Pwwp2b协同组蛋白去乙酰化酶调节棕色脂肪功能

Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Histone acetylation as well as methylation plays an essential role in modulating thermogenic adipocytes gene program and metabolism. Class I HDAC inhibitors were shown to induce brown adipose tissue mitochondrial biogenesis, enhance oxidative metabolism and increase browning of white adipose tissue. HDAC inhibitors demonstrate an outstanding insulin sensitizing activity in various preclinical models and clinical trials and may be developed into future therapeutics for insulin resistance and type 2 diabetes. However, our understanding of how HDACs are recruited to the target gene promoters in adipocytes is limited. Here our initial data show Pwwp2b is a BAT-enriched gene and regulates expression of thermogenic genes negatively. Pwwp2b can interact with class I HDACs. We deduce that Pwwp2b binds to specific methylated histone through its PWWP domain and inhibits thermogenic gene program by recruiting class I HDACs to target gene promoters. Pwwp2b may work as an epigenetic reader to coordinate histone methylation and acetylation. Our study will pave the way of Pwwp2b toward possible molecular targets in therapeutics of obesity.

棕色脂肪细胞和米色脂肪细胞具有将化学能转变为热能散出体外的特性，因而它们能调节体温，并有助于增加机体能量消耗来预防和治疗肥胖。组蛋白乙酰化和甲基化修饰都参与调节棕色脂肪和米色脂肪功能。I型组蛋白去乙酰化酶（HDACs）抑制剂可以诱导棕色脂肪细胞线粒体合成，增强氧化代谢，促进白色脂肪棕色化。目前，组蛋白去乙酰化酶抑制剂成为治疗糖尿病患者胰岛素抵抗的潜在新药物。但是我们对I型HDACs在脂肪细胞中如何被召募到靶基因的启动子区还不了解。本研究发现Pwwp2b基因在棕色脂肪组织中表达水平较高，是产热基因表达的负性调节蛋白,可与I型HDACs相互作用。它可能是表观遗传修饰的Readers，利用其PWWP结构域识别并结合特异性甲基化修饰组蛋白，并召募HDACs到产热基因启动子区发挥去乙酰化作用，从而抑制产热基因表达。本研究将为探索以Pwwp2b作为药物靶点治疗肥胖等代谢性疾病奠定基础。

哺乳动物体内存在两种具有产热功能的脂肪组织，即棕色脂肪组织和米色脂肪组织。产热脂肪组织通过激活或抑制产热基因的表达，响应生理状态的改变和环境温度的刺激，进而调控机体的代谢稳态。转录和表观遗传调控因子通过改变特定基因启动子上的组蛋白标记和染色体结构进而调控适应性产热进程。组蛋白乙酰化是最丰富的表观遗传标记之一，对转录产生重要影响，组蛋白乙酰转移酶 (HATs) 和组蛋白去乙酰化酶 (HDACs) 协同控制特定染色质位点乙酰化水平的动态转换。HDACs广泛参与肿瘤发生、免疫紊乱、神经退行性疾病发生等过程，也调控棕色和米色脂肪生理功能。已有研究报道，HDAC1通过去除组蛋白H3K27上的乙酰化修饰，增加H3K27me3修饰，从而负向调控棕色脂肪特异性基因的激活。然而，脂肪细胞中HDACs如何结合到特定基因转录起始区来调节产热过程尚不明确。此项研究利用Adiponectin-Cre驱动Pwwp2b脂肪组织特异性敲除鼠模型及棕色脂肪细胞系等，揭示了PWWP2B在棕色/米色脂肪组织中存在于核小体重塑和去乙酰化复合物中 (NuRD)，通过结合并稳定组蛋白去乙酰化酶HDAC1/2，降低基因启动子区乙酰化水平，进而发挥负向调控脂肪细胞产热的功能。本研究为以组蛋白去乙酰化酶复合物为靶点，治疗肥胖、糖尿病等代谢性疾病提供新的思路。