LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes
Abstract 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 express...
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2021
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oai:doaj.org-article:9929f6a3d4b34a3cb2452e62d3f230822021-12-02T15:55:03ZLSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes10.1038/s41598-021-89734-y2045-2322https://doaj.org/article/9929f6a3d4b34a3cb2452e62d3f230822021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89734-yhttps://doaj.org/toc/2045-2322Abstract 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.Songsong DanYuelin SongXiaotao DuanXiao PanCheng ChenShiqi SheTong SuJingchao LiXinyu ChenYanwen ZhouWenjie ChenXiaobing ZhangXiaoyun PanYing-Jie WangBo KangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
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Medicine R Science Q Songsong Dan Yuelin Song Xiaotao Duan Xiao Pan Cheng Chen Shiqi She Tong Su Jingchao Li Xinyu Chen Yanwen Zhou Wenjie Chen Xiaobing Zhang Xiaoyun Pan Ying-Jie Wang Bo Kang LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes |
| description |
Abstract 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. |
| format |
article |
| author |
Songsong Dan Yuelin Song Xiaotao Duan Xiao Pan Cheng Chen Shiqi She Tong Su Jingchao Li Xinyu Chen Yanwen Zhou Wenjie Chen Xiaobing Zhang Xiaoyun Pan Ying-Jie Wang Bo Kang |
| author_facet |
Songsong Dan Yuelin Song Xiaotao Duan Xiao Pan Cheng Chen Shiqi She Tong Su Jingchao Li Xinyu Chen Yanwen Zhou Wenjie Chen Xiaobing Zhang Xiaoyun Pan Ying-Jie Wang Bo Kang |
| author_sort |
Songsong Dan |
| title |
LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes |
| title_short |
LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes |
| title_full |
LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes |
| title_fullStr |
LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes |
| title_full_unstemmed |
LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes |
| title_sort |
lsd1-mediated demethylation of oct4 safeguards pluripotent stem cells by maintaining the transcription of pore-motif-containing genes |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/9929f6a3d4b34a3cb2452e62d3f23082 |
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