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LSD1 的支架功能控制着小鼠胚胎干细胞中的 DNA 甲基化。

The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.

机构信息

Department of Molecular Biology, Umeå University, Umeå, Sweden.

Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.

出版信息

Nat Commun. 2024 Sep 5;15(1):7758. doi: 10.1038/s41467-024-51966-7.

DOI:10.1038/s41467-024-51966-7
PMID:39237615
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11377572/
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) 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 results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1 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.

摘要

赖氨酸特异性组蛋白去甲基化酶 1（LSD1），可将赖氨酸 4 上的单甲基或二甲基化组蛋白 H3（H3K4me1/2）去甲基化，对早期胚胎发生和发育至关重要。在这里，我们表明 LSD1 对于小鼠胚胎干细胞（ESC）的自我更新不是必需的，但对于小鼠 ESC 的生长和分化是必需的。催化缺陷 LSD1（LSD1）的重新引入恢复了小鼠 ESC 的增殖能力，但 LSD1 的酶活性对于确保适当的分化是必不可少的。事实上，Lsd1 敲除（KO）小鼠 ESC 中 H3K4me1 的增加不会导致与干性相关的全局基因表达程序发生重大变化。然而，LSD1 的缺失而不是 LSD1 的缺失导致 DNMT1 和 UHRF1 蛋白的减少与全局低甲基化相关联。我们表明，LSD1 和 LSD1 通过与组蛋白去乙酰化酶 1（HDAC1）和泛素特异性肽酶 7（USP7）的相互作用，控制 UHRF1 和 DNMT1 的蛋白稳定性，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 在不依赖其赖氨酸去甲基化活性的情况下，控制小鼠 ESC 中 DNA 甲基化的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/58bdadb3f664/41467_2024_51966_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/80b925b812c6/41467_2024_51966_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/4fb05393ff4e/41467_2024_51966_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/c020b17e5758/41467_2024_51966_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/30f8e3abb6b3/41467_2024_51966_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/92bc124de942/41467_2024_51966_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/fb1427861a4b/41467_2024_51966_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/ab0a1c6dce01/41467_2024_51966_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/58bdadb3f664/41467_2024_51966_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/80b925b812c6/41467_2024_51966_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/4fb05393ff4e/41467_2024_51966_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/c020b17e5758/41467_2024_51966_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/30f8e3abb6b3/41467_2024_51966_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/92bc124de942/41467_2024_51966_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/fb1427861a4b/41467_2024_51966_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/ab0a1c6dce01/41467_2024_51966_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/245c/11377572/58bdadb3f664/41467_2024_51966_Fig8_HTML.jpg

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