Ubiquitination-dependent and -independent repression of target genes by SETDB1 reveal a context-dependent role for its methyltransferase activity during adipogenesis

被引：6

作者：

Zhang, Ji ^{[1
,2
]}

Matsumura, Yoshihiro ^{[1
]}

Kano, Yuka ^{[1
,3
]}

Yoshida, Ayano ^{[1
,4
]}

Kawamura, Takeshi ^{[5
,6
]}

Hirakawa, Hiroyuki ^{[1
,7
]}

Inagaki, Takeshi ^{[1
]}

Tanaka, Toshiya ^{[5
]}

Kimura, Hiroshi ^{[8
]}

Yanagi, Shigeru ^{[3
]}

Fukami, Kiyoko ^{[4
]}

Doi, Takefumi ^{[9
]}

Osborne, Timothy F. ^{[10
,11
]}

Kodama, Tatsuhiko ^{[5
]}

Aburatani, Hiroyuki ^{[12
]}

Sakai, Juro ^{[1
,2
]}

机构：

[1] Univ Tokyo, Div Metab Med, Res Ctr Adv Sci & Technol, Tokyo 1538904, Japan

[2] Tohoku Univ, Div Mol Physiol & Metab, Grad Sch Med, Sendai, Miyagi 9808574, Japan

[3] Tokyo Univ Pharm & Life Sci, Lab Mol Biochem, Hachioji, Tokyo, Japan

[4] Tokyo Univ Pharm & Life Sci, Lab Genome & Biosignal, Hachioji, Tokyo, Japan

[5] Univ Tokyo, Res Ctr Adv Sci & Technol, Lab Syst Biol & Med, Tokyo, Japan

[6] Univ Tokyo, Isotope Sci Ctr, Prote Lab, Tokyo, Japan

[7] Tokyo Med & Dent Univ TMDU, Grad Sch, Dept Physiol & Cell Biol, Tokyo, Japan

[8] Tokyo Inst Technol, Inst Innovat Res, Ctr Cell Biol, Yokohama, Kanagawa, Japan

[9] Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka, Japan

[10] Johns Hopkins Univ, Sch Med, Johns Hopkins All Childrens Hosp, Inst Fundamental Biomed Res, St Petersburg, FL USA

[11] Johns Hopkins Univ, Sch Med, Med, Div Endocrinol Diabet & Metab, St Petersburg, FL USA

[12] Univ Tokyo, Genome Sci Div, Res Ctr Adv Sci & Technol, Tokyo, Japan

来源：

GENES TO CELLS | 2021年 / 26卷 / 07期

关键词：

adipocytes; adipogenesis; bivalent chromatin domains; epigenome; histone methylation; post-translational modifications; ubiquitination; HISTONE H3; DNA METHYLATION; EPIGENETIC CONTROL; PROGENITOR CELLS; EXPRESSION; STEM; LYSINE; ESET; PHOSPHORYLATION; ORGANIZATION;

D O I：

10.1111/gtc.12868

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The lysine methyltransferase SETDB1, an enzyme responsible for methylation of histone H3 at lysine 9, plays a key role in H3K9 tri-methylation-dependent silencing of endogenous retroviruses and developmental genes. Recent studies have shown that ubiquitination of human SETDB1 complements its catalytic activity and the silencing of endogenous retroviruses in human embryonic stem cells. However, it is not known whether SETDB1 ubiquitination is essential for its other major role in epigenetic silencing of developmental gene programs. We previously showed that SETDB1 contributes to the formation of H3K4/H3K9me3 bivalent chromatin domains that keep adipogenic Cebpa and Pparg genes in a poised state for activation and restricts the differentiation potential of pre-adipocytes. Here, we show that ubiquitin-resistant K885A mutant of SETDB1 represses adipogenic genes and inhibits pre-adipocyte differentiation similar to wild-type SETDB1. We show this was due to a compensation mechanism for H3K9me3 chromatin modifications on the Cebpa locus by other H3K9 methyltransferases Suv39H1 and Suv39H2. In contrast, the K885A mutant did not repress other SETDB1 target genes such as Tril and Gas6 suggesting SETDB1 represses its target genes by two mechanisms; one that requires its ubiquitination and another that still requires SETDB1 but not its enzyme activity.

引用

页码：513 / 529

页数：17