Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy: Journal of Clinical Investigation

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

Research output: Contribution to journalArticlepeer-review

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. Copyright: © 2020, American Society for Clinical Investigation.
Original languageEnglish
Pages (from-to)2408-2421
Number of pages14
JournalJ. Clin. Invest.
Volume130
Issue number5
DOIs
Publication statusPublished - 2020

Keywords

  • cyclin dependent kinase inhibitor 2A
  • lamin A
  • lamin C
  • MyoD protein
  • peroxisome proliferator activated receptor gamma
  • polycomb group protein
  • transcription factor PAX7
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • controlled study
  • Emery Dreifuss muscular dystrophy
  • gene locus
  • gene loss
  • gene repression
  • immunohistochemistry
  • mouse
  • murine model
  • muscle regeneration
  • muscle stem cell
  • nonhuman
  • postnatal growth
  • priority journal
  • skeletal muscle satellite cell
  • stem cell self-renewal
  • transcription termination

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