Histone methyltransferase SUV420H2 regulates brown/beige adipocyte thermogenesis and energy homeostasis

 描述（由申请人提供）：肥胖现在被认为是一种流行病，它与一组代谢紊乱相关，包括胰岛素抵抗/2型糖尿病、血脂异常和心血管疾病。白色脂肪组织（WAT）参与能量储存，而棕色脂肪组织（BAT）由于解偶联蛋白1（UCP 1）的独特表达而将能量以热量形式耗散。在啮齿类动物中，存在两种类型的棕色脂肪细胞。传统的棕色脂肪细胞位于离散区域;而“可诱导的”米色脂肪细胞分散在WAT中，并且可以通过冷暴露或β3-肾上腺素能受体激活来诱导。棕色/米色脂肪细胞产热功能的激活提示肥胖及其相关代谢疾病。最近在人类中发现的功能性棕色和米色脂肪细胞表明，增加棕色/米色细胞功能可能是治疗肥胖的新方法。表观遗传机制在包括肥胖症在内的复杂疾病的调控中发挥着重要作用。杂色抑制因子4-20同源物2（Suppressor of variegation 4-20 homolog 2，Drosophila）（SUV 420 H2）是一种组蛋白甲基转移酶，对组蛋白H4赖氨酸20（H4 K20）的三甲基化非常重要。我们的初步数据表明，SUV 420 H2是重要的棕色和米色脂肪细胞发育的调节。在棕色和米色脂肪细胞中，SUV 420 H2的表达与UCP 1的表达平行;敲低SUV 420 H2显著降低，而过表达SUV 420 H2显著增加UCP 1水平。因此，我们假设组蛋白H4 K20甲基转移酶SUV 420 H2在调节棕色和米色脂肪细胞发育中是重要的，并进一步调节动物模型中的能量稳态。我们将使用棕色/米色脂肪细胞特异性SUV 420 H2缺陷小鼠和脂肪细胞特异性SUV 420 H2转基因小鼠来解决以下具体目标。在目标1中，我们将测试脂肪细胞SUV 420 H2在调节冷和饮食诱导的棕色和米色脂肪细胞产热中的重要性。我们将测试：1）在冷暴露期间，SUV 420 H2的棕色/米色脂肪细胞缺失是否损害，而SUV 420 H2的脂肪细胞特异性过表达是否增强棕色和米色脂肪细胞产热;以及2）具有SUV 420 H2的棕色/米色脂肪细胞缺失的小鼠是否倾向于;而具有SUV 420 H2的脂肪细胞特异性过表达的小鼠是否抵抗高脂肪饮食诱导的肥胖。在目的2中，我们将测试SUV 420 H2介导的4 E-BP 1启动子处的H4 K20三甲基化在调节PGC 1 α蛋白翻译和SUV 420 H2调节的棕色/米色脂肪细胞产热中的重要性。在目标3中，我们将使用H4 K20 me 3 ChIP-Seq和RNA-Seq方法的组合测试冷暴露期间棕色/米色脂肪细胞中的SUV 420 H2/H4 K20 me 3靶向细胞和分子途径以及饮食诱导的产热作用。

 DESCRIPTION (provided by applicant): Obesity is now considered as an epidemic problem, which is associated with a panel of metabolic disorders, including insulin resistance/type 2 diabetes, dyslipidemia and cardiovascular diseases. While white adipose tissue (WAT) is involved in energy storage, that of brown adipose tissue (BAT) is to dissipate energy as heat due to the unique expression of uncoupling protein 1 (UCP1). In rodents, there exist two types of brown adipocytes. Traditional brown adipocytes are located in discrete areas; whereas "inducible" beige adipocytes are dispersed in WAT, and can be induced by cold exposure or β3-adrenergic receptor activation. Activation of brown/beige adipocyte thermogenic function alleviates obesity and its associated metabolic diseases. Recent discovery of functional brown and beige adipocytes in humans suggest that increasing brown/beige cell function may be a novel approach in treating obesity. Epigenetic mechanisms play an important role in the regulation of complex diseases, including obesity. Suppressor of variegation 4-20 homolog 2 (Drosophila) (SUV420H2) is a histone methyltransferase that is important for the tri-methylation at histone H4 lysine 20 (H4K20). Our preliminary data suggest that SUV420H2 is important in the regulation of brown and beige adipocyte development. SUV420H2 expression parallels that of UCP1 expression in brown and beige adipocytes; knocking down of SUV420H2 significantly reduces, whereas overexpressing SUV420H2 significantly increases UCP1 levels. Therefore, we hypothesize that the histone H4K20 methyltransferase SUV420H2 is important in the regulation of brown and beige adipocyte development, and further regulates energy homeostasis in animal models. We will use brown/beige adipocyte specific SUV420H2 deficient mice and adipocyte-specific SUV420H2 transgenic mice to address the following specific aims. In Aim 1, we will test the importance of adipocyte SUV420H2 in the regulation of cold- and diet-induced brown and beige adipocyte thermogenesis. We will test: 1) whether brown/beige adipocyte-deletion of SUV420H2 impairs, whereas adipocyte-specific overexpression of SUV420H2 enhances brown and beige adipocyte thermogenesis during cold exposure; and 2) whether mice with brown/beige adipocyte-deletion of SUV420H2 are prone to; whereas mice with adipocyte-specific overexpression of SUV420H2 are resistant to high fat diet-induced obesity. In Aim 2, we will test the importance of SUV420H2-mediated H4K20 trimethylation at 4E-BP1 promoter in the regulation of PGC1α protein translation and SUV420H2-regulated brown/beige adipocyte thermogenesis. In Aim 3, we will test SUV420H2/H4K20me3-targeted cellular and molecular pathways in brown/beige adipocytes during cold exposure and in diet-induced thermogenesis using a combination of H4K20me3 ChIP-Seq and RNA-Seq approaches.