Genome-wide maps of H3K9me3 and H3K4me3 state in failing heart with or without chaetocin in animal model. Rattus norvegicus

Epigenetic status has been linked to cardiac hypertrophy and heart failure. Histone deacetylase inhibitors are promising drugs for preventing cardiac remodeling. We previously demonstrated very different patterns of histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 4 trimethylation (H3K4me3) in failing hearts compared to control hearts in both animal models and clinical heart specimens. Here, we focused on a heart failure-specific histone modification, H3K9me3, and investigated the prognostic efficacy of administering a histone H3K9 methyltransferase inhibitor, chaetocin, to Dahl salt-sensitive rats, an animal model of heart failure. Chaetocin delayed the timing of transition from cardiac hypertrophy to heart failure, and prolonged survival in this animal model. Mitochondrial dysfunction was improved with inhibitor use in the failing heart. ChIP-seq analysis demonstrated that heart failure caused an increase in H3K9me3 alignments in thousands of repetitive elements, including regions neighboring mitochondrial genes, and a corresponding reduction of this effect with inhibitor use. However, at 35 loci, heart failure was conversely associated with a reduction in H3K9me3 alignments, and inhibitor use reversed this effect. These data suggest that excessive heterochromatinization of repetitive elements in the failing heart might impair pumping function with mitochondrial gene silencing. H3K9 methyltransferase inhibitors may be a promising novel therapy for chronic heart failure. Overall design: Examination of 2 different histone modifications in 3 groups of rats.

表观遗传状态与心肌肥厚及心力衰竭密切相关。组蛋白去乙酰化酶抑制剂是预防心肌重构的极具潜力的药物。我们先前已证实，在动物模型与临床心脏标本中，衰竭心脏与对照心脏的组蛋白H3赖氨酸9三甲基化（H3K9me3）、组蛋白H3赖氨酸4三甲基化（H3K4me3）修饰模式存在显著差异。本研究聚焦于心力衰竭特异性组蛋白修饰H3K9me3，并以心力衰竭动物模型Dahl盐敏感性大鼠为对象，探究组蛋白H3K9甲基转移酶抑制剂毛壳菌素（chaetocin）的预后干预效果。在该动物模型中，毛壳菌素可延缓心肌肥厚向心力衰竭的转化进程，并延长模型大鼠的存活时间。使用该抑制剂可改善衰竭心脏的线粒体功能障碍。染色质免疫共沉淀测序（ChIP-seq）分析显示，心力衰竭可使数千个重复元件（包括线粒体基因邻近区域）的H3K9me3比对信号显著上调，而抑制剂给药可逆转这一效应。然而，在35个基因座上，心力衰竭反而会导致H3K9me3比对信号下调，而抑制剂给药可逆转这一现象。上述数据表明，衰竭心脏中重复元件的过度异染色质化可能通过沉默线粒体基因，损害心脏泵血功能。组蛋白H3K9甲基转移酶抑制剂或可成为慢性心力衰竭的新型潜在治疗手段。实验整体设计：对3组大鼠的2种不同组蛋白修饰进行检测分析。