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Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy
- Source :
- Journal of Clinical Investigation. May, 2020, Vol. 130 Issue 5, p2408, 14 p.
- Publication Year :
- 2020
-
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. The polycomb group (PcG) of proteins 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 show here that lamin A loss deregulated PcG positioning in muscle satellite stem cells, leading to derepression of non-muscle-specific genes and [p16.sup.INK4a], a senescence driver encoded in the Cdkn2a locus. This aberrant transcriptional program caused impairment in self-renewal, loss of cell identity, and premature exhaustion of the quiescent satellite cell pool. Genetic ablation of the Cdkn2a locus restored muscle stem cell properties in lamin A/C-null dystrophic mice. Our findings establish a direct link between lamin A and PcG epigenetic silencing and indicate that lamin A-dependent muscular dystrophy can be ascribed to intrinsic epigenetic dysfunctions of muscle stem cells.<br />Introduction The nuclear lamina (NL) is located in the inner part of the nuclear membrane and is composed of a complex network of type V filament proteins, the lamins (1, [...]
- Subjects :
- Thermo Fisher Scientific Inc.
Muscular dystrophy -- Genetic aspects
Epigenetic inheritance -- Genetic aspects -- Analysis
Transcription (Genetics) -- Genetic aspects -- Analysis
Stem cells -- Genetic aspects -- Analysis
Genomics -- Genetic aspects -- Analysis
Proteins -- Analysis -- Genetic aspects
Scientific equipment industry -- Genetic aspects -- Analysis
Genes
Genomes
Fatigue
Identity
Diseases
Health care industry
National Research Council
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 5
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.624327942
- Full Text :
- https://doi.org/10.1172/JCI128161