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细胞类型特异性基因的表达至关重要，但是，增强子如何从低乙酰化“启动”状态转变为高乙酰化活性状态尚不完全清楚。在这里，我们展示了包含 SET 结构域的 5 (SETD5) 与 NCoR-HDAC3 共阻遏物形成复合物，可防止两个主要脂肪生成调节基因Cebpa和Pparg增强子的组蛋白乙酰化在脂肪形成的早期。复合物中 SETD5 的丢失之后是增强子超乙酰化。SETD5 蛋白水平在增强子激活之前短暂增加并迅速降解，为过渡期间 SETD5 的丢失提供了一种机制。我们表明，泛素连接酶的 CDC20 共激活因子的诱导导致 APC/C 介导的 SETD5 在转变过程中的降解，并且这作为促进脂肪形成的分子开关起作用。