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

Elife. 2018 Mar 13;7:e31023. doi: 10.7554/eLife.31023.


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.

Keywords: CAF-1; D4Z4; DUX4; MBD3L; NuRD; chromosomes; facioscapulohumeral dystrophy; genes; human.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / genetics
  • Chromatin Assembly Factor-1 / genetics
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Developmental
  • Gene Silencing
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / genetics*
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / chemistry
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Muscle Fibers, Skeletal / chemistry
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophy, Facioscapulohumeral / genetics*
  • Muscular Dystrophy, Facioscapulohumeral / physiopathology
  • Nucleosomes / chemistry
  • Nucleosomes / genetics


  • CHAF1A protein, human
  • Chromatin
  • Chromatin Assembly Factor-1
  • DUX4L1 protein, human
  • Homeodomain Proteins
  • Nucleosomes
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex