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

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

Author information

1
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
2
Molecular and Cellular Biology Program, University of Washington, Seattle, United States.
3
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
4
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
5
Medical Scientist Training Program, University of Washington, Seattle, United States.
6
Department of Neurology, University of Rochester Medical Center, Rochester, United States.
7
Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
8
Department of Neurology, University of Washington, Seattle, United States.

Abstract

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

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