The mechanism of transcriptional repression by thyroid hormone receptor (TR) will be studied by creating a yeast model of TR action. Thyroid hormone is critical for intellectual and physical development in humans, and has effects on diverse organ systems ranging from bone to the cardiovascular system. Recent studies have shown that TR mediates repression by recruiting a histone deacetylase complex. However, the details of this interaction are unclear. Studies in mammalian cells have been complicated by the ubiquitous expression of other nuclear hormone receptors and comodulatory proteins that can interact with TR and affect TR action. Because histone deacetylases are fundamental chromatin remodeling proteins that are widely conserved, it is possible to model TR action by reconstituting TR-mediated gene regulation in a lower eukaryote, such as yeast. Yeast will be stably transformed with TR, along with a reporter gene and critical proteins involved in transcriptional repression, including nuclear receptor corepressor (N-CoR) and the corepressor protein mSin3A. This will result in a powerful model for generating and testing hypotheses of TR repression mechanisms. Initial studies will include testing the effects of different thyroid-hormone response elements (TREs) on repression, determining whether RXR is required for repression, and evaluating the role of local chromatin structure on TR-mediated repression. The generated data will have implications for gene regulation by all members of the nuclear receptor superfamily. It is hoped that a better understanding of the mechanisms of TR action will eventually lead to the development of novel ways in which the expression of thyroid hormone target genes can be modulated to affect the outcome of certain disease states.
