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The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy

Authors
  • Himeda, Charis L.
  • Jones, Peter L.
Type
Published Article
Journal
Annual Review of Genomics and Human Genetics
Publisher
Annual Reviews
Publication Date
Aug 31, 2019
Volume
20
Pages
265–291
Identifiers
DOI: 10.1146/annurev-genom-083118-014933
Source
Annual Reviews
Keywords
License
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Abstract

Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, provides a powerful model of the complex interplay between genetic and epigenetic mechanisms of chromatin regulation. FSHD is caused by dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, aberrant expression of the DUX4 gene in skeletal muscle. DUX4 is a pioneer transcription factor that activates a program of gene expression during early human development, after which its expression is silenced in most somatic cells. When misexpressed in FSHD skeletal muscle, the DUX4 program leads to accumulated muscle pathology. Epigenetic regulators of the disease locus represent particularly attractive therapeutic targets for FSHD, as many are not global modifiers of the genome, and altering their expression or activity should allow correction of the underlying defect.

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