COREPRESSORS AND NEGATIVE REGULATION BY THYROID HORMONE

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DESCRIPTION (Taken from the applicant's Abstract): Thyroid hormone receptors (TRs) bind to thyroid hormone response elements (TREs) in the regulatory regions of genes to stimulate or inhibit gene transcription. TRs bind in the presence or absence of ligand, triiodothyronine (T3). In the absence of ligand, TRs repress transcription of genes that are positively regulated by T3. Ligand-independent repression is mediated by a class of proteins termed co-repressors, including NCoR and SMRT, which bind TR in the absence of T3. TRs also exhibit ligand-independent effects on genes negatively regulated by a thyroid hormone. One these negative TREs, TRs enhance transcription in the absence of ligand. These effects are less well defined, but appear to be mediated by members of the co-repressor families, as well. The goals of these studies are (1) to characterize the effects of co-repressors on genes negatively regulated by thyroid hormone; (2) to identify and characterize NCoR isoforms; and (3) to determine how co-repressors interact with specific TR complexes. In these studies, we will focus on the interactions between co-repressors and TR-beta-2, a TR isoform that may play a distinct role in negative regulation. In addition, mutant TRs, found clinically in patients with syndromes of resistance to thyroid hormone (RTH) will be used to characterize interactions between TRs and co-repressor isoforms. This information will allow us to define further mechanisms underlying thyroid hormone resistance and thyroid hormone action, which will shed light on the basis of human hypothyroidism and hyperthyroidism. Moreover, an understanding of how TRs regulate gene transcription in the absence of ligand will provide further insight into the mechanisms of gene regulation in general. This project will be performed by Dr. Ronald Cohen under the guidance of Dr. Fredric Wondisford, in the Thyroid Unit and Endocrine Division of the Beth Israel Deaconess Medical Center. Dr. Wondisford has made major contributions to the understanding of the molecular mechanisms governing negative regulation of the TSH and TRH genes. There are also numerous investigators in the Endocrine Division and the surrounding Harvard Medical School community with interests in transcriptional regulation. This will provide an ideal environment to complete this project, and will provide a basis for Dr. Cohen's transition to an independent investigator.