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 3

LmnaΔ8–11–/– dystrophic MuSCs display PcG displacement.

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LmnaΔ8–11–/– dystrophic MuSCs display PcG displacement. (A) Heatmap rep...
(A) Heatmap reporting log2 ratios of observed over expected (colored bar) number of genes in the intersections between H3K27me3 targets identified in LmnaΔ8–11+/+ mice and the upregulated genes in LmnaΔ8–11–/– mice. Fisher’s exact test P = 2.38 × 10–5. (B–D) Average profile of H3K27me3 ChIP-seq signal calculated as the IP/input ratio over annotated mouse genes. (B) Average profile of H3K27me3 signal around the TSS. (C) Average profile of H3K27me3 signal along the gene body. TES, annotated transcript end. (D) Average profile of H3K27me3 signal in regions outside H3K27me3 peaks and outside annotated genes. (E) Normalized expression distribution of genes stratified using WT expression level in the 3 biological replicates (see Supplemental Methods). Distribution of average log2 transcripts per million (TPM + 0.1) values is plotted for WT and hom. Data in the boxes extend from the 25th to the 75th percentiles with the median indicated. The upper whisker extends from the hinge to the highest value that is within 1.5 × IQR of the hinge, where IQR is the interquartile range, or distance between the first and third quartiles. The lower whisker extends from the hinge to the lowest value within 1.5 × IQR of the hinge. Data beyond the end of the whiskers are outliers and plotted as points. (F) Average profile of H3K27me3 signal (IP/input) along the gene body using gene categories as in E. WT = LmnaΔ8–11+/+; hom = LmnaΔ8–11–/–.