SUV39H1在平滑肌细胞表型可塑性中调控KLF4和染色质重塑。

IF 7.4 1区 医学 Q1 HEMATOLOGY
Payel Chatterjee, Raja Chakraborty, Ashley J Sizer, Brendan J O'Brien, Peng Xu, Jonathan M Hwa, Yi Xie, Qin Yan, John Hwa, Kathleen A Martin
{"title":"SUV39H1在平滑肌细胞表型可塑性中调控KLF4和染色质重塑。","authors":"Payel Chatterjee, Raja Chakraborty, Ashley J Sizer, Brendan J O'Brien, Peng Xu, Jonathan M Hwa, Yi Xie, Qin Yan, John Hwa, Kathleen A Martin","doi":"10.1161/ATVBAHA.124.322179","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Reversible DNA methylation contributes to vascular smooth muscle cell (VSMC) phenotypic plasticity. This plasticity contributes to vascular growth and remodeling but also underlies pathologies, including intimal hyperplasia. We investigated the role of SUV39H1 (suppressor of variegation 3-9 homolog 1), a histone methyltransferase that generates trimethylation at histone H3 lysine 9 (H3K9me3), a repressive heterochromatin-associated epigenetic mark, in VSMC plasticity.</p><p><strong>Methods: </strong>We applied knockdown, quantitative polymerase chain reaction, Western blotting, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing, and RNA-sequencing in human coronary artery smooth muscle cells and murine carotid ligation to assess SUV39H1 functions in VSMC plasticity.</p><p><strong>Results: </strong>In normal mouse carotid artery, SUV39H1 and H3K9me3 were markedly increased, while the cognate H3K9me3 demethylase KDM4A rapidly decreased with carotid ligation and neointimal hyperplasia. In human coronary artery smooth muscle cells, SUV39H1 knockdown induced contractile genes, morphology, and contractility but inhibited migration and proliferation. We found that SUV39H1 was required for PDGF (platelet-derived growth factor) induction of KLF4, regulating miR143, KLF4 mRNA stability, and promoter accessibility. PDGF-induced SUV39H1 expression and SUV39H1-dependent H3K9me3 modification at contractile gene promoters. SUV39H1 knockdown increased KDM4A expression and binding to contractile promoters, suggesting an opposing regulatory relationship between the H3K9me3 writer and eraser in VSMCs. Chromatin immunoprecipitation assays with SUV39H1 knockdown revealed that SUV39H1 modifies H3K9me3 but also promotes a repressive state (increased 5mC and reduced H3K27Ac) at contractile gene promoters. Conversely, SUV39H1 induced an active state at the KLF4 promoter, reducing DNMT1 (DNA methyltransferases 1) recruitment and 5mC levels. Assay for transposase-accessible chromatin using sequencing revealed that SUV39H1 oppositely modifies chromatin accessibility at phenotype-specific human coronary artery smooth muscle cell promoters genome-wide. Consistently, transcriptomic profiling showed that SUV39H1 and TET2 oppositely influence SMC gene expression.</p><p><strong>Conclusions: </strong>We identify SUV39H1 as a potent PDGF-induced epigenetic regulator that promotes KLF4 expression and VSMC dedifferentiation. SUV39H1 regulates dynamic trimethylation at histone H3 lysine 9 in phenotypic switching, regulating mark deposition and the KDM4A demethylase. We report that SUV39H1 coordinately regulates DNA and histone methylation and histone acetylation. This altered chromatin accessibility by a heterochromatin-associated enzyme represents a new mechanism underlying VSMC plasticity.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4000,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"SUV39H1 Regulates KLF4 and Chromatin Remodeling in Smooth Muscle Cell Phenotypic Plasticity.\",\"authors\":\"Payel Chatterjee, Raja Chakraborty, Ashley J Sizer, Brendan J O'Brien, Peng Xu, Jonathan M Hwa, Yi Xie, Qin Yan, John Hwa, Kathleen A Martin\",\"doi\":\"10.1161/ATVBAHA.124.322179\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Reversible DNA methylation contributes to vascular smooth muscle cell (VSMC) phenotypic plasticity. This plasticity contributes to vascular growth and remodeling but also underlies pathologies, including intimal hyperplasia. We investigated the role of SUV39H1 (suppressor of variegation 3-9 homolog 1), a histone methyltransferase that generates trimethylation at histone H3 lysine 9 (H3K9me3), a repressive heterochromatin-associated epigenetic mark, in VSMC plasticity.