代谢综合征是一种全球性的慢性流行病,其发病机理由遗传与环境等因素共同决定。表观遗传修饰是在基因的核苷酸序列不发生改变的情况下,通过可遗传的变化调控基因表达。近年来研究发现,表观遗传修饰能够应答于环境因素、调控基因表达和...代谢综合征是一种全球性的慢性流行病,其发病机理由遗传与环境等因素共同决定。表观遗传修饰是在基因的核苷酸序列不发生改变的情况下,通过可遗传的变化调控基因表达。近年来研究发现,表观遗传修饰能够应答于环境因素、调控基因表达和信号转导进程。其中,染色质重塑复合物SWI/SNF(SWItch/Sucrose non fermentable,SWI/SNF)关键亚基Baf60a,在维持机体能量代谢稳态过程中发挥着重要作用。文中重点阐述了生理和病理状态下,Baf60a维持机体脂质代谢、胆固醇代谢、尿素循环及代谢节律性稳态的分子机制。深入探讨以Baf60a为基点的能量代谢调控网络,有望为代谢综合征的改善和治疗提供潜在药物治疗靶点和扎实的研究依据。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
拟南芥MRG2(Morf Related Genes 2)是MRG蛋白家族成员之一,可以识别组蛋白H3K4和H3K36甲基化修饰,但是对于它是否具有其他生物学功能,目前了解还非常有限.我们首先通过免疫共沉淀结合质谱分析获得了MRG2结合蛋白,并对其中一个染色质重塑...拟南芥MRG2(Morf Related Genes 2)是MRG蛋白家族成员之一,可以识别组蛋白H3K4和H3K36甲基化修饰,但是对于它是否具有其他生物学功能,目前了解还非常有限.我们首先通过免疫共沉淀结合质谱分析获得了MRG2结合蛋白,并对其中一个染色质重塑SWI/SNF复合体亚基BAF60蛋白进行了深入研究.体外Pull-down和双荧光互补实验证实了MRG2和BAF60在植物体内体外都能相互作用.已有研究表明:BAF60抑制异戊烯转移酶IPT(ISOPENTENYL TRANSFERASE)基因转录.RNA-seq和RT-qPCR数据都表明在mrg1mrg2双突变拟南芥植株中多个IPT基因转录水平明显升高.ChIP实验结果证明MRG2蛋白富集于IPT3基因编码区.综上所述,在植物细胞中MRG2和BAF60蛋白相互作用共同调控了IPT3基因的转录.这些研究对于理解MRG2在基因表达调控方面的功能具有重要意义.展开更多
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
文摘代谢综合征是一种全球性的慢性流行病,其发病机理由遗传与环境等因素共同决定。表观遗传修饰是在基因的核苷酸序列不发生改变的情况下,通过可遗传的变化调控基因表达。近年来研究发现,表观遗传修饰能够应答于环境因素、调控基因表达和信号转导进程。其中,染色质重塑复合物SWI/SNF(SWItch/Sucrose non fermentable,SWI/SNF)关键亚基Baf60a,在维持机体能量代谢稳态过程中发挥着重要作用。文中重点阐述了生理和病理状态下,Baf60a维持机体脂质代谢、胆固醇代谢、尿素循环及代谢节律性稳态的分子机制。深入探讨以Baf60a为基点的能量代谢调控网络,有望为代谢综合征的改善和治疗提供潜在药物治疗靶点和扎实的研究依据。
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.
文摘拟南芥MRG2(Morf Related Genes 2)是MRG蛋白家族成员之一,可以识别组蛋白H3K4和H3K36甲基化修饰,但是对于它是否具有其他生物学功能,目前了解还非常有限.我们首先通过免疫共沉淀结合质谱分析获得了MRG2结合蛋白,并对其中一个染色质重塑SWI/SNF复合体亚基BAF60蛋白进行了深入研究.体外Pull-down和双荧光互补实验证实了MRG2和BAF60在植物体内体外都能相互作用.已有研究表明:BAF60抑制异戊烯转移酶IPT(ISOPENTENYL TRANSFERASE)基因转录.RNA-seq和RT-qPCR数据都表明在mrg1mrg2双突变拟南芥植株中多个IPT基因转录水平明显升高.ChIP实验结果证明MRG2蛋白富集于IPT3基因编码区.综上所述,在植物细胞中MRG2和BAF60蛋白相互作用共同调控了IPT3基因的转录.这些研究对于理解MRG2在基因表达调控方面的功能具有重要意义.
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.
