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LSD1 介导的 OCT4 去甲基化通过维持 PORE 基序基因的转录来保护多能干细胞。

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

机构信息

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.

College of Life Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, China.

出版信息

Sci Rep. 2021 May 13;11(1):10285. doi: 10.1038/s41598-021-89734-y.

DOI:10.1038/s41598-021-89734-y
PMID:33986438
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8119428/
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.

摘要

赖氨酸可逆甲基化对于调控组蛋白至关重要，而且似乎也能精细调控非组蛋白。本文中，我们发现多潜能干细胞（PSCs）中的主转录因子 OCT4 多个赖氨酸残基发生了甲基化。在 PSCs 中高度表达的 LSD1 可直接与 OCT4 的柔性连接区的赖氨酸 222（K222）结合，并使其去甲基化。LSD1 活性降低会导致 OCT4-K222 甲基化，从而降低 PSCs 的分化潜能，同时促进 OCT4 蛋白的非蛋白酶体降解。此外，通过将 K222 突变为苯丙氨酸来模拟组蛋白赖氨酸的持续甲基化，可促进 OCT4 PORE 同源二聚体的“锁定”模式结合，从而紧密结合并阻断多个含有 PORE 基序的靶基因的转录，这些靶基因参与细胞命运决定和细胞连接组织的调控，从而降低 PSCs 的多能性。因此，LSD1 介导的 OCT4 去甲基化在限制 OCT4 PORE 同源二聚体与含有 PORE 基序的基因的“锁定”模式结合方面发挥着关键作用，从而维持它们的转录，以保障 PSCs 的多能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c6bc4de55e75/41598_2021_89734_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c7b5d9c448ed/41598_2021_89734_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/d987365715e5/41598_2021_89734_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c6b91f4b4936/41598_2021_89734_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/0e7aeb226bf8/41598_2021_89734_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c6bc4de55e75/41598_2021_89734_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c7b5d9c448ed/41598_2021_89734_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/d987365715e5/41598_2021_89734_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c6b91f4b4936/41598_2021_89734_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/0e7aeb226bf8/41598_2021_89734_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4453/8119428/c6bc4de55e75/41598_2021_89734_Fig5_HTML.jpg

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