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散失，这是由于 UCP1的独特表达，是整体能源消耗不可或缺的一部分。有两种类型的棕色 啮齿动物体内的脂肪细胞。传统的棕色脂肪细胞位于不连续的区域，而可诱导的米色 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。而当 许多研究致力于评价棕色/米色细胞调节中的遗传因素。 在这一过程中，包括组蛋白乙酰化在内的表观遗传调控尚不清楚。证据 这表明，表观遗传事件，包括组蛋白乙酰化，在 肥胖的发展。最近的研究报道，I类HDAC抑制剂(HDACi)可以改善 老鼠。然而，HDAC家族的确切成员和I类HDAC的确切机制 产生这些有益效果的原因尚不清楚。组蛋白脱乙酰基酶1(HDAC1)具有清除乙酰基的功能 基团由组蛋白中的赖氨酸残基组成，从而沉默基因的表达。我们已公布的和初步的数据 提示HDAC1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(H3K27)乙酰化(H3K27ac)。因此，我们假设HDAC1 调节遗传模型中的适应性产热、脂肪分解、能量代谢和肥胖。目标1将 确定HDAC1在调节适应性产热、能量代谢和饮食诱导中的作用 遗传模型中的肥胖。我们已经产生了棕色/米色脂肪细胞缺乏或缺乏的遗传小鼠 高表达HDAC1，并将表征冷诱导产热和饮食诱导的表型 这些小鼠的肥胖。我们将进一步研究通过CHIP-SEQ鉴定的孤儿核受体NR4A1， 作为一个下游信号，介导H3K27ac由于HDAC1缺乏而诱导的生热程序。目标2 将确定HDAC1是否通过NR4A1介导的脂解程序调节脂解。我们已经产生了 脂肪(白色和棕色)特异性HDAC1缺失或过度表达的遗传模型。我们将确定：a) 脂肪细胞特异性的HDAC1缺失是否增强，而HDAC1的特异性过表达则抑制 脂肪细胞脂解；b)HDAC1缺乏增强的H3K27ac是否将NR4A1重新招募到脂解基因 启动子，导致白色脂肪的基因表达增强和随后的脂肪分解。目标3将决定 β肾上腺素能信号调节HDAC1活性的分子途径。我们将确定：A)β 肾上腺素能激活解离由HDAC1和共抑制物RIP140组成的抑制复合体 和Rb，在基础状态下抑制生热程序；和b)β肾上腺素能激活减少 组蛋白CBP乙酰化的HDAC1活性。我们的研究将为识别小说提供新的见解 在肥胖治疗中增加棕色/米色脂肪细胞的表观遗传学靶点。

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.