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NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins.

eLife | 2018

The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins. These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells. Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. Together, these findings identify NuRD and CAF-1 as mediators of DUX4 chromatin repression and suggest a mechanism for the amplification of DUX4 expression in FSHD muscle cells.

Pubmed ID: 29533181 RIS Download

Research resources used in this publication

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: T32CA009657
  • Agency: NINDS NIH HHS, United States
    Id: P01 NS069539
  • Agency: NIGMS NIH HHS, United States
    Id: T32GM007270
  • Agency: NIAMS NIH HHS, United States
    Id: R01AR066248
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007270
  • Agency: NINDS NIH HHS, United States
    Id: P01NS069539
  • Agency: NICHD NIH HHS, United States
    Id: T32HD007183
  • Agency: NIAMS NIH HHS, United States
    Id: R01 AR045203
  • Agency: NHGRI NIH HHS, United States
    Id: T32HG000035
  • Agency: NCI NIH HHS, United States
    Id: T32 CA009657
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007266
  • Agency: NHGRI NIH HHS, United States
    Id: T32HG00035
  • Agency: NIAMS NIH HHS, United States
    Id: R01AR045203

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