Abstract
Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases1,2. 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 development3,4. 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 β-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 β-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor α (Ppara) and Ucp1 expression. Furthermore, we demonstrate that β-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 Pparγ and Rxrα and their co-activators Pgc1α (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.
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Acknowledgements
We thank B. M. Spiegelman for the HIB1B cells, L. Xia for construction of the targeting vector, K. E. Gardner for critical reading of the manuscript, D. Pump and K. Hua (UNC Clinical Nutrition Research Unit, DK56350) for calorimetry and MRI, and N. Takahashi for helpful comments. Y.Z. is an investigator of the Howard Hughes Medical Institute.
Author Contributions K.T. and Y.Z. designed the experiments and prepared the manuscript. K.T. performed most of the experiments. Y.O. provided the data for Supplementary Fig. 3. E.K. analysed microarray data and generated Supplementary Figs 6 and 7.
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Tateishi, K., Okada, Y., Kallin, E. et al. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458, 757–761 (2009). https://doi.org/10.1038/nature07777
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DOI: https://doi.org/10.1038/nature07777
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