Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy.
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 dystro...
| Publicado en: | Journal of Clinical Investigation Vol. 130; no. 5; pp. 2408 - 2422 |
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| Autores principales: | , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
American Society for Clinical Investigation
May2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=143108740&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 143108740 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00219738 0YX jtl: Journal of Clinical Investigation issn: 00219738 maglogo: N pubinfo: dt: May2020 vid: 130 iid: 5 pid: 11983 pub: American Society for Clinical Investigation place: Ann Arbor, Michigan artinfo: ui: 143108740 143108740 NLM31999646 143108740 10.1172/JCI128161 NLM31999646 143108740 ppf: 2408 ppct: 14 formats: tig: atl: Dysfunctional polycomb transcriptional repression contributes to lamin A/C-dependent muscular dystrophy. aug: au: 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 affil: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy sug: subj: Animal Diseases Metabolism Genes Proteins Metabolism Muscular Dystrophy Metabolism Proteins RNA Mice Muscular Dystrophy Pathology Animal Diseases Animal Diseases Pathology Muscular Dystrophy Muscle, Skeletal Metabolism Animal Studies Muscle, Skeletal Pathology Validation Studies Comparative Studies Evaluation Research Multicenter Studies ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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