LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes

被引：7

作者：

Dan, Songsong ^{[1
]}

Song, Yuelin ^{[2
]}

Duan, Xiaotao ^{[3
]}

Pan, Xiao ^{[2
]}

Chen, Cheng ^{[1
]}

She, Shiqi ^{[1
]}

Su, Tong ^{[2
]}

Li, Jingchao ^{[2
]}

Chen, Xinyu ^{[1
]}

Zhou, Yanwen ^{[1
]}

Chen, Wenjie ^{[1
]}

Zhang, Xiaobing ^{[1
]}

Pan, Xiaoyun ^{[1
]}

Wang, Ying-Jie ^{[1
]}

Kang, Bo ^{[1
]}

机构：

[1] Zhejiang Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, State Key Lab Diag & Treatment Infect Dis,Sch Med, Natl Clin Res Ctr Infect Dis,Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China

[2] Zhejiang Univ, Coll Life Sci, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China

[3] Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing 100850, Peoples R China

来源：

SCIENTIFIC REPORTS | 2021年 / 11卷 / 01期

关键词：

INTERACTION NETWORK; SELF-RENEWAL; DNA-BINDING; POU-DOMAIN; METHYLATION; PROMOTES; DIFFERENTIATION; DEGRADATION; NANOG; WWP2;

D O I：

10.1038/s41598-021-89734-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Reversible lysine methylation is essential for regulating histones and emerges to critically regulate non-histone proteins as well. Here we show that the master transcription factor OCT4 in pluripotent stem cells (PSCs) was methylated at multiple lysine residues. LSD1 that is highly expressed in PSCs can directly interact with and demethylate OCT4 at lysine 222 (K222) in the flexible linker region. Reduced LSD1 activity led to the methylation of OCT4-K222 that diminished the differentiation potential of PSCs while facilitating proteasome-independent degradation of OCT4 proteins. Furthermore, site-specifically replacing K222 with phenylalanine to mimic the constitutively methylated lysine promoted the 'locked-in' mode engagement of the OCT4 PORE-homodimers that tightly bind to and block the transcription of multiple PORE-motif-containing target genes regulating cell fate determination and cell junction organization, and thereby reducing the pluripotency of PSCs. Thus, LSD1-mediated demethylation of OCT4 plays a crucial role in restricting the 'locked-in' mode binding of OCT4 PORE-homodimers to the PORE-motif-containing genes and thereby maintaining their transcription to safeguard the pluripotency of PSCs.

引用

页数：14

共 48 条

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