</p><p><strong>Methods: </strong>We applied knockdown, quantitative polymerase chain reaction, Western blotting, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing, and RNA-sequencing in human coronary artery smooth muscle cells and murine carotid ligation to assess SUV39H1 functions in VSMC plasticity.</p><p><strong>Results: </strong>In normal mouse carotid artery, SUV39H1 and H3K9me3 were markedly increased, while the cognate H3K9me3 demethylase KDM4A rapidly decreased with carotid ligation and neointimal hyperplasia. In human coronary artery smooth muscle cells, SUV39H1 knockdown induced contractile genes, morphology, and contractility but inhibited migration and proliferation. We found that SUV39H1 was required for PDGF (platelet-derived growth factor) induction of KLF4, regulating miR143, KLF4 mRNA stability, and promoter accessibility. PDGF-induced SUV39H1 expression and SUV39H1-dependent H3K9me3 modification at contractile gene promoters. SUV39H1 knockdown increased KDM4A expression and binding to contractile promoters, suggesting an opposing regulatory relationship between the H3K9me3 writer and eraser in VSMCs. Chromatin immunoprecipitation assays with SUV39H1 knockdown revealed that SUV39H1 modifies H3K9me3 but also promotes a repressive state (increased 5mC and reduced H3K27Ac) at contractile gene promoters. Conversely, SUV39H1 induced an active state at the KLF4 promoter, reducing DNMT1 (DNA methyltransferases 1) recruitment and 5mC levels. Assay for transposase-accessible chromatin using sequencing revealed that SUV39H1 oppositely modifies chromatin accessibility at phenotype-specific human coronary artery smooth muscle cell promoters genome-wide. Consistently, transcriptomic profiling showed that SUV39H1 and TET2 oppositely influence SMC gene expression.</p><p><strong>Conclusions: </strong>We identify SUV39H1 as a potent PDGF-induced epigenetic regulator that promotes KLF4 expression and VSMC dedifferentiation. SUV39H1 regulates dynamic trimethylation at histone H3 lysine 9 in phenotypic switching, regulating mark deposition and the KDM4A demethylase. We report that SUV39H1 coordinately regulates DNA and histone methylation and histone acetylation. This altered chromatin accessibility by a heterochromatin-associated enzyme represents a new mechanism underlying VSMC plasticity.</p>\",\"PeriodicalId\":8401,\"journal\":{\"name\":\"Arteriosclerosis, Thrombosis, and Vascular Biology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2025-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arteriosclerosis, Thrombosis, and Vascular Biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/ATVBAHA.124.322179\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arteriosclerosis, Thrombosis, and Vascular Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/ATVBAHA.124.322179","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:可逆DNA甲基化有助于血管平滑肌细胞(VSMC)表型可塑性。这种可塑性有助于血管生长和重塑,但也可能导致包括内膜增生在内的病理。我们研究了SUV39H1(抑制杂色3-9同源物1)在VSMC可塑性中的作用,SUV39H1是一种组蛋白甲基转移酶,在组蛋白H3赖氨酸9 (H3K9me3)上产生三甲基化,这是一种抑制性异染色质相关的表观遗传标记。方法:采用敲低、定量聚合酶链反应、Western blotting、染色质免疫沉淀、转座酶可及染色质测序、rna测序等方法,在人冠状动脉平滑肌细胞和小鼠颈动脉结扎中评估SUV39H1在VSMC可塑性中的功能。结果:在正常小鼠颈动脉中,SUV39H1和H3K9me3明显升高,而同源H3K9me3去甲基化酶KDM4A随着颈动脉结扎和新生内膜增生而迅速降低。在人冠状动脉平滑肌细胞中,SUV39H1敲低诱导收缩基因、形态和收缩性,但抑制迁移和增殖。我们发现SUV39H1是PDGF(血小板衍生生长因子)诱导KLF4、调节miR143、KLF4 mRNA稳定性和启动子可及性所必需的。pdgf诱导SUV39H1表达和SUV39H1依赖的H3K9me3在收缩基因启动子上的修饰。SUV39H1敲低增加了KDM4A的表达和与收缩启动子的结合,提示VSMCs中H3K9me3写入者和擦除者之间存在相反的调控关系。SUV39H1敲低的染色质免疫沉淀试验显示,SUV39H1修饰了H3K9me3,但也促进了收缩基因启动子的抑制状态(增加5mC和减少H3K27Ac)。相反,SUV39H1诱导KLF4启动子的活性状态,降低DNMT1 (DNA甲基转移酶1)的募集和5mC水平。利用测序技术对转座酶可接近的染色质进行分析,发现SUV39H1在全基因组范围内相反地修饰表型特异性人类冠状动脉平滑肌细胞启动子的染色质可接近性。转录组学分析一致显示SUV39H1和TET2相反地影响SMC基因的表达。结论:我们发现SUV39H1是一种有效的pdgf诱导的表观遗传调节剂,可促进KLF4表达和VSMC去分化。SUV39H1调节表型转换中组蛋白H3赖氨酸9的动态三甲基化,调节标记沉积和KDM4A去甲基化酶。我们报道SUV39H1协调调节DNA和组蛋白甲基化和组蛋白乙酰化。这种异染色质相关酶对染色质可及性的改变代表了VSMC可塑性的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
SUV39H1 Regulates KLF4 and Chromatin Remodeling in Smooth Muscle Cell Phenotypic Plasticity.

