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accounts.Our long-term goal is to define the epigenetic mechanisms that regulate the transcriptional activity of genes encodingfunctionally distinct G protein-coupled receptors (GPCR). In addition to modulating gene expression, receptor activity is
associated with cell proliferation and migration. Our preliminary studies provide strong evidence that epigenetic modifications
play a critical role in regulating the transcription of GPCRs during these processes. Based on our data and recent experimental
findings, we hypothesize that epigenetic mechanisms, including DNA methylation and histone modifications, are essential forthe proper regulation of GPCR transcription during cell proliferation and migration in the heart. The R21 phase of this projectpage 1 / 2

will focus on identifying the molecular mechanisms by which epigenetic modifications regulate GPCR gene expression during
cardiac development. We have identified an important subset of GPCRs as novel essential players that regulate cellproliferation. Specifically, we have identified several differentially methylated and histone-modified GPCRs that regulate
cardiac cell proliferation. Based on these findings, we propose the following Specific Aims: Aim 1: To determine whether DNA
methylation and histone modifications regulate the transcription of the Cardiac Myocyte Growth Gene (CMGG) family ofGPCRs. Aim 2: To determine whether the epigenetic effects of these GPCRs are mediated by the differential expression of noncoding RNAs and RNA binding proteins. In this way, we will begin to define a novel axis of epigenetic regulation of gene
expression that is critical for heart development. During the R33 phase of this project, we plan to define the roles of theseGPCRs in heart development and to investigate the molecular mechanisms by which these GPCRs regulate the cell cycle. As anessential step towards translating our results into meaningful clinical therapies, we will then develop antagonists for theseGPCRs. Collectively, our work will identify novel epigenetic f678ea9f9e
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