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.


The nuclear envelope protein lamin A is encoded by the lamin A/C (LMNA) gene, which can contain missense mutations that cause Emery-Dreifuss muscular dystrophy (EDMD) (p.R453W). We fused mutated forms of the lamin A protein to bacterial DNA adenine methyltransferase (Dam) to define euchromatic-heterochromatin (epigenomic) transitions at the nuclear envelope during myogenesis (using DamID-seq). Lamin A missense mutations disrupted appropriate formation of lamin A–associated heterochromatin domains in an allele-specific manner—findings that were confirmed by chromatin immunoprecipitation–DNA sequencing (ChIP-seq) in murine H2K cells and DNA methylation studies in fibroblasts from muscular dystrophy patient who carried a distinct LMNA mutation (p.H222P). Observed perturbations of the epigenomic transitions included exit from pluripotency and cell cycle programs [euchromatin (open, transcribed) to heterochromatin (closed, silent)], as well as induction of myogenic loci (heterochromatin to euchromatin). In muscle biopsies from patients with either a gain- or change-of-function LMNA gene mutation or a loss-of-function mutation in the emerin gene, both of which cause EDMD, we observed inappropriate loss of heterochromatin formation at the Sox2 pluripotency locus, which was associated with persistent mRNA expression of Sox2. Overexpression of Sox2 inhibited myogenic differentiation in human immortalized myoblasts. Our findings suggest that nuclear envelopathies are disorders of developmental epigenetic programming that result from altered formation of lamina-associated domains.

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