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 6

LmnaΔ8–11–/– MuSCs acquire senescence transcriptional traits.

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LmnaΔ8–11–/– MuSCs acquire senescence transcriptional traits. (A) Repre...
(A) Representative image of myofiber-derived MuSCs from LmnaΔ8–11 mice at d19 immunostained for p-p38 and PAX7 after 48 hours of culture. Scale bars: 25 μm. (B) Quantification of asymmetric and symmetric divisions assessed by p-p38 distribution as shown in A. (C) Quantification of asymmetric apico-basal division versus symmetric planar divisions. n = 46 ± 6 doublets of MuSCs per genotype, n = 7–9 mice per group. Data in B and C are the mean ± SEM. (D) GSEA of expression data from old and young mouse quiescent satellite cells (25). Upregulated (log[fold change] > 1) genes in hom versus WT comparison added to Biocarta mouse pathways from the gskb R package were used as gene sets (NES = 4.70, FDR < 1 × 10–4). (E) ChIP-seq of H3K27me3 mark and RNA-seq signal tracks on the Cdkn1a/p21 locus. Promoter regions are highlighted by light blue rectangles. Statistics by 2-way ANOVA with multiple comparisons. **P < 0.01; ***P < 0.001. WT = LmnaΔ8–11 /+; het = LmnaΔ8–11+/–; hom = LmnaΔ8–11–/–.