snRNA-seq analysis in multinucleated myogenic FSHD cells identifies heterogeneous FSHD transcriptome signatures associated with embryonic-like program activation and oxidative stress-induced apoptosis.

The sporadic nature of DUX4 expression in FSHD muscle challenges comparative transcriptome analyses between FSHD and control samples. A variety of DUX4 and FSHD-associated transcriptional changes have been identified, but bulk RNA-seq strategies prohibit comprehensive analysis of their spatiotemporal relation, interdependence and role in the disease process. In this study, we used single-nucleus RNA-sequencing of nuclei isolated from patient- and control-derived multinucleated primary myotubes to investigate the cellular heterogeneity in FSHD.

SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic derepression of the 4q-linked D4Z4 macrosatellite repeat resulting in inappropriate expression of the D4Z4 repeat-encoded DUX4 gene in skeletal muscle. In 5% of FSHD cases, D4Z4 chromatin relaxation is due to germline mutations in one of the chromatin modifiers SMCHD1, DNMT3B or LRIF1. The mechanism of SMCHD1- and LRIF1-mediated D4Z4 repression is not clear.

A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.

Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor, which is mutated in > 95% of Facioscapulohumeral dystrophy (FSHD) type 2 cases. In FSHD2, SMCHD1 mutations ultimately result in the presence of the cleavage stage transcription factor DUX4 in muscle cells due to a failure in epigenetic repression of the D4Z4 macrosatellite repeat on chromosome 4q, which contains the DUX4 locus. While binding of SMCHD1 to D4Z4 and its necessity to maintain a repressive D4Z4 chromatin structure in somatic cells are well documented, it is unclear how SMCHD1 is recruited to D4Z4, and how it exerts its repressive properties on chromatin.

Intronic variants in FSHD: testing the potential for CRISPR-Cas9 genome editing.

Background: Facioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of the retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional de-repression of in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants in .