CHD4 ensures stem cell lineage fidelity during skeletal muscle regeneration

Abstract

Summary Regeneration of skeletal muscle requires resident stem cells called satellite cells. Here, we report that the chromatin remodeler CHD4, a member of the nucleosome remodeling and deacetylase (NuRD) repressive complex, is essential for the expansion and regenerative functions of satellite cells. We show that conditional deletion of the Chd4 gene in satellite cells results in failure to regenerate muscle after injury. This defect is principally associated with increased stem cell plasticity and lineage infidelity during the expansion of satellite cells, caused by de-repression of non-muscle-cell lineage genes in the absence of Chd4 . Thus, CHD4 ensures that a transcriptional program that safeguards satellite cell identity during muscle regeneration is maintained. Given the therapeutic potential of muscle stem cells in diverse neuromuscular pathologies, CHD4 constitutes an attractive target for satellite cell-based therapies.

Three‐dimensional chromatin re‐organization during muscle stem cell aging

“…These results indicate that age‐dependent expression changes are driven by co‐accessible sites leaving or joining chromatin hubs. For example, the matched CCANs containing Chd5 , a core member of the nucleosome remodeling and deacetylase (NuRD) complex (Sreenivasan et al, 2021 ) that was enriched in young peak‐to‐gene linkages, and Ndufc1 , a member of the NADH:ubiquinone oxidoreductase family upregulated in aged MuSCs, revealed altered connectivity with each gene body (Figure S5 H,I). Together, these findings reveal extensive rewiring of connections between promoters and distal regulatory elements within chromatin hubs during aging that produce changes in gene expression.…”

The chromatin remodeler CHD3 is highly expressed in mature neurons and regulates genes involved in synaptic development and function

“…This overlap shows that there may be a certain level of redundancy between CHD4 and CHD3 within a neurodevelopmental context and/or that CHD4 may be able to partly take over from CHD3. In previously reported work, the disruption of Chd4 in mouse thymus 44 and satellite cells from mouse skeletal muscles 45 induced compensatory upregulation of Chd3 as well. Overexpression of CHD3 has been reported to result in a decrease of CHD4 transcript levels in human cell lines 16 .…”

Three-dimensional chromatin re-organization during muscle stem cell aging

“…The copyright holder for this preprint this version posted September 21, 2022. ; https://doi.org/10.1101/2022.09.21.508601 doi: bioRxiv preprint expression changes are driven by co-accessible sites leaving or joining chromatin hubs. For example, the matched CCANs containing Mta2, a core member of the nucleosome remodeling and deacetylase (NuRD) complex 57 that was enriched in young peak-to-gene linkages, and Ndufc1, a member of the NADH:ubiquinone oxidoreductase family upregulated in aged MuSCs, revealed altered connectivity with each gene body (Supp. Figure H-I).…”