

    Article  PubMed  CAS  Google Scholar 

  • Schmid CW, Deininger PL (1975) Sequence organization of the human genome. Cell 6:345–358

    Article  PubMed  CAS  Google Scholar 

  • Silva J, Mak W, Zvetkova I, Appanah R, Nesterova TB, Webster Z, Peters AH, Jenuwein T, Otte AP, Brockdorff N (2003) Establishment of histone h3 methylation on the inactive x chromosome requires transient recruitment of eed-enx1 polycomb group complexes. Dev Cell 4:481–495

    Article  PubMed  CAS  Google Scholar 

  • Smith KP, Byron M, Clemson CM, Lawrence JB (2004) Ubiquitinated proteins including uH2A on the human and mouse inactive X chromosome: enrichment in gene rich bands. Chromosoma 113:324–335

    Article  PubMed  CAS  Google Scholar 

  • Snider L, Asawachaicharn A, Tyler AE, Geng LN, Petek LM, Maves L, Miller DG, Lemmers RJ, Winokur ST, Tawil R, van der Maarel SM, Filippova GN, Tapscott SJ (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

    Article  PubMed  CAS  Google Scholar 

  • Sullivan BA, Karpen GH (2004) Centromeric chromatin exhibits a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nat Struct Mol Biol 11:1076–1083

    Article  PubMed  CAS  Google Scholar 

  • Tawil R (2008) Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5:601–606

    Article  PubMed  CAS  Google Scholar 

  • Tsien F, Sun B, Hopkins NE, Vedanarayanan V, Figlewicz D, Winokur S, Ehrlich M (2001) Methylation of the FSHD syndrome-linked subtelomeric repeat in normal and FSHD cell cultures and tissues. Mol Genet Metab 74:322–331

    Article  PubMed  CAS  Google Scholar 

  • Tsumagari K, Qi L, Jackson K, Shao C, Lacey M, Sowden J, Tawil R, Vedanarayanan V, Ehrlich M (2008) Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers. Nucleic Acids Res 36:2196–2207

    Article  PubMed  CAS  Google Scholar 

  • Tupler R, Berardinelli A, Barbierato L, Frants R, Hewitt JE, Lanzi G, Maraschio P, Tiepolo L (1996) Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. J Med Genet 33:366–370

    Article  PubMed  CAS  Google Scholar 

  • van Deutekom JC, Wijmenga C, van Tienhoven EA, Gruter AM, Hewitt JE, Padberg GW, van Ommen GJ, Hofker MH, Frants RR (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

    Article  PubMed  Google Scholar 

  • van Deutekom JC, Bakker E, Lemmers RJ, van der Wielen MJ, Bik E, Hofker MH, Padberg GW, Frants RR (1996) Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1. Hum Mol Genet 5:1997–2003

    Article  PubMed  Google Scholar 

  • van Overveld PG, Lemmers RJ, Deidda G, Sandkuijl LA, Padberg GW, Frants RR, van der Maarel SM (2002) Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity. Hum Mol Genet 9:2879–2884

    Article  Google Scholar 

  • van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM (2003) Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet 35:315–317

    Article  PubMed  CAS  Google Scholar 

  • Warburton PE, Hasson D, Guillem F, Lescale C, Jin X, Abrusan G (2008) Analysis of the largest tandemly repeated DNA families in the human genome. BMC Genomics 9:533

    Article  PubMed  CAS  Google Scholar 

  • Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, Dauwerse HG, Gruter AM, Hofker MH, Moerer P, Williamson R et al (1992) Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 2:26–30

    Article  PubMed  CAS  Google Scholar 

  • Zeng W, Greef CG, Chen YY, Chien R, Kong X, Gregson HC, Winokur ST, Pyle A, Robertson KD, Schiesing JA, Kimonis VE, Balog J, Frants RR, Ball AR, Lock LF, Donovan PJ, van der Maarel SM, Yokomori K (2009) Specific loss of histone H3 lysine 9 trimethylation and HP1g/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy. PLoS Genetics 5:e1000559

    Article  PubMed  CAS  Google Scholar 

  • Zhang K, Mosch K, Fischle W, Grewal SI (2008) Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin. Nat Struct Mol Biol 15:381–388

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

I am very grateful to Lisa H. Chadwick for comments on the manuscript and the helpful suggestions made by anonymous reviewers. I apologize to those whose work I did not cite due to space. This work was supported by a grant from the National Institutes of Health (GM073120, B.P.C.).

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  1. Department of Biological Science, Florida State University, 3090 King Life Sciences Building, Tallahassee, FL, 32306, USA

    Brian P. Chadwick

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Correspondence to Brian P. Chadwick.

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Communicated by E.A. Nigg

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Chadwick, B.P. Macrosatellite epigenetics: the two faces of DXZ4 and D4Z4. Chromosoma 118, 675–681 (2009). https://doi.org/10.1007/s00412-009-0233-5

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