NUCLEAR RECEPTOR COREPRESSORS ACTIVATE RATHER THAN SUPPRESS BASAL TRANSCRIPTION OF GENES THAT ARE NEGATIVELY REGULATED BY THYROID-HORMONE

A group of transcriptional cofactors referred to as corepressors (CoRs ) were recently shown to play a central role in basal silencing of gen es that contain positive triiodothyronine (T3) response elements, In a reciprocal manner, negatively regulated genes are stimulated by unlig anded thyroid hormone receptor (TR) and repressed upon the addition of T3, We used a TR beta mutant, called P214R, which fails to interact w ith CoRs, to examine whether CoRs also play a role in the control of g enes that are negatively regulated in response to T3, In studies of th ree negatively regulated genes (the pituitary thyroid-stimulating horm one alpha-subunit [TSH alpha], TSH beta, and hypothalamic thyrotropin- releasing hormone [TRH] genes), stimulation of basal promoter activity by unliganded TR beta was impaired by introducing the P214R CoR mutat ion, Coexpression of each of the CoRs SMRT (silencing mediator for ret inoid receptors and TRs) and NCoR (nuclear receptor CoR) enhanced basa l stimulation of the negatively regulated promoters in a TR-dependent manner, but this effect was not seen with the P214R TR mutant. The mec hanism of CoR effects on negatively regulated promoters was explored f urther with a series of GAL4-TR chimeric receptors and mutants that al lowed TR effects to be assessed independently of receptor interactions with DNA, These experiments revealed that, like the negative regulati on of genes by wild-type TR, basal activation occurred with GAL4-TR, b ut not with the GAL4-P214R mutant, and was reversed by the addition of T3, These results suggest that TR interactions with negatively regula ted genes may be driven through protein-protein interactions, We concl ude that a subset of negatively regulated genes are controlled by a no vel mechanism that involves TR-mediated recruitment and basal activati on by SMRT and NCoR. Addition of T3 reverses basal activation, perhaps by dissociation of CoRs.