Department of Cardiology, Keio University School of Medicine, Shinjuku-ku Tokyo, Japan.
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Kanagawa, Japan.
Sci Rep. 2017 Jan 4;7:39752. doi: 10.1038/srep39752.
Histone acetylation has been linked to cardiac hypertrophy and heart failure. However, the pathological implications of changes in histone methylation and the effects of interventions with histone methyltransferase inhibitors for heart failure have not been fully clarified. Here, we focused on H3K9me3 status in the heart and investigated the effects of the histone H3K9 methyltransferase inhibitor chaetocin on prognoses in Dahl salt-sensitive rats, an animal model of chronic heart failure. Chaetocin prolonged survival and restored mitochondrial dysfunction. ChIP-seq analysis demonstrated that chronic stress to the heart induced H3K9me3 elevation in thousands of repetitive elements, including intronic regions of mitochondria-related genes, such as the gene encoding peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Furthermore, chaetocin reversed this effect on these repetitive loci. These data suggested that excessive heterochromatinization of repetitive elements of mitochondrial genes in the failing heart may lead to the silencing of genes and impair heart function. Thus, chaetocin may be a potential therapeutic agent for chronic heart failure.
组蛋白乙酰化与心肌肥厚和心力衰竭有关。然而，组蛋白甲基化变化的病理意义以及组蛋白甲基转移酶抑制剂干预心力衰竭的效果尚未完全阐明。在这里，我们专注于心脏中的 H3K9me3 状态，并研究了组蛋白 H3K9 甲基转移酶抑制剂 chaetocin 对 Dahl 盐敏感大鼠（一种慢性心力衰竭的动物模型）预后的影响。Chaetocin 延长了存活时间并恢复了线粒体功能障碍。ChIP-seq 分析表明，心脏的慢性应激导致数千个重复元件中的 H3K9me3 升高，包括与线粒体相关基因的内含子区域，例如编码过氧化物酶体增殖物激活受体-γ共激活因子 1α的基因。此外，chaetocin 逆转了对这些重复基因座的这种影响。这些数据表明，衰竭心脏中线粒体基因的重复元件过度异染色质化可能导致基因沉默并损害心脏功能。因此，chaetocin 可能是治疗慢性心力衰竭的潜在治疗剂。
