Our goal is to define how nuclear receptor ligands and cofactor complexes influence physiology and disease by controlling patterns of gene expression. The underlying hypothesis of this proposal is that receptor signaling is mediated by ligand directed chromatin modifications and that the resulting induced epigenomic state (epi-state) mobilizes groups or networks of genes to produce unique cell function and physiology. To do this, in Aim I we will use state-of-the-art protein chemistry techniques to define the dynamic properties of PPARd epi-genomic complexes assembled in the presence of two selective modulators GW1516 and Syndag CBL-28. These will be performed in the presence and absence of two gene expression modulators-the exercise mimetic AICAR and high-fat diet induced obesity.
Specific Aim II will establish the comparative changes in gene expression signatures that correlate to changes in the above complexes. In addition, we will monitor shifts in key metabolic parameters influenced by treatment with the above ligands and modulators. The recent availability of massively parallel sequencing technology and advances in methods for chromatin immunoprecipitation now makes it possible to determine the specific genomic locations (cistrome) of nuclear receptors on a genome-wide scale.
Aim III will determine the PPARd cistrome in skeletal muscle and cultured muscle cell lines by obtaining millions of sequencing reads of ChIP products and mapping these to reference genomes. We will also determine how diet induced obesity (DIO), receptor ligands and AICAR globally impact PPARd binding.
Aim I V will define the epigenetic signatures of PPARd by mapping key histone acetylation activation and methylation markers in cells and muscle that have been treated with GW1516, AICAR or high fat diets. To the extent that epigenomic control is a new and rapidly evolving field, we believe that nuclear receptors play a critical role in driving it and the NR field forward. By making key links between the epigenome and normal physiology this application provides a unique means to extend this understanding to metabolic disease and facilitates the development of new classes of drugs that can treat diseases of metabolism by treating the genome.

Public Health Relevance

This proposal is directed at identifying how nuclear hormone receptors modulate the structure, function and accessibility of the genome to control gene expression and body physiology. Receptor regulated pathways are particularly relevant to the epidemics of obesity, diabetes and cardiovascular disease in the United States and this work is anticipated to provide insights for the development of new diagnostics and therapeutics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Margolis, Ronald N
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Salk Institute for Biological Studies
La Jolla
United States
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