Our goal is to define how oxidative nuclear receptor (ox-NR) ligands and cofactor complexes influence physiology and disease by controlling patterns of gene expression. The underlying hypothesis of this proposal is that ox-NR 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 a protein chemistry approach to define the dynamic properties of epi-genomic complexes (epi-complexes) assembled by nuclear receptors involved in regulating oxidative metabolism (ox-NRs). Changes induced in epi-complexes isolated from metabolically active tissues, such as muscle and brown adipose tissue, by environmental modulators including exercise, cold exposure, and fasting, will identify key epigenetic regulators required for context-specific gene regulation.
Specific Aim II will establish the comparative changes in gene expression signatures that correlate to changes in the above epi-complexes. In addition, we will monitor shifts In key metabolic parameters influenced by the metabolic stressors and treatment with ox-NR ligands and modulators.
In Aim III, chromatin mmunoprecipitation coupled to massively parallel sequencing (ChlP-Seq) experiments will determine the specific genomic locations (cistromes) of ox-NRs in the metabolically active tissues. Stimuli-Induced alterations in ox-NR cistromes, combined with the changes in gene expression identified in Aim II, will allow causal associations to be drawn between epi-complexes and gene regulation.
Aim I V will define the epigenetic signatures of ox-NRs by mapping key histone acetylation activation and methylation markers in metabolically active tissues with and without stress induction. We believe that nuclear receptors play a critical role in driving epigenomic control. By making key links between the epigenome, metabolism 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 oxidative 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 and this work Is anticipated to provide insights for the development of hew 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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Special Emphasis Panel (NSS)
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Silva, Corinne M
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Salk Institute for Biological Studies
La Jolla
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