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血管成形术可诱导损伤动脉的表观基因组重塑。

Angioplasty induces epigenomic remodeling in injured arteries.

机构信息

Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA.

Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA.

出版信息

Life Sci Alliance. 2022 Feb 15;5(5). doi: 10.26508/lsa.202101114. Print 2022 May.

DOI:10.26508/lsa.202101114
PMID:35169042
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8860099/
Abstract

Neointimal hyperplasia/proliferation (IH) is the primary etiology of vascular stenosis. Epigenomic studies concerning IH have been largely confined to in vitro models, and IH-underlying epigenetic mechanisms remain poorly understood. This study integrates information from in vivo epigenomic mapping, conditional knockout, gene transfer and pharmacology in rodent models of IH. The data from injured (IH-prone) rat arteries revealed a surge of genome-wide occupancy by histone-3 lysine-27 trimethylation (H3K27me3), a gene-repression mark. This was unexpected in the traditional view of prevailing post-injury gene activation rather than repression. Further analysis illustrated a shift of H3K27me3 enrichment to anti-proliferative genes, from pro-proliferative genes where gene-activation mark H3K27ac(acetylation) accumulated instead. H3K27ac and its reader BRD4 (bromodomain protein) co-enriched at ; conditional BRD4 knockout in injured mouse arteries reduced H3K27me3 and its writer EZH2, which positively regulated another pro-IH chromatin modulator UHRF1. Thus, results uncover injury-induced loci-specific H3K27me3 redistribution in the epigenomic landscape entailing BRD4→EZH2→UHRF1 hierarchical regulations. Given that these players are pharmaceutical targets, further research may help improve treatments of IH.

摘要

血管狭窄的主要病因是新生内膜增生/增殖（IH）。关于 IH 的表观基因组学研究主要局限于体外模型，而 IH 相关的表观遗传机制仍知之甚少。本研究整合了体内表观基因组图谱、条件性基因敲除、基因转移和药理学在 IH 啮齿动物模型中的信息。损伤（IH 易感）大鼠动脉的研究数据显示，组蛋白-3 赖氨酸-27 三甲基化（H3K27me3）的全基因组占有率激增，H3K27me3 是一种基因抑制标记。这与传统的损伤后基因激活而非抑制的观点相悖，令人意外。进一步分析表明，H3K27me3 从增殖基因向抗增殖基因富集的转移，而增殖基因则积累了基因激活标记 H3K27ac（乙酰化）。H3K27ac 及其阅读器 BRD4（溴结构域蛋白）共同在 ; 条件性 BRD4 基因敲除可减少损伤小鼠动脉中的 H3K27me3 及其作者 EZH2，EZH2 正向调节另一个促 IH 染色质调节剂 UHRF1。因此，结果揭示了损伤诱导的特定于位置的 H3K27me3 在表观基因组景观中的重新分布，涉及 BRD4→EZH2→UHRF1 的层次调控。鉴于这些参与者是药物靶点，进一步的研究可能有助于改善 IH 的治疗方法。

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