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In addition to providing a potential mechanism for basal repression, the presence of corepressors may also explain the ability of TH to act as a positive modulator for basal transcription. In the presence of saturating amounts of hormone, corepressors are displaced from the receptor and the gene-activating proteins are associated with the TR-RXR heterodimer. This heterodimer is capable of robust transcriptional activation in the absence of corepressors, presumably due to the increased co-activating ability of the liganded receptor. Thus, corepressors may play a critical role in determining the functional response of a target gene to thyroid hormones. As a heterodimer consisting of the DNA-binding domains of TR and RAR, their distinct roles in regulating gene expression are also being explored. The RAR/TR complex may be more specific for the estrogen response element (ERE) than for the TRE or for the thyroid hormone response element (TRE) as a monomer in vitro. This is in contrast to the thyroid hormone-responsive element (TRE) which is not a specific element for TR in the absence of RAR. RAR/TR binding to the TRE is approximately 10-fold stronger than to the ERE and is not affected by cooperative binding of TH and retinol to the RAR.
The RAR/TR heterodimer is capable of enhanced transcriptional activation by the liganded RAR/RXR heterodimer in the absence of corepressors (111-114). This leads to the speculation that corepressors may displace the liganded receptor from the heterodimer, thus allowing the gene-activating proteins to remain bound to the heterodimer. Corepressors may also facilitate liganded TR/RXR heterodimer binding to the TRE, or RAR/RXR binding to the ERE (Figure 3e-3, below). Therefore, co-repressors may play a role in determining the specificity of receptor/receptor complexes in the absence of hormone as well as in the presence of hormone, providing a potential mechanism for ligand-specific gene regulation. In the absence of corepressors, the liganded receptor may function as a transcriptional activator or repressor in vivo, depending on the surrounding chromatin environment. Thus, corepressors may play a role in determining the functional response of target genes to TH.
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