# Integrative Physiology of Thyroid Hormone Receptors and Nuclear Receptor Corepressors

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $578,340

## Abstract

PROJECT SUMMARY
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 co...

## Key facts

- **NIH application ID:** 10152647
- **Project number:** 5R01DK043806-31
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MITCHELL A. LAZAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $578,340
- **Award type:** 5
- **Project period:** 1991-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152647

## Citation

> US National Institutes of Health, RePORTER application 10152647, Integrative Physiology of Thyroid Hormone Receptors and Nuclear Receptor Corepressors (5R01DK043806-31). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10152647. Licensed CC0.

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