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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK057978-34
Application #
8249444
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
1979-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
34
Fiscal Year
2012
Total Cost
$718,825
Indirect Cost
$341,489
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Zheng, Xinde; Boyer, Leah; Jin, Mingji et al. (2016) Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration. Elife 5:
Wall, Christopher E; Yu, Ruth T; Atkins, Anne R et al. (2016) Nuclear receptors and AMPK: can exercise mimetics cure diabetes? J Mol Endocrinol 57:R49-58
Liu, Weilin; Struik, Dicky; Nies, Vera J M et al. (2016) Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 113:2288-93
Xia, Xue; Kumru, Ozan S; Blaber, Sachiko I et al. (2016) An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities. J Pharm Sci 105:3507-3519
Booth, D R; Ding, N; Parnell, G P et al. (2016) Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases. Genes Immun 17:213-9
Yoshihara, Eiji; Wei, Zong; Lin, Chun Shi et al. (2016) ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells. Cell Metab 23:622-34
Hulin, Julie-Ann; Nguyen, Thi Diem Tran; Cui, Shuang et al. (2016) Barx2 and Pax7 Regulate Axin2 Expression in Myoblasts by Interaction with β-Catenin and Chromatin Remodelling. Stem Cells 34:2169-82
Kim, Jung A; Roy, Roland R; Zhong, Hui et al. (2016) PPARδ preserves a high resistance to fatigue in the mouse medial gastrocnemius after spinal cord transection. Muscle Nerve 53:287-96
Fan, Weiwei; Evans, Ronald M (2016) Exercise Mimetics: Impact on Health and Performance. Cell Metab :
Sousa, Cristovão M; Biancur, Douglas E; Wang, Xiaoxu et al. (2016) Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536:479-83

Showing the most recent 10 out of 89 publications