Research ArticleMuscular Dystrophy

Laminopathies disrupt epigenomic developmental programs and cell fate

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Science Translational Medicine  20 Apr 2016:
Vol. 8, Issue 335, pp. 335ra58
DOI: 10.1126/scitranslmed.aad4991

Bad LADS alter muscle cell fate

The lamin A/C (LMNA) gene encodes a key structural protein (lamin) in the nuclear envelope, a double lipid bilayer membrane that separates the cytoplasm and nucleus. The nuclear lamina—a fibrillar network organized around the nuclear membrane’s inner face—performs both structural and functional roles and interacts with chromatin at a great many genomic regions—called lamina-associated domains (LADs)—which are heterochromatic (transcriptionally repressed) domains. Mutations in LMNA cause Emery-Dreifuss muscular dystrophy (EDMD). Perovanovic and colleagues now show that these mutations interfere with the building of lamin A–associated heterochromatin in an allele-specific manner.

The authors used a variety of techniques to map heterochromatin-euchromatin (transcriptionally active) transitions during the differentiation of muscle cells. They found that the EDMD mutations messed up the normal chromatin-structure (epigenomic) transitions during the differentiation of mouse cells and fibroblasts from muscular dystrophy patients who carried LMNA mutations. During muscle formation, normal heterochromatin to euchromatin transitions that take place at myogenic loci drive muscle differentiation. Muscle biopsies from patients carrying mutations that cause EDMD showed a loss of heterochromatin formation at the Sox2 pluripotency locus, which continued to be expressed and inhibited muscle cell differentiation. The new work suggests that so-called nuclear envelopathies, such as EDMD, are caused by aberrant LADS that disrupt developmental epigenetic programming.

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