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可调节的DNA甲基转移酶1降解揭示了DNA甲基转移酶1/DNA甲基转移酶3B在DNA甲基化和基因组组织中的协同作用。

Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization.

作者信息

Scelfo Andrea, Barra Viviana, Abdennur Nezar, Spracklin George, Busato Florence, Salinas-Luypaert Catalina, Bonaiti Elena, Velasco Guillaume, Bonhomme Frédéric, Chipont Anna, Tijhuis Andréa E, Spierings Diana C J, Guérin Coralie, Arimondo Paola, Francastel Claire, Foijer Floris, Tost Jӧrg, Mirny Leonid, Fachinetti Daniele

机构信息

Institut Curie, PSL Research University, Sorbonne Université, CNRS, UMR 144 , Paris, France.

Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.

出版信息

J Cell Biol. 2024 Apr 1;223(4). doi: 10.1083/jcb.202307026. Epub 2024 Feb 20.

DOI:10.1083/jcb.202307026
PMID:38376465
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10876481/
Abstract

DNA methylation (DNAme) is a key epigenetic mark that regulates critical biological processes maintaining overall genome stability. Given its pleiotropic function, studies of DNAme dynamics are crucial, but currently available tools to interfere with DNAme have limitations and major cytotoxic side effects. Here, we present cell models that allow inducible and reversible DNAme modulation through DNMT1 depletion. By dynamically assessing whole genome and locus-specific effects of induced passive demethylation through cell divisions, we reveal a cooperative activity between DNMT1 and DNMT3B, but not of DNMT3A, to maintain and control DNAme. We show that gradual loss of DNAme is accompanied by progressive and reversible changes in heterochromatin, compartmentalization, and peripheral localization. DNA methylation loss coincides with a gradual reduction of cell fitness due to G1 arrest, with minor levels of mitotic failure. Altogether, this system allows DNMTs and DNA methylation studies with fine temporal resolution, which may help to reveal the etiologic link between DNAme dysfunction and human disease.

摘要

DNA甲基化(DNAme)是一种关键的表观遗传标记,可调节维持整体基因组稳定性的关键生物学过程。鉴于其多效性功能,对DNAme动力学的研究至关重要,但目前可用的干扰DNAme的工具存在局限性且具有主要的细胞毒性副作用。在此,我们展示了通过DNMT1缺失实现可诱导和可逆的DNAme调节的细胞模型。通过动态评估诱导的被动去甲基化在细胞分裂过程中对全基因组和位点特异性的影响,我们揭示了DNMT1和DNMT3B之间的协同活性,而不是DNMT3A,以维持和控制DNAme。我们表明,DNAme的逐渐丧失伴随着异染色质、区室化和外周定位的渐进性和可逆性变化。DNA甲基化的丧失与由于G1期停滞导致的细胞适应性逐渐降低以及轻微水平的有丝分裂失败相吻合。总之,该系统允许以精细的时间分辨率进行DNA甲基转移酶和DNA甲基化研究,这可能有助于揭示DNAme功能障碍与人类疾病之间的病因联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/e28e4cae30b8/JCB_202307026_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/d55b770be71c/JCB_202307026_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/774a4344b501/JCB_202307026_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/74c6a12e6961/JCB_202307026_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/c576c66b415e/JCB_202307026_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/246205968b49/JCB_202307026_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/933eb39e2bcf/JCB_202307026_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/e91017a93d50/JCB_202307026_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/53f1db092236/JCB_202307026_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/e28e4cae30b8/JCB_202307026_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/d55b770be71c/JCB_202307026_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/774a4344b501/JCB_202307026_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/74c6a12e6961/JCB_202307026_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/c576c66b415e/JCB_202307026_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/246205968b49/JCB_202307026_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/933eb39e2bcf/JCB_202307026_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/e91017a93d50/JCB_202307026_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/53f1db092236/JCB_202307026_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c769/10876481/e28e4cae30b8/JCB_202307026_FigS5.jpg

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