Role of Jhdm2a in regulating metabolic gene expression and obesity resistance.
Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a 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 loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol 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 beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.
Tateishi
Keisuke
K
Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.
Okada
Yuki
Y
Kallin
Eric M
EM
Zhang
Yi
Y
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005990:Glycerol / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D000071256:Uncoupling Protein 1
D007473:Ion Channels; D024101:Mitochondrial Proteins; D011943:Receptors, Adrenergic, beta; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D005990:Glycerol