Elevated H3K27ac in aged skeletal muscle tissue drives a fibrogenic conversion of muscle satellite cells

A variety of epigenetic alterations impairs functions of cells and tissues during aging, but it is not known if epigenetic alterations are associated with aging muscle. Here, we examined the changes of a panel of histone marks and found H3K27ac (an active enhancer mark) is markedly increased during aging in human skeletal muscle tissues. Our integrated analysis showed that enhancer activation during muscle aging is associated with the up-regulation of extracelluar matrix (ECM) genes, which may result in stiffness of the niche environment of satellite cells (SCs). An age-related fibrogenic conversion of geriatric SCs was observed through differential gene expression analysis. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation reverted the ECM up-regulation and fibrogenic conversion of SCs, suggesting that ECM increase in aging muscle is indeed a result of enhancer activation. The study here not only uncovered a novel aspect of muscle aging that is associated with enhancer remodeling but also highlighted JQ1 as a potential treatment approach for restoring SC function in aging muscle. 3 ChIP-seq experiments were performed

多种表观遗传修饰异常会在衰老进程中损伤细胞与组织的功能，但目前尚不明确表观遗传改变是否与肌肉衰老相关。本研究针对一组组蛋白修饰进行了检测，发现作为活性增强子标记的H3K27ac在人类骨骼肌组织的衰老过程中显著上调。整合分析结果显示，肌肉衰老过程中的增强子激活与细胞外基质（extracellular matrix, ECM）基因的表达上调存在关联，这可能会导致肌卫星细胞（satellite cells, SCs）所处微环境的硬度增加。通过差异基因表达分析，我们观察到衰老肌卫星细胞出现了年龄相关的成纤维样转化。在小鼠模型中，使用增强子激活抑制剂JQ1处理衰老肌肉，可逆转细胞外基质基因的表达上调以及肌卫星细胞的成纤维样转化，这证实衰老肌肉中的细胞外基质增加确实由增强子激活所介导。本研究不仅揭示了肌肉衰老中与增强子重塑相关的全新维度，同时还提出JQ1可作为恢复衰老肌肉中肌卫星细胞功能的潜在治疗方案。本研究共完成3次染色质免疫共沉淀测序（ChIP-seq）实验。