HDAC1 regulates thermogenic program via H3K27 deacetylation

项目摘要 当能量摄入和能量消耗之间持续不平衡时，肥胖就会发生。 适应性产热，其中棕色脂肪组织（BAT）的功能是将能量作为热量耗散， UCP 1的独特表达，是整体能量消耗的组成部分。棕色有两种 啮齿动物的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位于离散区域。 脂肪细胞分散在WAT中，可以通过冷暴露或β肾上腺素能激活来诱导。而 许多研究致力于评价棕色/米色细胞的遗传调节因素。 功能，很多是未知的表观遗传调控，包括组蛋白乙酰化在这一过程中。证据 收敛表明，表观遗传事件，包括组蛋白乙酰化，图突出， 肥胖症的发展。最近的研究报道，I类HDAC抑制剂（HDACi）改善肥胖， 小鼠然而，HDAC家族的确切成员和I类HDACi 发挥这些有益的效果是未知的。组蛋白脱乙酰酶1（HDAC 1）的功能是去除乙酰基 组蛋白中的赖氨酸残基，从而沉默基因表达。我们公布的和初步的数据 提示HDAC 1缺乏促进棕色脂肪细胞产热程序和白色脂肪细胞脂解 通过增加组蛋白赖氨酸27（H3 K27）乙酰化（H3 K27 ac）。因此，我们假设HDAC 1 在遗传模型中调节适应性产热、脂解、能量代谢和肥胖。目标1将 确定HDAC 1在调节适应性产热、能量代谢和饮食诱导的 肥胖的遗传模型。我们已经产生了棕色/米色脂肪细胞缺陷或 过表达HDAC 1，并将表征冷诱导产热和饮食诱导的表型。 肥胖的老鼠。我们将进一步研究通过ChIP-Seq鉴定的孤儿核受体NR 4A 1， 作为下游信号介导H3 K27 ac诱导的产热程序由于HDAC 1缺陷。目的2 将确定HDAC 1是否通过NR 4A 1介导的脂肪分解程序调节脂肪分解。我们已经生成 具有脂肪（白色和棕色）特异性HDAC 1缺失或过表达的遗传模型。我们将确定：a） 脂肪细胞特异性HDAC 1缺失是否增强，而HDAC 1特异性过表达是否抑制 脂肪细胞脂解; B）HDAC 1缺乏是否增强H3 K27 ac将NR 4 A1募集至脂解基因 启动子，导致增强的基因表达和随后的白色脂肪中的脂解。目标3将决定 β肾上腺素能信号调节HDAC 1活性的分子途径。我们将确定：a）β 肾上腺素能激活使由HDAC 1和辅助阻遏物RIP 140组成的阻遏复合物解离 和RB抑制基础状态下的产热程序; B）β肾上腺素能激活减少 通过组蛋白CBP乙酰化的HDAC 1活性。我们的研究将为识别新的 表观遗传靶点增加棕色/米色脂肪细胞在治疗肥胖症。

Project Abstract Obesity develops when a persistent imbalance between energy intake and energy expenditure occurs. Adaptive thermogenesis, in which brown adipose tissue (BAT) functions to dissipate energy as heat due to the unique expression of UCP1, is an integral part of overall energy expenditure. There are two types of brown adipocytes in rodents. Traditional brown adipocytes are located in discrete areas, whereas inducible beige adipocytes are dispersed in WAT and can be induced by cold exposure or β adrenergic activation. While numerous studies have been devoted to the evaluation of genetic factors in regulation of brown/beige cell function, much is unknown about epigenetic regulations including histone acetylation in this process. Evidence converges to suggest that epigenetic events, including histone acetylation, figure prominently in the development of obesity. Recent studies reported that class I HDAC inhibitor (HDACi) ameliorates obesity in mice. However, the exact member of the HDAC family and the precise mechanism whereby class I HDACi exerts these beneficial effects are not known. Histone deacetylase 1 (HDAC1) functions to remove acetyl groups from lysine residues in histone, thereby silencing gene expression. Our published and preliminary data suggest that HDAC1 deficiency promotes brown adipocyte thermogenic program and white adipocyte lipolysis via increasing histone lysine 27 (H3K27) acetylation (H3K27ac). Therefore, we hypothesize that HDAC1 regulates adaptive thermogenesis, lipolysis, energy metabolism and obesity in genetic models. Aim 1 will determine the role of HDAC1 in regulation of adaptive thermogenesis, energy metabolism and diet-induced obesity in genetic models. We have generated genetic mice with brown/beige adipocytes deficient or overexpressing HDAC1 and will characterize the phenotypes of cold-induced thermogenesis and diet-induced obesity in these mice. We will further investigate the orphan nuclear receptor NR4A1, identified via ChIP-Seq, as a downstream signal mediating H3K27ac-induced thermogenic program due to HDAC1 deficiency. Aim 2 will determine whether HDAC1 regulates lipolysis via a NR4A1-mediated lipolytic program. We have generated genetic models with fat (white and brown)-specific HDAC1 deletion or overexpression. We will determine: a) whether adipocyte-specific deletion of HDAC1 enhances, whereas specific overexpression of HDAC1 inhibits adipocyte lipolysis; b) whether enhanced H3K27ac by HDAC1 deficiency recruits NR4A1 to the lipolytic gene promoters, resulting in enhanced gene expression and subsequent lipolysis in white fat. Aim 3 will determine the molecular pathway whereby β adrenergic signal regulates HDAC1 activity. We will determine: a) β adrenergic activation disassociates a repressive complex consisting of HDAC1 and the co-repressors RIP140 and RB, which suppress the thermogenic program at basal state; and b) β adrenergic activation decreases HDAC1 activity via acetylation by the histone CBP. Our studies will shed new insights into identifying novel epigenetic targets for increasing brown/beige adipocytes in the treatment of obesity.