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 Kimura; Youichiro Wada; Tatsuhiko Kodama; Takeshi Inagaki; Timothy F Osborne; Hiroyuki Aburatani; Koichi Node; Juro Sakai

doi:10.1038/s41467-021-27321-5

Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis

Nat Commun. 2021 Dec 2;12(1):7045. doi: 10.1038/s41467-021-27321-5.

Authors

Yoshihiro Matsumura^#¹, Ryo Ito^#², Ayumu Yajima^#^{3

4}, Rei Yamaguchi², Toshiya Tanaka⁵, Takeshi Kawamura⁶, Kenta Magoori³, Yohei Abe³, Aoi Uchida³, Takeshi Yoneshiro³, Hiroyuki Hirakawa^{3

7}, Ji Zhang^{3

2}, Makoto Arai^{3

2}, Chaoran Yang², Ge Yang², Hiroki Takahashi², Hitomi Fujihashi³, Ryo Nakaki^{8

9}, Shogo Yamamoto⁸, Satoshi Ota⁸, Shuichi Tsutsumi⁸, Shin-Ichi Inoue², Hiroshi Kimura¹⁰, Youichiro Wada⁶, Tatsuhiko Kodama⁵, Takeshi Inagaki^{3

11}, Timothy F Osborne¹², Hiroyuki Aburatani⁸, Koichi Node⁴, Juro Sakai^{13

14}

Affiliations

¹ Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [email protected].
² Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan.
³ Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
⁴ Department of Cardiovascular Medicine, Saga University, Saga, Japan.
⁵ Department of Nuclear Receptor Medicine, Laboratories for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
⁶ Isotope Science Center, The University of Tokyo, Tokyo, Japan.
⁷ Department of Physiology and Cell Biology, Tokyo Medical and Dental University (TMDU), Graduate School, Tokyo, Japan.
⁸ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
⁹ Rhelixa Inc, Tokyo, Japan.
¹⁰ Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.
¹¹ Laboratory of Epigenetics and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
¹² Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, and Medicine in the Division of Endocrinology, Diabetes and Metabolism of the Johns Hopkins University School of Medicine, Petersburg, FL, USA.
¹³ Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [email protected].
¹⁴ Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Acetylation
Adipogenesis / genetics*
Anaphase-Promoting Complex-Cyclosome / genetics
Anaphase-Promoting Complex-Cyclosome / metabolism
Animals
CCAAT-Enhancer-Binding Proteins / genetics*
CCAAT-Enhancer-Binding Proteins / metabolism
Cdc20 Proteins / genetics
Cdc20 Proteins / metabolism
Enhancer Elements, Genetic
Gene Expression Regulation
HEK293 Cells
Histone Deacetylases / genetics*
Histone Deacetylases / metabolism
Histones / genetics
Histones / metabolism
Humans
Methyltransferases / genetics*
Methyltransferases / metabolism
Mice
Mice, Nude
Nuclear Receptor Co-Repressor 1 / genetics*
Nuclear Receptor Co-Repressor 1 / metabolism
PPAR gamma / genetics*
PPAR gamma / metabolism
Protein Binding
Proteolysis
Sf9 Cells
Signal Transduction

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, mouse
Cdc20 Proteins
Cdc20 protein, mouse
Histones
Ncor1 protein, mouse
Nuclear Receptor Co-Repressor 1
PPAR gamma
Pparg protein, mouse
Methyltransferases
SETD5 protein, mouse
Anaphase-Promoting Complex-Cyclosome
Histone Deacetylases
histone deacetylase 3