Spatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis
Yoshihiro Matsumura, Ryo Ito, Ayumu Yajima, Rei Yamaguchi, Toshiya Tanaka, Takeshi Kawamura, Kenta Magoori, Yohei Abe, Aoi Uchida, Takeshi Yoneshiro, Hiroyuki Hirakawa, Ji Zhang, Makoto Arai, Chaoran Yang, Ge Yang, Hiroki Takahashi, Hitomi Fujihashi, Ryo Nakaki, Shogo Yamamoto, Satoshi Ota, Shuichi Tsutsumi, Shin‐ichi Inoue, Hiroshi Kimurâ, Youichiro Wada, Tatsuhiko Kodama, Takeshi Inagaki, Timothy F. Osborne, Hiroyuki Aburatani, Koichi Node, Juro Sakai
Abstract
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.