文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期，新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

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

相似文献

[1]
Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization.

J Cell Biol. 2024-4-1

[2]
DNMT1 regulates the timing of DNA methylation by DNMT3 in an enzymatic activity-dependent manner in mouse embryonic stem cells.

PLoS One. 2022

[3]
Knockdown of Dnmt1 and Dnmt3a gene expression disrupts preimplantation embryo development through global DNA methylation.

J Assist Reprod Genet. 2021-12

[4]
Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas.

Med Sci Monit. 2018-7-13

[5]
Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases.

Adv Exp Med Biol. 2022

[6]
Different expression patterns of DNA methyltransferases during horse testis development.

Gene. 2024-8-20

[7]
Hydrogen gas alleviates sepsis-induced neuroinflammation and cognitive impairment through regulation of DNMT1 and DNMT3a-mediated BDNF promoter IV methylation in mice.

Int Immunopharmacol. 2021-6

[8]
Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells.

Nat Genet. 2015-5

[9]
Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas.

J Neurooncol. 2011-1-13

[10]
Dnmt1, Dnmt3a and Dnmt3b cooperate in photoreceptor and outer plexiform layer development in the mammalian retina.

Exp Eye Res. 2017-6

引用本文的文献

[1]
DNA methylation influences human centromere positioning and function.

Nat Genet. 2025-9-4

[2]
Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents.

bioRxiv. 2025-7-31

[3]
Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications.

J Hematol Oncol. 2025-7-30

[4]
DNA methylation protects cancer cells against senescence.

Nat Commun. 2025-7-1

[5]
GSK-3484862, a DNMT1 degrader, promotes expression in lung cancer cells.

NAR Cancer. 2025-5-27

[6]
Selective chemical tracking of DNA methylomes in live cells.

Epigenomics. 2025-6

[7]
Induction of DNA Demethylation: Strategies and Consequences.

Epigenomes. 2025-4-12

[8]
Structure-Activity Relationship Studies of DNA Methyltransferase 1 Monovalent Degraders.

J Med Chem. 2025-2-13

[9]
Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation.

Cell. 2025-2-20

[10]
DNMT1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major DNA methylation loss.

Cell Mol Life Sci. 2024-12-18

本文引用的文献

[1]
The genome-wide mutational consequences of DNA hypomethylation.

Sci Rep. 2023-4-27

[2]
Diverse silent chromatin states modulate genome compartmentalization and loop extrusion barriers.

Nat Struct Mol Biol. 2023-1

[3]
Structural basis for activation of DNMT1.

Nat Commun. 2022-11-21

[4]
Chromatin epigenetics and nuclear lamina keep the nucleus in shape: Examples from natural and accelerated aging.

Biol Cell. 2023-1

[5]
Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.

Nat Cancer. 2021-10

[6]
Unraveling the functional role of DNA demethylation at specific promoters by targeted steric blockage of DNA methyltransferase with CRISPR/dCas9.

Nat Commun. 2021-9-29

[7]
DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity.

Cell Rep. 2021-9-21

[8]
Dnmt1 has de novo activity targeted to transposable elements.

Nat Struct Mol Biol. 2021-7

[9]
Navigating the DNA methylation landscape of cancer.

Trends Genet. 2021-11

[10]
Twelve years of SAMtools and BCFtools.

Gigascience. 2021-2-16

文献AI研究员

20分钟写一篇综述，助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索