Role Of Jhdm2a In Regulating Metabolic Gene Expression And Obesity Resistance

摘要

Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethy-lases. The H3K9-specific demethylase Jhdm2a (also known as Jmjdla and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the Joss of Jhdm2a function disrupts β-adrenergic-stimulated gly-cerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by β-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor a (Ppara) and Ucpl expression. Furthermore, we demonstrate that β-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucpl gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppary and Rxra and their co-activators Pgclα (also known as Ppargcla), CBP/ p300 (Crebbp) and Srcl (Ncoal) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.