Dysfunctional polycomb transcriptional repression contributes to lamin A/C–dependent muscular dystrophy
Open Access
- 1 May 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (5), 2408-2421
- https://doi.org/10.1172/jci128161
Abstract
Lamin A is a component of the inner nuclear membrane that, together with epigenetic factors, organizes the genome in higher order structures required for transcriptional control. Mutations in the Lamin A/C gene cause several diseases, belonging to the class of laminopathies, including muscular dystrophies. Nevertheless, molecular mechanisms involved in the pathogenesis of Lamin A-dependent dystrophies are still largely unknown. Polycomb group of proteins (PcG) are epigenetic repressors and Lamin A interactors, primarily involved in the maintenance of cell identity. Using a murine model of Emery-Dreifuss Muscular Dystrophy (EDMD), we showed here that Lamin A loss deregulated PcG positioning in muscle satellite stem cells leading to de-repression of non-muscle specific genes and p16INK4a, a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional programme caused impairment in self-renewal, loss of cell identity and premature exhaustion of quiescent satellite cell pool. Genetic ablation of Cdkn2a locus restored muscle stem cell properties in Lamin A/C null dystrophic mice. Our findings established a direct link between Lamin A and PcG epigenetic silencing and indicated that Lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells.Funding Information
- Italian Minister of Health (GR-2013-02355413)
- AFM-Téléthon (21030)
- cariplo (2017-0649)
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