The goal of this application is to specifically relate TR biochemistry and molecular biology to the cellular and molecular physiological effects of T3. It has become clear that regulation by TR involves repression by unliganded TR as well as ligand dependent activation, and this repression is thought be dependent on the recruitment of corepressor proteins by the unliganded TR. The first specific aim is to determine mechanisms by which different regions of TR regulate both interactions with corepressors N-CoR and SMRT, and ligand-independent and -dependent heterodimerization with retinoid X receptor (RXR). It is hypothesized that RXR differentially recognizes the liganded and unliganded conformations of TR, and this will be tested using mutations based on the known structure of the TR ligand binding domain.
The second aim i s to determine the ability of RXR to regulate functional interactions with N-CoR and SMRT and with candidate coactivators. It is hypothesized that the differential recognition of liganded and unliganded forms of TR by RXR results in regulation of repression as well as transactivation. This will be tested by determining the requirement for RXR in corepressor and coactivator binding and function.
The third aim i s determine the principles underlying AF-2 dependent transactivation by TR, and it is hypothesized that DNA binding and RXR heterodimerization increase the specificity of coactivator binding. The contributions of the DNA binding site as well as RXR heterodimerization in regulating coactivator function will be determined. The fourth specific aim is to identify mechanisms by which N-CoR and SMRT inhibit basal transcription. It is hypothesized that each of multiple repression domains in N-CoR recruits proteins that stabilize the repression complex and/or function to repress transcription. Such proteins will be cloned and characterized using dihybrid screens in yeast. These studies will provide insight into hormone action in general, and enhance understanding of many pathophysiological states.
|Armour, Sean M; Remsberg, Jarrett R; Damle, Manashree et al. (2017) An HDAC3-PROX1 corepressor module acts on HNF4? to control hepatic triglycerides. Nat Commun 8:549|
|Poleshko, Andrey; Shah, Parisha P; Gupta, Mudit et al. (2017) Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. Cell 171:573-587.e14|
|Hong, Sungguan; Zhou, Wenjun; Fang, Bin et al. (2017) Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat Med 23:223-234|
|Remsberg, Jarrett R; Ediger, Benjamin N; Ho, Wesley Y et al. (2017) Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion. Mol Metab 6:30-37|
|Lazar, Mitchell A (2017) Maturing of the nuclear receptor family. J Clin Invest 127:1123-1125|
|Wang, Yi; Frank, David B; Morley, Michael P et al. (2016) HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-? Signaling Regulation. Dev Cell 36:303-15|
|Teng, Xin; Emmett, Matthew J; Lazar, Mitchell A et al. (2016) Lactate Dehydrogenase C Produces S-2-Hydroxyglutarate in Mouse Testis. ACS Chem Biol 11:2420-7|
|Papazyan, Romeo; Sun, Zheng; Kim, Yong Hoon et al. (2016) Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP. Cell Metab 24:863-874|
|Zhang, Liguo; He, Xuelian; Liu, Lei et al. (2016) Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch. Dev Cell 36:316-30|
|Lee, Jae Man; Wagner, Martin; Xiao, Rui et al. (2014) Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112-5|
Showing the most recent 10 out of 64 publications