The scaffolding function of LSD1 controls DNA methylation in mouse ESCs

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-09-05 DOI:10.1038/s41467-024-51966-7

Sandhya Malla, Kanchan Kumari, Carlos A. García-Prieto, Jonatan Caroli, Anna Nordin, Trinh T. T. Phan, Devi Prasad Bhattarai, Carlos Martinez-Gamero, Eshagh Dorafshan, Stephanie Stransky, Damiana Álvarez-Errico, Paulina Avovome Saiki, Weiyi Lai, Cong Lyu, Ludvig Lizana, Jonathan D. Gilthorpe, Hailin Wang, Simone Sidoli, Andre Mateus, Dung-Fang Lee, Claudio Cantù, Manel Esteller, Andrea Mattevi, Angel-Carlos Roman, Francesca Aguilo

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Abstract

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1^MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but not LSD1^MUT results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1^MUT control protein stability of UHRF1 and DNMT1 through interaction with HDAC1 and the ubiquitin-specific peptidase 7 (USP7), consequently, facilitating the deacetylation and deubiquitination of DNMT1 and UHRF1. Our studies elucidate a mechanism by which LSD1 controls DNA methylation in mouse ESCs, independently of its lysine demethylase activity.

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LSD1 的支架功能控制着小鼠 ESC 的 DNA 甲基化

赖氨酸特异性组蛋白去甲基化酶1（LSD1）能使赖氨酸4上的单甲基化或二甲基化组蛋白H3（H3K4me1/2）去甲基化，它对早期胚胎发生和发育至关重要。在这里，我们发现 LSD1 对小鼠胚胎干细胞（ESC）的自我更新是不可或缺的，但对小鼠 ESC 的生长和分化却是必需的。重新导入催化功能受损的 LSD1（LSD1MUT）可恢复小鼠 ESC 的增殖能力，但 LSD1 的酶活性对确保正确分化至关重要。事实上，LSD1基因敲除（KO）小鼠ESC中H3K4me1的增加并不会导致与干性有关的全局基因表达程序发生重大变化。然而，消减LSD1而非LSD1MUT会导致DNMT1和UHRF1蛋白减少，并与全局低甲基化相耦合。我们的研究表明，LSD1和LSD1MUT通过与HDAC1和泛素特异性肽酶7（USP7）相互作用，控制UHRF1和DNMT1的蛋白质稳定性，从而促进DNMT1和UHRF1的去乙酰化和去泛素化。我们的研究阐明了 LSD1 在赖氨酸去甲基化酶活性之外控制小鼠 ESC 中 DNA 甲基化的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.