Hickenlooper Samuel M, Davis Kathryn, Szulik Marta W, Sheikh Hanin, Miller Mickey, Valdez Steven, Bia Ryan, Franklin Sarah
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112, United States.
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132, United States.
ACS Omega. 2022 Aug 23;7(35):30710-30719. doi: 10.1021/acsomega.2c00984. eCollection 2022 Sep 6.
Heart disease is the leading cause of death in the developed world, and its comorbidities such as hypertension, diabetes, and heart failure are accompanied by major transcriptomic changes in the heart. During cardiac dysfunction, which leads to heart failure, there are global epigenetic alterations to chromatin that occur concomitantly with morphological changes in the heart in response to acute and chronic stress. These epigenetic alterations include the reversible methylation of lysine residues on histone proteins. Lysine methylations on histones H3K4 and H3K9 were among the first methylated lysine residues identified and have been linked to gene activation and silencing, respectively. However, much less is known regarding other methylated histone residues, including histone H4K20. Trimethylation of histone H4K20 has been shown to repress gene expression; however, this modification has never been examined in the heart. Here, we utilized immunoblotting and mass spectrometry to quantify histone H4K20 trimethylation in three models of cardiac dysfunction. Our results show that lysine methylation at this site is differentially regulated in the cardiomyocyte, leading to increased H4K20 trimethylation during acute hypertrophic stress in cell models and decreased H4K20 trimethylation during sustained ischemic injury and cardiac dysfunction in animal models. In addition, we examined publicly available data sets to analyze enzymes that regulate H4K20 methylation and identified two demethylases (KDM7B and KDM7C) and two methyltransferases (KMT5A and SMYD5) that were all differentially expressed in heart failure patients. This is the first study to examine histone H4K20 trimethylation in the heart and to determine how this post-translational modification is differentially regulated in multiple models of cardiac disease.
心脏病是发达国家的主要死因，其合并症如高血压、糖尿病和心力衰竭伴随着心脏主要的转录组变化。在导致心力衰竭的心脏功能障碍期间，染色质会发生全局性的表观遗传改变，这些改变与心脏在急性和慢性应激下的形态变化同时出现。这些表观遗传改变包括组蛋白上赖氨酸残基的可逆甲基化。组蛋白H3K4和H3K9上的赖氨酸甲基化是最早被鉴定出的甲基化赖氨酸残基，分别与基因激活和沉默有关。然而，对于其他甲基化组蛋白残基，包括组蛋白H4K20，人们了解得要少得多。组蛋白H4K20的三甲基化已被证明会抑制基因表达；然而，这种修饰从未在心脏中进行过研究。在这里，我们利用免疫印迹和质谱法对三种心脏功能障碍模型中的组蛋白H4K20三甲基化进行了定量。我们的结果表明，该位点的赖氨酸甲基化在心肌细胞中受到差异调节，导致在细胞模型的急性肥厚应激期间H4K20三甲基化增加，而在动物模型的持续性缺血损伤和心脏功能障碍期间H4K20三甲基化减少。此外，我们检查了公开可用的数据集，以分析调节H4K20甲基化的酶，并鉴定出两种去甲基化酶（KDM7B和KDM7C）和两种甲基转移酶（KMT5A和SMYD5），它们在心力衰竭患者中均有差异表达。这是第一项研究心脏中组蛋白H4K20三甲基化，并确定这种翻译后修饰在多种心脏病模型中是如何受到差异调节的研究。
