Metabolic dysfunction within a tissue is a nucleating event in the etiology of many of the most prevalent human diseases today. A primary goal of the Lazar laboratory is to define the transcriptional mechanisms that control metabolic homeostasis and delineate how these systems are disrupted during disease progression. Histone deacetylase 3 (HDAC3) is a class I deacetylase that, through interaction with the nuclear receptor corepressors NCoR or SMRT, drives repressive chromatin remodeling to transcriptionally regulate critical metabolic pathways. The essential function of HDAC3 is demonstrated through murine knockout studies; whole body knockout is lethal while tissue specific deletions result in a plethora of maladaptive phenotypes including lethal cold intolerance in brown adipose tissue (BAT) and massive hepatic steatosis in liver. However, there are still large gaps in our understanding of the tissue-specific mechanisms that underlie these phenotypes. Recent work indicates that HDAC3 not only represses transcription via NCoR/SMRT, but is also necessary to activate the transcription of specific and essential genes in certain contexts. While the repressive role has been described, it is unknown how HDAC3 activates transcription at specific loci. In addition, work from the Lazar lab and others has shown that HDAC3 has indispensable functions that are not dependent upon its deacetylase activity. The goal of this proposal is to interrogate the specific mechanisms by which HDAC3 regulates transcription of a diverse array of metabolic pathways in a tissue-specific manner.
Specific Aim 1 is to identify tissue specific HDAC3 protein-protein interactions in brown adipose tissue and liver. The Lazar lab has pioneered a new method called NEAT ChIP-MS (Nuclear Extraction Affinity Tag ChIP-mass spec) to identify and quantitate protein-protein interactions in vivo. We will utilize this method to characterize the HDAC3 interactome in BAT and compare it to the liver interactome in order to define common and tissue-specific interactions. In the liver, knockout of HDAC3 leads to de-repression of lipogenic genes, ultimately causing fatty liver. Conversely, HDAC3 KO in BAT leads to the inability to activate expression of critical thermogenic genes. The reliance of these tissues on repressive (liver) and activating (BAT) HDAC3 activity is of great interest and comparison of the HDAC3 interactome in both contexts with yield important insights on these divergent functions.
Specific Aim 2 is to define the enzymatic substrates of HDAC3 in vivo. Fatty liver as a result of HDAC3 deletion is largely rescued through the expression of catalytically inactive HDAC3. Conversely, mice lacking HDAC3 activity due to mutations in NCoR and SMRT display lethal cold intolerance, mimicking HDAC3 knockout in BAT. We will use affinity enrichment of acetyl peptides followed by proteomic analysis in WT, KO, and mutant models to determine, for the first time, the catalytic substrates of HDAC3 in liver and BAT. These innovative studies address long standing questions regarding HDAC3 function. Together, the combination of state-of-the-art ?omics? approaches will generate new insights into the mechanism of action of this critical metabolic regulator.

Public Health Relevance

Many of the most prevalent diseases of our time, including diabetes, obesity, cardiovascular disease, and cancer are characterized by changes in metabolic function. We seek to understand the mechanisms that control metabolic homeostasis and how these systems are interrupted by environmental stressors such as diet and age to cause disease. The specific goal of this proposal is to interrogate the mode of action of critical metabolic regulatory protein histone deacetylase 3 (HDAC3) in order to develop new insights into the etiology of metabolic disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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