Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan.
Nat Commun. 2021 Dec 2;12(1):7045. doi: 10.1038/s41467-021-27321-5.
Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated "primed" state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.
增强子激活对于细胞分化过程中特定细胞类型的基因表达至关重要，然而，增强子如何从低乙酰化的“启动”状态转变为高乙酰化的活跃状态尚不完全清楚。在这里，我们表明 SET 结构域包含 5（SETD5）与 NCoR-HDAC3 共抑制因子形成复合物，该复合物可防止主脂肪生成调节基因 Cebpa 和 Pparg 在脂肪生成早期的增强子发生组蛋白乙酰化。复合物中 SETD5 的丢失伴随着增强子的过度乙酰化。SETD5 蛋白水平在增强子激活之前短暂增加并迅速降解，为 SETD5 在过渡期间丢失提供了一种机制。我们表明，诱导泛素连接酶的 CDC20 共激活因子导致 APC/C 介导的 SETD5 在过渡期间的降解，这作为一种分子开关，促进了脂肪生成。
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