Myod1 and GR coordinate myofiber-specific transcriptional enhancers

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 thatMyod1 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.

Automated summary

Skeletal muscle size can be remodeled through various cues, with Myod1, GR, and Nrf1 identified as key players in muscle-specific enhancer-promoter communication. The study reveals that these factors control gene expression through direct contacts, transcription factor Nrf1 regulation, and Ctcf-anchored chromatin loops, orchestrating myofiber size regulation in a myofiber-specific manner. Additionally, GR negatively regulates muscle mass and strength in mice by down-regulating anabolic pathways.