Histone modification landscape and the key significance of H3K27me3 in myocardial ischaemia/reperfusion injury

作     者：Le Ni Bowen Lin Yanping Zhang Lingjie Hu Jianghua Lin Fengmei Fu Meiting Shen Can Li Lei Chen Jian Yang Dan Shi Yi-Han Chen 

作者机构：Department of CardiologyShanghai East HospitalTongji University School of MedicineShanghai200120China Key Laboratory of Arrhythmias of the Ministry of Education of ChinaShanghai East HospitalTongji University School of MedicineShanghai200120China Department of Vascular and CardiologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025China Jinzhou Medical UniversityLiaoning121000China Shanghai Frontiers Science Center of Nanocatalytic MedicineShanghai200092China Department of Pathology and PathophysiologyTongji University School of MedicineShanghai200092China Research Units of Origin and Regulation of Heart RhythmChinese Academy of Medical SciencesShanghai200092China 

出 版 物：《Science China(Life Sciences)》 (中国科学（生命科学英文版）)

年 卷 期：2023年第66卷第6期

页      面：1264-1279页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (82088101,81930013,82000377,31871491) the National Key Research and Development Plan (2019YFA0801501) Key Research Center Construction Project of Shanghai (2022ZZ01008) Shanghai Key clinical specialty Project (shslczdzk06202) Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (PWZxq2017-05) Top-level Clinical Discipline Project of Shanghai Pudong District (PWYgf2021-01) Program for the Research Unit of Origin and Regulation of Heart Rhythm,Chinese Academy of Medical Sciences (2019RU045) Innovative research team of high-level local universities in Shanghai and a key laboratory program of the Education Commission of Shanghai Municipality (ZDSYS14005)。 

主　　题：histone modification myocardial ischemia/reperfusion EZH2 H3K27me3 angiogenesis 

摘      要：Histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion(I/R)injury.However,a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established.Here,we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury.Disease-specific histone mark alterations were mainly found in H3K27me3-,H3K27ac-,and H3K4me1-marked regions 24 and 48 h after I/R.Genes differentially modified by H3K27ac,H3K4me1 and H3K27me3 were involved in immune response,heart conduction or contraction,cytoskeleton,and angiogenesis.H3K27me3 and its methyltransferase polycomb repressor complex 2(PRC2)were upregulated in myocardial tissues after I/R.Upon selective inhibition of EZH2(the catalytic core of PRC2),the mice manifest improved cardiac function,enhanced angiogenesis,and reduced fibrosis.Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro.This study delineates a landscape of histone modifications in myocardial I/R injury,and identifies H3K27me3 as a key epigenetic modifier in I/R process.The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention.