H3.3K36M 同源组蛋白通过 DNA 甲基化的丧失破坏表观遗传记忆的建立

IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu
{"title":"H3.3K36M 同源组蛋白通过 DNA 甲基化的丧失破坏表观遗传记忆的建立","authors":"Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu","doi":"10.1016/j.molcel.2024.09.015","DOIUrl":null,"url":null,"abstract":"Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"51 1","pages":""},"PeriodicalIF":14.5000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation\",\"authors\":\"Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu\",\"doi\":\"10.1016/j.molcel.2024.09.015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.\",\"PeriodicalId\":18950,\"journal\":{\"name\":\"Molecular Cell\",\"volume\":\"51 1\",\"pages\":\"\"},\"PeriodicalIF\":14.5000,\"publicationDate\":\"2024-10-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cell\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.molcel.2024.09.015\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.molcel.2024.09.015","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

组蛋白 H3.3 经常在肿瘤中发生突变,其中赖氨酸 36 变蛋氨酸突变(K36M)是软骨母细胞瘤的特征之一。众所周知,H3.3K36M 会改变表观遗传景观,但它对基因表达动态的影响仍不清楚。在这里,我们使用一种合成报告基因来测量 H3.3K36M 招募 ZNF10 Krüppel-associated box(KRAB)结构域后对沉默和表观遗传记忆的影响,ZNF10 Krüppel-associated box(KRAB)结构域是人类最大一类抑制因子的一部分,与 H3K9me3 沉积有关。我们发现,H3.3K36M 会减少 H3K36 甲基化,增加组蛋白乙酰化,从而导致表观遗传记忆和启动子甲基化在 KRAB 释放数周后减少。我们提出了一个建立和维持表观遗传记忆的模型,在该模型中,H3K36甲基化途径是维持组蛋白去乙酰化和将H3K9me3域转化为DNA甲基化以获得稳定的表观遗传记忆所必需的。我们的定量模型可以为致癌机制提供信息,并指导表观遗传编辑工具的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation
Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
期刊介绍: Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信