Background: Reversible DNA methylation contributes to vascular smooth muscle cell (VSMC) phenotypic plasticity. This plasticity contributes to vascular growth and remodeling but also underlies pathologies, including intimal hyperplasia. We investigated the role of SUV39H1 (suppressor of variegation 3-9 homolog 1), a histone methyltransferase that generates trimethylation at histone H3 lysine 9 (H3K9me3), a repressive heterochromatin-associated epigenetic mark, in VSMC plasticity.

Methods: We applied knockdown, quantitative polymerase chain reaction, Western blotting, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing, and RNA-sequencing in human coronary artery smooth muscle cells and murine carotid ligation to assess SUV39H1 functions in VSMC plasticity.

Results: In normal mouse carotid artery, SUV39H1 and H3K9me3 were markedly increased, while the cognate H3K9me3 demethylase KDM4A rapidly decreased with carotid ligation and neointimal hyperplasia. In human coronary artery smooth muscle cells, SUV39H1 knockdown induced contractile genes, morphology, and contractility but inhibited migration and proliferation. We found that SUV39H1 was required for PDGF (platelet-derived growth factor) induction of KLF4, regulating miR143, KLF4 mRNA stability, and promoter accessibility. PDGF-induced SUV39H1 expression and SUV39H1-dependent H3K9me3 modification at contractile gene promoters. SUV39H1 knockdown increased KDM4A expression and binding to contractile promoters, suggesting an opposing regulatory relationship between the H3K9me3 writer and eraser in VSMCs. Chromatin immunoprecipitation assays with SUV39H1 knockdown revealed that SUV39H1 modifies H3K9me3 but also promotes a repressive state (increased 5mC and reduced H3K27Ac) at contractile gene promoters. Conversely, SUV39H1 induced an active state at the KLF4 promoter, reducing DNMT1 (DNA methyltransferases 1) recruitment and 5mC levels. Assay for transposase-accessible chromatin using sequencing revealed that SUV39H1 oppositely modifies chromatin accessibility at phenotype-specific human coronary artery smooth muscle cell promoters genome-wide. Consistently, transcriptomic profiling showed that SUV39H1 and TET2 oppositely influence SMC gene expression.

Conclusions: We identify SUV39H1 as a potent PDGF-induced epigenetic regulator that promotes KLF4 expression and VSMC dedifferentiation. SUV39H1 regulates dynamic trimethylation at histone H3 lysine 9 in phenotypic switching, regulating mark deposition and the KDM4A demethylase. We report that SUV39H1 coordinately regulates DNA and histone methylation and histone acetylation. This altered chromatin accessibility by a heterochromatin-associated enzyme represents a new mechanism underlying VSMC plasticity.

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
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
×
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:604180095
Book学术官方微信