PWWP2B Fine-Tunes Adipose Thermogenesis by Stabilizing HDACs in a NuRD Subcomplex.
PWWP2B Fine-Tunes Adipose Thermogenesis by Stabilizing HDACs in a NuRD Subcomplex.
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PWWP2B 通过稳定 NuRD 子复合物中的 HDAC 来微调脂肪产热
DOI：
10.1002/advs.202102060
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Pan D
中科院分区：
文献类型：
--
作者：
Yan L;Jin W;Zhao Q;Cui X;Shi T;Xu Y;Li F;Jin W;Zhang Z;Zhang Z;Tang QQ;Pan D
组蛋白脱乙酰酶(HDACs)广泛参与许多生物过程，以及控制棕色和米色脂肪生理，但HDACs组装成转录机制以微调生热程序的确切分子机制仍不明确。含有2b的PWWP结构域(PWWP2B)是核小体重塑和去乙酰化复合体(NuRD)的一个组成部分，它与产热基因启动子上的HDAC1/2相互作用并稳定下来，从而抑制其表达。体内消融Pwwp2b促进脂肪细胞产热，改善饮食诱导的肥胖。有趣的是，Pwwp2b不仅是一个富含棕色脂肪的基因，而且在寒冷和交感刺激的刺激下也能显著诱导，这可能是一种生理刹车，以避免棕色和米色脂肪细胞的产热过度激活。这项工作揭示了微调脂肪细胞产热的负调控机制，并强调包含2b的PWWP结构域(PWWP2B)是保持适当生热活性的内在刹车。PWWP2B稳定NuRD亚复合体中的HDAC1/2，并促进NuRD介导的致热基因启动子上的脱乙酰化。PWWP2B-HDAC相互协调以防止因激活生热程序而消耗过多的能量。
Histone deacetylases (HDACs) are widely involved in many biological processes, as well as in control of brown and beige adipose physiology, but the precise molecular mechanisms by which HDACs are assembled into transcriptional machinery to fine‐tune thermogenic program remain ill‐defined. PWWP domain containing 2b (PWWP2B), which is identified as a component of the nucleosome remodeling and deacetylation complex (NuRD), interacts and stabilizes HDAC1/2 at the thermogenic gene promoters to suppress their expression. Ablation of Pwwp2b promotes adipocyte thermogenesis and ameliorates diet‐induced obesity in vivo. Intriguingly, Pwwp2b is not only a brown fat‐enriched gene but also dramatically induced by cold and sympathetic stimulation, which may serve as a physiological brake to avoid over‐activation of thermogenesis in brown and beige fat cells. This work reveals a negative regulation mechanism to fine‐tune adipocyte thermogenesis, and highlights PWWP domain containing 2b (PWWP2B) as an intrinsic brake to keep thermogenic activity appropriately. PWWP2B stabilizes HDAC1/2 in a NuRD subcomplex, and promotes NuRD‐mediated deacetylation on thermogenic gene promoters. PWWP2B‐HDACs coordinate to prevent dissipating too much energy from activation of thermogenic program.
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