Skeletal muscle plays a key role in metabolic homeostasis. Brg1/Brm-associated factor (Baf) 60c, a subunit of the mating type switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes, was previously i...Skeletal muscle plays a key role in metabolic homeostasis. Brg1/Brm-associated factor (Baf) 60c, a subunit of the mating type switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes, was previously identified to be robustly involved in glycolytic muscle function and systemic metabolic balance. However, whether Baf60c regulates the secreted factors and couples the skeletal muscle function to systemic metabolism remains unclear. Here, we uncover that Baf60c regulates the expression of a series of secreted factors, among which Musclin, a recently identified negative regulator of beige adipocyte thermogenesis, was top-ranked in the upregulated factors in Baf60c-deficient muscle. Mechanistically, Baf60c physically interacts with the transcription factor myocyte enhancer factor 2c (Mef2c) and modulates the chromatin accessibility at the proximal promoter regions upstream of the Musclin gene transcription start site (TSS), therefore negatively regulating Musclin gene expression in the skeletal muscle. Further in vivo metabolic assays demonstrate that muscle-specific Baf60c ablation inhibits thermogenesis and elevates blood glucose. Conversely, muscle-specific overexpression of Baf60c increases thermogenesis and energy expenditure and improves systemic glucose metabolism. Together, this work uncovers Baf60c/Mef2c-mediated chromatin remodeling signaling in myocytes that control adipose tissue thermogenesis and systemic metabolism through Musclin-mediated muscle-fat crosstalk.展开更多
Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate...Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWlISNF chromatin.remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological sigrials. The ATP-dependent SWl/SNF ing complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different m^abolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.展开更多
基金supported by the grants from the National Natural Science Foundation of China(82100904,81670740,82300910,82425012,32471170,and 92457301)the Zhejiang Provincial Natural Science Foundation of China(LQ21C110001 and LQ23H070005).
文摘Skeletal muscle plays a key role in metabolic homeostasis. Brg1/Brm-associated factor (Baf) 60c, a subunit of the mating type switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes, was previously identified to be robustly involved in glycolytic muscle function and systemic metabolic balance. However, whether Baf60c regulates the secreted factors and couples the skeletal muscle function to systemic metabolism remains unclear. Here, we uncover that Baf60c regulates the expression of a series of secreted factors, among which Musclin, a recently identified negative regulator of beige adipocyte thermogenesis, was top-ranked in the upregulated factors in Baf60c-deficient muscle. Mechanistically, Baf60c physically interacts with the transcription factor myocyte enhancer factor 2c (Mef2c) and modulates the chromatin accessibility at the proximal promoter regions upstream of the Musclin gene transcription start site (TSS), therefore negatively regulating Musclin gene expression in the skeletal muscle. Further in vivo metabolic assays demonstrate that muscle-specific Baf60c ablation inhibits thermogenesis and elevates blood glucose. Conversely, muscle-specific overexpression of Baf60c increases thermogenesis and energy expenditure and improves systemic glucose metabolism. Together, this work uncovers Baf60c/Mef2c-mediated chromatin remodeling signaling in myocytes that control adipose tissue thermogenesis and systemic metabolism through Musclin-mediated muscle-fat crosstalk.
基金This work was supported by the National Natural Science Foundation of China （Grant No. 81670740）, the Thousand Young Talents Plan of China, and the National Key Research and Development Programme of China （No. 2016YFC1305303） to Z.X.M. by National Natural Science Foundation of China （Grant Nos. 81570759 and 81270938）, National Key Research and Development Programme of China （No. 2016YFC1305301）, Zhejiang Provincial Key Science and Technol- ogy Project （No. 2014C03045-2）, Key Disciplines of Medicine （Innovation discipline,11-CX24） to J.F. and by NIH grant （No. DKl12800） to J.D.L.
文摘Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWlISNF chromatin.remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological sigrials. The ATP-dependent SWl/SNF ing complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different m^abolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.
