NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins.
Amy E CampbellSean C ShadleSujatha JagannathanJong-Won LimRebecca ResnickRabi TawilSilvère M van der MaarelStephen J TapscottPublished in: 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.
Keyphrases
- skeletal muscle
- transcription factor
- induced apoptosis
- poor prognosis
- gene expression
- cell cycle arrest
- crispr cas
- muscular dystrophy
- dna damage
- high glucose
- genome wide
- endothelial cells
- endoplasmic reticulum stress
- oxidative stress
- insulin resistance
- adipose tissue
- type diabetes
- cell proliferation
- binding protein
- cell death
- metabolic syndrome
- genome editing
- long non coding rna
- dna binding
- pi k akt