Dysfunctional polycomb transcriptional repression contributes to lamin A/C‚Äìdependent muscular dystrophy
Authors: Laura Antonelli
Marco De Bardi
Federica Lucini
Francesco Gregoretti
Gloria Pegoli
Andrea Bianchi
Chiara Lanzuolo
Alice Cortesi
Chiara Mozzetta
Francesco Ferrari
Cristiano Petrini
Roberto Rizzi
Sara Valsoni
Valentina Rosti
Claudia Bearzi
Gennaro Oliva
Beatrice Bodega
Diego Pasini
Journal: Journal of Clinical Investigation (2020)
Discipline: CLINICAL MEDICINE
Keywords: Epigenetics; Mouse stem cells; Muscle Biology; Skeletal muscle; Stem cells.
Affiliations: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy., Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy., Santa Lucia Foundation, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Rome, Italy., Institute of Biomedical Technologies, CNR, Milan, Italy., IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy., Institute for High Performance Computing and Networking, CNR, Naples, Italy., IEO European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy., Department of Health Sciences, University of Milan, Milan, Italy., Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza," CNR, Pavia, Italy., Institute of Biochemistry and Cell Biology, CNR, Rome, Italy.

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. 

Retracted: No

PubPeer comments:
 The use of the *Delta* 8-11 - - *LMNA* mutant mouse cannot bring to conclusions relative to human laminopathies. While human AD EDMD is caused by single nucleotide mutations, short insertions or deletions in one of the two LMNA alleles, the Delta 8-11 - - mutant mouse is LMNA deficient (even though it disposes of C-terminally truncated Lamin A produced in very low amounts). Furthermore, by the 8th week of life, *Delta* 8-11 - - mutant mice die; on the contrary, humans with EDMD do not have a rapid onset dystrophy. Thus, the use of H222P mice *(Bonne G et al Ann Neurol. 2000;48(2):170u201380; Arimura T et al Hum Mol Genet. 2005;14(1):155u201369)* would have been more suitable for the study - or at least experiments with this model should have been performed in parallel with the *Delta* 8-11 - - mutant strain. , 
 #1 We agree and we indeed performed such experiments, which were included in a previous version of the manuscript. However, in our hands we did not reveal any defect in the total amount of MuSCs, in the cross-sectional area of the muscle fibers or in the balance of QSCs (PAX7+ MYOD-) vs ASCs (PAX7+ MYOD+), compared to wild type mice. Also, challenging the muscles with repeated injuries with cardiotoxin (CTX), no differences in the regeneration efficiency of wt and H222P H222P littermates could be found, thus suggesting that no defects in MuSCs activation in the muscle stem cell niche occur in this genetic context. Further, we want to highlight that the main goal of our work was to interrogate the role of Lamin A C in maintaining MuSCs identity and regenerative capacity, thus the Delta 8-11 - - LMNA mutant mice, in which the expression of the entire protein is compromised, were the more suitable to our purposes. ,