Dysfunctional polycomb transcriptional repression contributes to lamin A/C–dependent muscular dystrophy
Andrea Bianchi, … , Claudia Bearzi, Chiara Lanzuolo
Andrea Bianchi, … , Claudia Bearzi, Chiara Lanzuolo
Published January 30, 2020
Citation Information: J Clin Invest. 2020;130(5):2408-2421. https://doi.org/10.1172/JCI128161.
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Research Article Muscle biology

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

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.

Authors

Andrea Bianchi, Chiara Mozzetta, Gloria Pegoli, Federica Lucini, Sara Valsoni, Valentina Rosti, Cristiano Petrini, Alice Cortesi, Francesco Gregoretti, Laura Antonelli, Gennaro Oliva, Marco De Bardi, Roberto Rizzi, Beatrice Bodega, Diego Pasini, Francesco Ferrari, Claudia Bearzi, Chiara Lanzuolo

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Figure 7

Cdkn2a genetic ablation restores regenerative capacity of LmnaΔ8–11–/– dystrophic mice.

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Cdkn2a genetic ablation restores regenerative capacity of LmnaΔ8–11–/– ...
(A) Transcriptional analysis of p16INK4 and p19ARF at the Cdkn2a locus in LmnaΔ8–11 mouse MuSCs (left graph) at d19 and d26 and whole muscles (right graph) at d26. Values were normalized to Gapdh and compared with the average of WT amplification. nd, not detected. n = 3–10 animals per genotype. (B) Immunohistochemical staining of PAX7 and MYOD markers in Cdkn2a/LmnaΔ8–11 mice at d19. Basement membrane of muscle fibers was stained with anti-laminin. Activated, ASC (PAX7+/MYOD+) and self-renewing, QSC (PAX7+MYOD–) MuSCs are shown. Scale bars: 50 μm. (C) Quantification of MuSC pool composition in B. n = 4–5 animals per genotype. Data in A and C are the mean ± SEM. (D) Quantification of myofiber size, evaluated by the cross-sectional area (CSA). n = 600 muscle fibers. n = 4–5 animals per genotype. The horizontal lines within the boxes represent the medians, upper and lower bounds of the boxes represent quartiles Q3 (75th percentile) and Q1 (25th percentile), respectively, and whiskers min to max. *P < 0.05; **P < 0.01; ***P < 0.001 by unpaired t test (A) or by 1-way (D) or 2-way (C) ANOVA with multiple comparisons. WT = LmnaΔ8–11+/+; hom = LmnaΔ8–11–/–.