STUDIES ON THE REPRESSION OF BASAL TRANSCRIPTION (SILENCING) BY ARTIFICIAL AND NATURAL HUMAN THYROID-HORMONE RECEPTOR-BETA MUTANTS

Thyroid hormone receptors (TRs) are ligand-dependent transcription fac tors that regulate target gene transcription. Interestingly, in the ab sence of ligand, TRs also can repress basal transcription of positivel y regulated target genes, suggesting that unliganded TR may have a dis tinct role in gene regulation. In this paper, DNA binding, truncation, and natural human TR beta mutants were used in cotransfection and ele ctrophoretic mobility shift assays to study various aspects of TR-medi ated basal repression. Presently, little is known about the role(s) of natural human TR beta mutants on basal repression. These results show that: 1) TR binding to DNA likely is required for basal repression; 2 ) the amino-terminal region of TR is not required for basal repression ; 3) TR homodimer binding is not absolutely required for basal repress ion, as TR mutants that selectively form TR-retinoid X receptor hetero dimers can mediate basal repression; and 4) TR mutants with poor T-3-b inding affinity likely have constitutive basal repression, even in the presence of ligand. These findings provide new insight on the mechani sm of basal repression by unliganded TRs.