The Mediator Med23 controls a transcriptional switch for muscle stem cell proliferation and differentiation in muscle regeneration

Yi Fang; Chunlei Yuan; Chonghui Li; Chengjiang Lu; Wei Yu; Gang Wang

doi:10.1016/j.celrep.2024.114177

The Mediator Med23 controls a transcriptional switch for muscle stem cell proliferation and differentiation in muscle regeneration

Cell Rep. 2024 Apr 30;43(5):114177. doi: 10.1016/j.celrep.2024.114177. Online ahead of print.

Authors

Yi Fang¹, Chunlei Yuan², Chonghui Li¹, Chengjiang Lu¹, Wei Yu², Gang Wang³

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, China; State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
² State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, China.
³ State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai 200438, China. Electronic address: gwang_fd@fudan.edu.cn.

PMID: 38691453
DOI: 10.1016/j.celrep.2024.114177

Abstract

Muscle stem cells (MuSCs) contribute to a robust muscle regeneration process after injury, which is highly orchestrated by the sequential expression of multiple key transcription factors. However, it remains unclear how key transcription factors and cofactors such as the Mediator complex cooperate to regulate myogenesis. Here, we show that the Mediator Med23 is critically important for MuSC-mediated muscle regeneration. Med23 is increasingly expressed in activated/proliferating MuSCs on isolated myofibers or in response to muscle injury. Med23 deficiency reduced MuSC proliferation and enhanced its precocious differentiation, ultimately compromising muscle regeneration. Integrative analysis revealed that Med23 oppositely impacts Ternary complex factor (TCF)-targeted MuSC proliferation genes and myocardin-related transcription factor (MRTF)-targeted myogenic differentiation genes. Consistently, Med23 deficiency decreases the ETS-like transcription factor 1 (Elk1)/serum response factor (SRF) binding at proliferation gene promoters but promotes MRTF-A/SRF binding at myogenic gene promoters. Overall, our study reveals the important transcriptional control mechanism of Med23 in balancing MuSC proliferation and differentiation in muscle regeneration.

Keywords: CP: Stem cell research; Elk1; MRTF-A; Med23; Mediator; differentiation; muscle regeneration; muscle stem cell; proliferation.