Epigenomic basis of resilience to heart failure

项目总结/摘要 表观基因组特征集中支撑心血管健康。其中，DNA甲基化具有 作为一种稳定的，但不是不可变的，染色质修饰，可以与基因表达相关 但是修饰基因组的非基因区域，通过除 在它发生的地方进行转录。在这项资助中，我们试图确定这些表观基因组标记是否可以 在发生严重并发症之前预测心力衰竭，并探索潜在的 表观基因组对心血管疾病的恢复机制。与其研究疾病的过程， 了解为什么有些人会发生心力衰竭，而另一些人则不会。 我们在小鼠模型中的初步工作表明，小鼠心脏中的DNA甲基化与 在暴露于环境应激（例如异丙肾上腺素）之前疾病的严重程度。关于这一点， 初步观察，我们现在已经在一组近交系和重组近交系中表征了DNA甲基化组 小鼠品系，使我们能够探索DNA甲基化如何与遗传变异相互作用的基本原理 来影响心血管的恢复力。我们现在试图将这种现象转化为人类，识别多- 心力衰竭的基因座表观基因组风险指标，将有弹性的个体与那些 随着时间的推移容易出现心血管并发症。这些指标将成为一种新的精度等级的基础 心力衰竭的预后和诊断工具。 我们的研究小组已经启动了一项IRB批准的临床项目，以测量表观遗传因素， 心脏手术患者的血液，通过创新的数据将这些因素与临床数据联系起来- 挖掘平台，询问电子医疗记录。截至2019年2月，我们已经招募了约250名 对其中110例患者进行了亚硫酸氢盐测序（剩余患者的样品在处理中）。移动 今后，独立于本申请，我们将继续扩大这一队列，以包括代表性抽样 在洛杉矶地区的成年人口中。我们将在这项资助中测试的假设是DNA甲基化 机械地支撑对心脏病理的不同弹性，并且是一类新的 人类心力衰竭的生物标志物。

PROJECT SUMMARY/ABSTRACT Epigenomic features centrally underpin cardiovascular health. Among these, DNA methylation has emerged as a stable, but not immutable, chromatin modification that can be associated with gene expression but yet decorates non-genic regions of the genome, influencing cellular function by means other than transcription at the locus it occurs. In this grant we seek to determine whether these epigenomic marks can serve to predict—prior to the development of severe complications—heart failure, and to explore the underlying mechanisms of epigenomic resilience to cardiovascular disease. Rather than studying the disease process, we see to understand why some individuals develop heart failure whereas others do not. Our preliminary work in mouse models shows that DNA methylation in the heart of mice correlates with the severity of disease prior to the exposure to environmental stress (e.g. isoproterenol). Following up on this initial observation, we have now characterized DNA methylomes in a panel of inbred and recombinant inbred mouse strains, allowing us to explore the basic principles of how DNA methylation interacts with genetic variation to influence cardiovascular resilience. We now seek to translate this phenomenon to humans, identifying multi- locus epigenomic risk metrics for heart failure that distinguish resilient individuals from those more susceptible to cardiovascular complications over time. These metrics will be the basis for a new class of precision prognostic and diagnostic tools in heart failure. Our research team has initiated an IRB-approved clinical program to measure epigenetic factors in the blood of patients undergoing cardiac surgery, linking these factors to clinical data through an innovative data- mining platform that interrogates electronic medical records. As of February 2019, we have enrolled ~250 patients and performed bisulfite sequencing on 110 of them (remaining patients’ samples in process). Moving forward, independent of this application, we continue to expand this cohort to include a representative sampling of the adult population in the Los Angeles region. The hypothesis we will test in this grant is that DNA methylation mechanistically underpins differential resilience to cardiac pathology and is a source of a novel class of biomarkers for human heart failure.