Role of Epigenetic Regulator KDM5A in Heart Failure

心力衰竭(HF)是世界范围内死亡的主要原因。心衰与心肌细胞(CM)死亡增加和线粒体功能障碍有关。线粒体功能障碍与发育相关机制的研究进展 尽管基因表达的表观遗传调控在控制心脏重构和心力衰竭的发病机制中发挥了作用，但心力衰竭的进展是复杂的，仍然未知。事实上，表观遗传改变，如组蛋白甲基化，与心衰有因果关系。然而，在HF中，写入和擦除表观遗传标记的酶，特别是组蛋白去甲基酶的确切作用尚不清楚。我们最近证实了KDM5A在人类心力衰竭样本中的激活。我们还发现，在扩张型心肌病(DCM)小鼠模型中，KDM5A活性和蛋白水平在心功能障碍之前被诱导。对KDM5A靶点的基因功能分析表明，它们中的大多数富含氧化磷酸化(OXPHOS)和代谢，在衰竭的心脏样本中受到抑制。调节KDM5A蛋白水平的机制以及KDM5A激活在HF中的表型后果尚不清楚。初步结果表明：1.KDM5A在横动脉缩窄(TAC)所致心肌肥厚小鼠的心脏中被诱导。2.USP38(泛素特异肽酶38)是一种去泛素酶，调节心肌细胞中KDM5A的水平。KDM5A稳态水平与USP38相关，两者均在出生后降低，且均由HF诱导。SiRNA介导的USP38在CM中的敲除导致KDM5A水平降低。3.心肌细胞功能研究表明，KDM5A可抑制OXPHOS相关基因的表达。基于这些发现，我们认为在心力衰竭中，KDM5A的功能效应因USP38蛋白水平的增加而得到加强。在成人CM中，KDM5A的激活导致OXPHOS基因的抑制，导致线粒体功能障碍、细胞死亡和随后的表型。因此，本研究的主要目的是确定KDM5A在心力衰竭中的激活机制，并阐明其在心力衰竭发病机制中的作用。这一假设将在三个具体目标上进行检验。在目标1中，我们将确定KDM5A在HF中的调节机制。在目标2中，我们将确定KDM5A激活对心力衰竭OXPHOS基因和其他靶基因表达的影响，最后在目标3中，我们将确定KDM5A激活在心力衰竭中的致病作用。

Heart failure (HF) is a major cause of mortality worldwide. HF is linked to increased cardiac myocyte (CM) death and mitochondrial dysfunction. Mechanisms linking mitochondrial dysfunction and the development or progression of HF are complex and remain unknown, although epigenetic regulation of gene expression plays a role in governing cardiac remodeling and HF pathogenesis. Indeed, epigenetic alterations such as histone methylation, have been causally associated with HF. However, the precise role of enzymes that write and erase epigenetic marks, especially those of histone demethylases, in HF is unknown. We recently demonstrated activation of KDM5A in human HF samples. We also found that KDM5A activity and protein levels are induced, prior to cardiac dysfunction, in mouse models of dilated cardiomyopathy (DCM). Gene function analysis of KDM5A targets revealed that most of them are enriched for OXPHOS (oxidative phosphorylation) and metabolism and are suppressed in failing heart samples. The mechanisms that regulate KDM5A protein levels, as well as the phenotypic consequences of KDM5A activation in HF, are unknown. Preliminary findings show that 1. KDM5A is induced in the hearts of mice with cardiac hypertrophy caused by transverse aortic constriction (TAC) 2. USP38 (ubiquitin-specific peptidase 38), a deubiquitinating enzyme, regulates KDM5A levels in cardiac myocytes. KDM5A steady-state levels are correlated with USP38, both are decreased after birth and induced by HF. SiRNA-mediated USP38 knockdown in CM led to a reduction in KDM5A levels. 3. Gain of function studies in cardiac myocytes show that KDM5A suppress expression of genes involved in OXPHOS. Based on these findings, we propose that in heart failure, the functional effect of KDM5A is reinforced by increased protein levels by USP38. KDM5A activation in adult CM leads to suppression of OXPHOS genes, resulting in mitochondrial dysfunction, cell death, and ensuing phenotypes. Therefore, main goals of this proposal are to determine the mechanism of activation of KDM5A in HF, and to delineate its role in the pathogenesis of HF. The hypothesis will be tested in three specific aims. In aim 1 we will determine the mechanism of KDM5A regulation in HF. In aim 2 we will determine the effect of KDM5A activation on expression of OXPHOS genes and other targets in HF and finally in aim 3 we will determine the pathogenic role of KDM5A activation in HF.