A major goal of this laboratory is to understand the mechanisms by which nuclear receptors (NRs) regulate gene expression and metabolism. Thyroid hormone receptors (TRs) are classical NRs that regulate lipid and energy metabolism. TRs switch from transcriptional repressors to activators in response to their cognate hormone. Repression is mediated by NR corepressors, NCoR and SMRT, which function in multiprotein complexes containing histone deacetylase 3 (HDAC3), whose catalytic activity requires direct interaction with NCoR/SMRT. However, recent studies suggest a more complex mechanism for TR repression. Further, the roles of NCoR/SMRT and HDAC3 in metabolism and inflammation are highly tissue-specific via mechanisms that remain to be understood. We have pioneered a systems approach that combines state-of-the-art in vivo omics approaches with genetic and environmental manipulations and metabolic phenotyping to unravel the complex mechanisms by which NRs, corepressors and HDAC3 control normal physiology and contribute to the pathophysiology of metabolic diseases.
Specific Aim 1 is to determine the interactions and functions of thyroid hormone receptor beta on chromatin. The coregulator switch model of hormone action is largely based on in vitro experiments using artificial systems. By combining expertise in cistromics with quantitative proteomics by NEAT ChIP-MS (Nuclear Extraction Affinity Tag ChIP-mass spec) we will interrogate the hormone-dependent protein and genomic interactions of TR?1to elucidate, for the first time, the in vivo protein interactions of TR? and their physiological functions.
Specific Aim 2 is to determine the physiological, tissue-specific functions of nuclear receptor corepressors. NCoR depletion phenocopies loss of HDAC3 in liver but not in brown adipose tissue (BAT). We will determine the basis of this difference by comparing and contrasting transcriptomes, cistromes, enhancer activities, and metabolic phenotypes upon cdeletion of HDAC3 and NCoR/SMRT.
Specific Aim 3 is to determine the physiological, tissue-specific functions of HDAC3 and its enzyme activity. Catalytically inactive HDAC3 partially rescues the steatosis of livers lacking HDAC3 and, in macrophages, and can replace HDAC3 in controlling the LPS (M1) response but not the response to IL4 (M2). We will use a combination of NEAT ChIP-MS, cistromics, and enhancer quantitation in wild type, mutant, and knockout models to elucidate the transcription factors and protein partners underlying the gene-specific requirement for HDAC3 enzyme activity. The tissue specificity of HDAC3 interactions and enzyme activity will be addressed by comparing the results of NEAT ChIP-MS on endogenous epitope-tagged wild-type and catalytically inactive HDAC3 in liver, macrophages, and BAT. These innovative studies address major questions regarding the mechanisms of action of TRs, NR corepressors, and HDAC3 and will shed new light on the transcriptional and epigenomic control of key metabolic pathways, with the goal of gaining deeper insights into metabolic disorders such as obesity, diabetes, and cardiovascular disease, as well as cancer.

Public Health Relevance

The epidemics of metabolic diseases including obesity and diabetes are due to environmental factors such as hypernutrition impinging on our genomes. We are using state-of-the-art methodologies to study the effect of thyroid hormone and environmental factors on the epigenome, which refers to everything in the cell nucleus that interacts with the DNA sequences of the genome to determine how genes are regulated. The impact of our work will be great, as it will yield new general insights into hormone action and how normal metabolic physiology is regulated, as well as the effects of challenging environments, including hypernutrition, that cause metabolic abnormalities contributing to the epidemics of diabetes and obesity in the United States and worldwide. These studies have the potential to lead to inform new and safer therapies of metabolic disorders, including obesity, diabetes, and cardiovascular disease, as well as cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Silva, Corinne M
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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