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 p16INK4a, 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.

Bianchi, A., Mozzetta, C., Pegoli, G., Lucini, F., Valsoni, S., Rosti, V., et al. (2020). Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy. THE JOURNAL OF CLINICAL INVESTIGATION, 130(5), 2408-2421 [10.1172/JCI128161].

Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy

Lucini F.;Rosti V.;Cortesi A.;
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 p16INK4a, 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.
Articolo in rivista - Articolo scientifico
Muscle Stem Cells (MuSCs); Lamin A; Polycomb, cell fate; differentiation; premature senescence; muscular dystrophy;
English
2408
2421
14
Bronze Open Access
Bianchi, A., Mozzetta, C., Pegoli, G., Lucini, F., Valsoni, S., Rosti, V., et al. (2020). Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy. THE JOURNAL OF CLINICAL INVESTIGATION, 130(5), 2408-2421 [10.1172/JCI128161].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/348119
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