Role of Jhdm2a in regulating metabolic gene expression and obesity resistance
| Autor: | Keisuke Tateishi, Eric M. Kallin, Yuki Okada, Yi Zhang |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Glycerol
Jumonji Domain-Containing Histone Demethylases Peroxisome proliferator-activated receptor Biology Ion Channels Article Mitochondrial Proteins Mice Histone H3 Adipose Tissue Brown Receptors Adrenergic beta Gene expression Animals Obesity Muscle Skeletal Cells Cultured Uncoupling Protein 1 Mice Knockout chemistry.chemical_classification Regulation of gene expression Multidisciplinary Gene Expression Profiling Oxidoreductases N-Demethylating Cell biology Mice Inbred C57BL Nuclear receptor coactivator 1 Phenotype Gene Expression Regulation Biochemistry chemistry Histone methyltransferase Knockout mouse biology.protein Demethylase Energy Metabolism Oxidation-Reduction |
| Zdroj: | Nature. 458:757-761 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | The histone demethylase Jhdm2a/Kdm3a has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Tateishi et al., using Jhdm2a-knockout mice, demonstrate that Jhdm2a also regulates expression of metabolic genes such as Ppara and Ucp1. In addition, the obese phenotype of the knockout mice indicates the demethylase is involved in regulation of weight control. The histone demethylase Jhdm2a (also known as Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Here the authors disrupt the Jhdm2a gene in mice to demonstrate that Jhdm2a also regulates expression of metabolic genes such as Ppara and Ucp1; the obese phenotype of the knockout mice indicates the demethylase is involved in regulation of weight control. 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. |
| Databáze: | OpenAIRE |
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