One of the major challenges in managing and treating heart failure patients is to develop disease modifying drugs that can prevent, reverse, or slow down the disease progression. Upon pathological insults, the heart undergoes a series of histopathological and structural changes (cardiac remodeling), including left ventricular hypertrophy (LVH) that can progress to heart failure. Emerging evidence indicates that cardiac remodeling and failure are associated with reprogramming of gene expression that may have a causative role in the disease progression. Understanding mechanisms involved could provide a key to develop new interventional therapeutics. Epigenetic modification of chromatin, including histone methylation, governs a multitude of genomic functions, in particular gene transcription. Trimethylation of histone 3 lysine 9 (H3K9me3) is a conserved histone modification normally associated with gene silencing, and was found to be dramatically altered in hypertrophic and failing hearts in mouse and humans. To understand the role of H3K9me3 and its specific demethylase JMJD2A in the reprogramming of gene expression, we generated JMJD2A transgenic and knockout (KO) mouse lines. Our studies with these genetically modified mice suggest that JMJD2A regulates cardiac gene expression in response to hypertrophic stimuli and is required for pathological hypertrophic remodeling. We propose two specific aims to test this hypothesis.
Aim 1. To identify the epigenetic mechanisms by which JMJD2A regulates cardiac gene expression during pathological hypertrophic remodeling. We will generate the genomic landscapes of H3-K4/K9/K27/K36-me3 using ChIP-seq technology. Our objective is to identify the epigenetic signatures that mark the "fetal" genes and genes involved in the cardiac contractile apparatus under both physiological and pathological conditions. The observed differential genomic H3-K9/K36-me3 peaks between WT and JMJD2A KO mice will be superimposed with differential gene expression profiles to identify potential transcriptional targets of JMJD2A.
Aim 2. To unravel the molecular mechanism(s) by which JMJD2A regulates the expression of genes involved in cardiac hypertrophy and failure. The genomic approach will be complemented with classic molecular and biochemical methods in this aim to identify the molecular mechanisms by which JMJD2A regulates the transcription of genes identified in aim 1 and those identified in the preliminary studies. We postulate that JMJD2A is recruited to the target by its cognate transcription factor, and/or co-repressor during hypertrophic remodeling, and functions as either a co-activator or a co-repressor. Promoter analysis and biochemical methods including co-immunoprecipitation and GST-pull down assays will be used to identify putative transcription factors and co-repressors that may interact with JMJD2A. Our ongoing experiments indicated that small molecule inhibitors of JMJD2A inhibited myocyte hypertrophy in vitro. The success of the proposal will provide mechanistic insights to design therapeutic strategies of utilizing this class of inhibitors to combat cardiac hypertrophy and failure in the future.
The proposed research is relevant to public health because the success of the proposal could help us in the future to design disease modifying drugs to prevent, reverse, or slow down the progression of cardiac hypertrophy and heart failure.
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