Université de Strasbourg, CNRS UMR7104, INSERM U1258, IGBMC, F-67400 Illkirch, France.
Centre de Recherche en Myologie, UMRS974-Sorbonne Université-INSERM U974-Association Institut de Myologie, France.
Nucleic Acids Res. 2021 May 7;49(8):4472-4492. doi: 10.1093/nar/gkab226.
Skeletal muscle is a dynamic tissue the size of which can be remodeled through the concerted actions of various cues. Here, we investigated the skeletal muscle transcriptional program and identified key tissue-specific regulatory genetic elements. Our results show that Myod1 is bound to numerous skeletal muscle enhancers in collaboration with the glucocorticoid receptor (GR) to control gene expression. Remarkably, transcriptional activation controlled by these factors occurs through direct contacts with the promoter region of target genes, via the CpG-bound transcription factor Nrf1, and the formation of Ctcf-anchored chromatin loops, in a myofiber-specific manner. Moreover, we demonstrate that GR negatively controls muscle mass and strength in mice by down-regulating anabolic pathways. Taken together, our data establish Myod1, GR and Nrf1 as key players of muscle-specific enhancer-promoter communication that orchestrate myofiber size regulation.
骨骼肌是一种动态组织，其大小可以通过各种信号的协同作用进行重塑。在这里，我们研究了骨骼肌的转录程序，并确定了关键的组织特异性调节遗传元件。我们的结果表明，Myod1 与许多骨骼肌增强子结合，与糖皮质激素受体 (GR) 合作控制基因表达。值得注意的是，这些因素控制的转录激活是通过与靶基因启动子区域的直接接触发生的，通过 CpG 结合转录因子 Nrf1 和形成 CTCF 锚定的染色质环，以肌纤维特异性的方式发生。此外，我们证明 GR 通过下调合成代谢途径负调控小鼠的肌肉质量和力量。总之，我们的数据确立了 Myod1、GR 和 Nrf1 作为肌特异性增强子-启动子通讯的关键因子，协调肌纤维大小的调节。
