Metabolism and Endocrinology Division, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
Genes Cells. 2009 Aug;14(8):991-1001. doi: 10.1111/j.1365-2443.2009.01326.x. Epub 2009 Jul 15.
Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. Recent studies demonstrated that most covalent histone lysine modifications are reversible and the jumonji C (JmjC)-domain-containing proteins have been shown to possess such demethylase activities. However, there is little information available on the biological roles of histone lysine demethylation in intact animal model systems. JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and alpha-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a-/-) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a-/- mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome.
组蛋白 H3 赖氨酸 9（H3K9）甲基化是异染色质形成和转录沉默的关键表观遗传标记。最近的研究表明，大多数共价组蛋白赖氨酸修饰是可逆的，并且含有 JmjC 结构域的蛋白质已被证明具有这种去甲基化酶活性。然而，在完整的动物模型系统中，关于组蛋白赖氨酸去甲基化的生物学作用的信息很少。JHDM2A（含有 JmjC 结构域的组蛋白去甲基酶 2A，也称为 JMJD1A）通过铁和α-酮戊二酸依赖性氧化反应催化 H3K9 单甲基化和二甲基化的去除。在这里，我们证明 JHDM2a 还调节与能量稳态相关的代谢基因，包括抗脂肪生成、脂肪储存调节、葡萄糖转运和 2 型糖尿病。缺乏 JHDM2a 的小鼠（JHDM2a-/-）会发展出成年起病的肥胖、高甘油三酯血症、高胆固醇血症、高胰岛素血症和高瘦素血症，这些都是代谢综合征的标志。JHDM2a-/-小鼠还表现出禁食诱导的体温过低，表明能量消耗减少，呼吸商也更高，表明脂肪利用减少用于能量产生。这些观察结果可以解释这些小鼠的肥胖表型。因此，H3K9 去甲基酶 JHDM2a 是参与能量消耗和脂肪储存的基因的关键调节剂，这表明它是肥胖和代谢综合征的一个以前未被认识的关键调节剂。
