The in vivo role of nuclear receptor corepressors in thyroid hormone action

Abstract

Background: The thyroid hormone receptor (TR) isoforms interact with a variety of coregulators depending upon the availability of T3 to mediate their transcriptional effect. Classically, in the absence of ligand, the TRs recruit the nuclear corepressors, NCoR and SMRT, to mediate transcriptional repression on positively regulated TR target genes. However, new insight into the roles of NCoR and SMRT using in vivo models have better defined the role of nuclear corepressors both in the absence and presence of T3.

Scope of review: This review will place the variety of in vivo nuclear corepressor mouse models developed to date in context of thyroid hormone action. Based on these models, we will also discuss how corepressor availability together with the levels of endogenous nuclear receptor ligands including T3 controls multiple signaling pathways.

Major conclusions: Nuclear corepressors mediate repression of positive TR targets in the absence of T3in vivo. Even more importantly they attenuate activation of these targets at the normal physiological levels of ligands by TR and other nuclear receptors. While the role of corepressors in the regulation of negative TR targets and HPT axis remains poorly understood, lack of corepressor recruitment to TR in the animals leads to a compensatory change in the set point of HPT axis that allows to balance the increased sensitivity to T3 action in other tissues.

General significance: Available data indicate that targeting specific interactions between corepressors and TR or other nuclear receptors presents a new therapeutic strategy for endocrine and metabolic disorders. This article is part of a Special Issue entitled Thyroid hormone signalling.

Figure 1

Schematic representation of the structure of wild type NCoR and SMRT as well as various mutants discussed in this review. Repression domains (RD), deacetylase activation domain (DAD) and receptor-interacting domains (RID) are indicated. RID3 of SMRT is shown in lighter color to reflect the fact that the predominantly expressed SMRT isoform contains only RID2 and RID1.

Figure 2

A model of TR-mediated regulation of transcription. On a positively regulated target gene, in the absence of thyroid hormone (upper left) TR-RXR hederodimer recruits the corepressor complex to repress transcription. In the presence of high concentrations of TH (upper right) most of the receptors bind TH which induces the conformational change that leads to release of corepressors and recruitment of coactivators to maximally activate transcription. At intermediate concentrations of TH corresponding to a normal euthyroid state (upper middle) only some of the receptors bind the ligand. The complex between TR, hormone, coactivators and corepressors is in a dynamic balance that achieves moderate activation of transcription. Removal of corepressors at this state results to the increased availability of TR for the ligand and coactivators, leading to the increased sensitivity to the hormone. Paradoxically, on negatively regulated targets, corepressor complexes recruited in the absence of hormone may activate transcription, while coactivators that are recruited when TR binds TH, mediate transcriptional repression.