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.

Dysfunctional polycomb transcriptional repression contributes to Lamin A/C dependent muscular dystrophy / Bianchi, Andrea; Mozzetta, Chiara; Pegoli, Gloria; Lucini, Federica; Valsoni, Sara; Rosti, Valentina; Petrini, Cristiano; Cortesi, Alice; Gregoretti, Francesco; Antonelli, Laura; Oliva, Gennaro; De Bardi, Marco; Rizzi, Roberto; Bodega, Beatrice; Pasini, Diego; Ferrari, Francesco; Bearzi, Claudia; Lanzuolo, Chiara. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - (2020). [10.1172/JCI128161]

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

Mozzetta, Chiara
Co-primo
Investigation
;
Rizzi, Roberto;Ferrari, Francesco;Lanzuolo, Chiara
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. 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.
2020
epigenetics; mouse stem cells; muscle biology; skeletal muscle; stem cells
01 Pubblicazione su rivista::01a Articolo in rivista
Dysfunctional polycomb transcriptional repression contributes to Lamin A/C dependent muscular dystrophy / Bianchi, Andrea; Mozzetta, Chiara; Pegoli, Gloria; Lucini, Federica; Valsoni, Sara; Rosti, Valentina; Petrini, Cristiano; Cortesi, Alice; Gregoretti, Francesco; Antonelli, Laura; Oliva, Gennaro; De Bardi, Marco; Rizzi, Roberto; Bodega, Beatrice; Pasini, Diego; Ferrari, Francesco; Bearzi, Claudia; Lanzuolo, Chiara. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - (2020). [10.1172/JCI128161]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1362868
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