Journal
ELIFE
Volume 7, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.31023
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Funding
- National Cancer Institute [T32CA009657]
- National Human Genome Research Institute [T32HG00035, T32HG000035]
- National Institute of General Medical Sciences [T32GM007270]
- FSH Society [FSHS-22014-01]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [T32HD007183]
- National Institute of Neurological Disorders and Stroke [P01NS069539]
- Prinses Beatrix Spierfonds [W.OP14-01]
- Spieren voor Spieren
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR066248, R01AR045203]
- Friends of FSH Research
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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.
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