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.

Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy / A. Bianchi, C. Mozzetta, G. Pegoli, F. Lucini, S. Valsoni, V. Rosti, C. Petrini, A. Cortesi, F. Gregoretti, L. Antonelli, G. Oliva, M. de Bardi, R. Rizzi, B. Bodega, D. Pasini, F. Ferrari, C. Bearzi, C. Lanzuolo. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 130:5(2020 May 01), pp. 2408-2421. [10.1172/JCI128161]

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

Bodega B.;Pasini D.;
2020-05-01

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.
epigenetics; mouse stem cells; muscle biology; skeletal muscle; stem cells; animals; cyclin-dependent kinase inhibitor p16; lamin type A; mice; mice, knockout; muscle, skeletal; muscular dystrophy, animal; muscular dystrophy, Emery-Dreifuss; polycomb-group proteins; repressor proteins; epigenesis, genetic; transcription, genetic
Settore BIO/11 - Biologia Molecolare
Article (author)
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/903881
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 18
social impact