UNLIGANDED THYROID-HORMONE RECEPTOR-ALPHA CAN TARGET TATA-BINDING PROTEIN FOR TRANSCRIPTIONAL REPRESSION

Unliganded human thyroid hormone receptor alpha (hTR alpha) can repres s transcription by inhibiting the formation of a functional preinitiat ion complex (PIC) on promoters bearing thyroid hormone receptor (TR)-b inding elements. Here we demonstrate that hTR alpha directly contacts the TATA-binding protein (TBP) and that preincubation of hTR alpha wit h TBP completely alleviates TR-mediated repression in vitro. Using ste pwise preassembled PICs, we show that hTR alpha targets either the TBP /TFIIA or the TBP/TFIIA/TFIIB steps of PIC assembly for repression. We also show that the repression domain of hTR alpha maps to the C-termi nal ligand-binding region and that direct TR-TBP interactions can be i nhibited by thyroid hormone. Together, these results suggest a model i n which unliganded hTR alpha contacts promoter-bound TBP and interfere s with later steps in the initiation of transcription.