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.
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.
|Hong, Suk-Hyun; Fang, Sungsoon; Lu, Benson C et al. (2018) Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis. Proc Natl Acad Sci U S A 115:10381-10386|
|Ahmadian, Maryam; Liu, Sihao; Reilly, Shannon M et al. (2018) ERR? Preserves Brown Fat Innate Thermogenic Activity. Cell Rep 22:2849-2859|
|Wei, Zong; Yoshihara, Eiji; He, Nanhai et al. (2018) Vitamin D Switches BAF Complexes to Protect ? Cells. Cell 173:1135-1149.e15|
|Fan, Weiwei; He, Nanhai; Lin, Chun Shi et al. (2018) ERR? Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1?/?-Deficient Muscle. Cell Rep 22:2521-2529|
|Shalom-Barak, Tali; Liersemann, Jaclyn; Memari, Babak et al. (2018) Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor ?-Retinoid X Receptor ? Coactivator. Mol Cell Biol 38:|
|Sherman, Mara H; Yu, Ruth T; Tseng, Tiffany W et al. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A 114:1129-1134|
|He, Nanhai; Fan, Weiwei; Henriquez, Brian et al. (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A 114:12542-12547|
|Fan, Weiwei; Waizenegger, Wanda; Lin, Chun Shi et al. (2017) PPAR? Promotes Running Endurance by Preserving Glucose. Cell Metab 25:1186-1193.e4|
|Fan, Weiwei; Evans, Ronald M (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab 25:242-247|
|Dickey, Audrey S; Sanchez, Dafne N; Arreola, Martin et al. (2017) PPAR? activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci Transl Med 9:|
Showing the most recent 10 out of 113 publications