謝 詩雨, 伊藤 亮, Tumenjargal Myagmar, 松村 欣宏, 米代 武司, 酒井 寿郎
Beige adipocytes are thermogenic brown-like adipocytes which are induced by chronic cold exposure in subcutaneous white adipose tissue (scWAT). Biochemical reactions in mitochondria take part in thermogenesis, and mitochondrial function and mass are tightly regulated for adaptation to cold environment. Beige adipogenesis is regulated through both transcriptional network and epigenetic mechanisms. JMJD1A (Jumonji C domain-containing proteins) is a histone H3 lysine 9 demethylase, contributing to the control of adaptive thermogenesis under cold environment. Cold stress stimulates β adrenergic receptor (βAR) and further induce the phosphorylation of JMJD1A at serine residue 265 (S265). During chronic cold stress, thermogenesis is induced in white adipose tissues (WAT) via a histone demethylation mechanism mediated by the interaction between JMJD1A and nuclear receptor PPARγ. (Abe Y et al Nat Commun 2018). However, it is still unclear what role βAR stimulated methylation change play during the cold adaptation and whether mitochondrial biogenesis and function are involved in the regulation. In this research, we generated point-mutant mice where histidine 1122 was mutated to tyrosine (Jmjd1aHY/HY), inactivating the demethylation activity to analyze the functions of histone demethylation by JMJD1A during adaptive thermogenesis. We observed that Jmjd1aHY/HY exhibit obesity and showed adaptable BAT function against acute cold stress. While under chronic cold exposure, Jmjd1aHY/HY showed lower thermogenic gene expressions and impaired beige adipogenesis. Moreover, comprehensive transcriptome and epigenome analysis revealed the impaired induction of thermogenesis and oxidative phosphorylation genes (OXPHOS) expression in Jmjd1aHY/HY, accompanied with downregulation of OXPHOS regulator genes and decreased total mitochondrial contents in scWAT. Altogether, JMJD1A regulates thermogenic genes expression by a 2-step mechanism in vivo, and it also regulates OXPHOS genes expressions and mitochondrial biogenesis through histone demethylation.