A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear hormone receptor peroxisome proliferator-activated receptor 3 (PPAR3) controls adipogenesis and mediates antidiabetic effects of drugs that improve insulin sensitivity but cause unwanted side effects. We hypothesize that target gene- and tissue-selective modulation of gene expression by PPAR3 are dictated by different modes of PPAR3 binding and synergy between PPAR3 and cooperating transcription factors, leading to a defining spectrum of epigenetic marks on target genes. To test this concept, we are performing genome-wide analysis of PPAR3 binding and epigenetic changes during adipogenesis.
Specific Aim 1 is to delineate PPAR3 gene targets in adipocytes on a genome-wide scale, and understand their modes of regulation. We hypothesize that target gene-specific regulation of adipocyte gene expression by PPAR3 is due to complex relationships between binding and function. Preliminary data utilizing chromatin immunoprecipitation (ChIP) followed by hybridization to high density genomic arrays reveals PPAR3 binding to a large number of novel gene targets, at varying distances from transcriptional start sites, in cooperation with other transcription factors.
Specific Aim 2 is to determine the epigenetic changes that occur during adipogenesis and their relation to PPAR3 binding. PPAR3 recruits coregulators with enzyme activity, but little is known about the histone modifications at endogenous target genes. We hypothesize that, during adipogenesis and upon treatment of adipocytes with ligands, target gene regulation is determined by patterns of epigenetic marks related to the mode of PPAR3 binding, e.g. direct or indirect, and to cooperation with specific transcription factors. Preliminary data show that adipogenesis and PPAR3 ligands indeed influence histone acetylation and methylation on a genome-wide scale, in a target-gene and function-specific manner. The Third Specific Aim is to understand the mechanisms of cell-type specific gene regulation by PPAR3. PPAR3 is expressed at highest levels in adipocytes, but is also expressed and functional in macrophages, where its functions overlap but have significant differences. We hypothesize that this tissue-specificity is due to differential PPAR3 gene localization, cooperating transcription factors, and epigenetic regulation. This will be tested by genome-wide location analysis of PPAR3 as well as informative epigenetic marks in macrophages. Comparison with PPAR3 function in adipocytes will reveal mechanisms of tissue-selectivity that can be exploited in designing PPAR3 modulators that selectively regulate gene expression. Overall, these innovative studies will generate major new insights into PPAR3 and its role in adipogenesis and metabolism. The knowledge gained from this work will shed new light on the transcriptional and epigenetic control of key biological pathways, including metabolism and inflammation, with the potential to lead to new and deeper insights into metabolic disorders, including obesity and diabetes, and cardiovascular disease, that are epidemic in modern society. Relevance Understanding how genes are regulated in fat cells will provide insight into obesity, which is characterized by increased and abnormal fat cells. The focus on the nuclear receptor PPAR3 is appropriate because this is the master regulator of fat cell formation and function, and a target of anti-diabetic drugs that mitigate insulin resistance that is a devastating consequence of obesity. Thus, the insights gained from this work are likely to lead to new and deeper insights that may be translated into novel treatment strategies for metabolic disorders, including obesity, diabetes, and cardiovascular disease.
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