Transcriptional repression by the thyroid hormone receptor: Function of corepressor complexes

Purpose of review: Thyroid hormone receptors form heterodimers with the receptor for 9-cis-retinoic acid and bind to thyroid response elements in the promoters of target genes. In the absence of thyroid hormone, the thyroid hormone receptor/receptor for 9-cis-retinoic acid heterodimer represses transcription through the recruitment of large multiple subunit corepressor complexes containing histone deacetylase activity. On ligand binding, thyroid hormone receptor/receptor for 9-cis-retinoic acid releases the corepressor complexes and recruits coactivator complexes. This review focuses on the nature of the corepressor complexes that associate with thyroid hormone receptor and how they function to repress transcription. Recent findings: Several corepressor complexes have been implicated in repression by the "unliganded" thyroid hormone receptor (apo-thyroid hormone receptor), including the histone deacetylase-1/2-containing Sin3 and Mi2/NuRD and the histone deacetylase-3-containing nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT). Previously it was thought that N-CoR and SMRT recruit histone deacetylase activity by associating with Sin3; however, it is now clear that N-CoR and SMRT are a distinct class of corepressor complexes containing histone deacetylase-3. SMRT and N-CoR potentiate the enzymatic activity of histone deacetylase-3 through direct binding. Recent studies also reveal an essential role for histone binding subunits in targeting SMRT and N-CoR complexes to chromatin. Several reports indicate that thyroid hormone receptor-β preferentially interacts with N-CoR, whereas thyroid hormone receptor-α recruits both N-CoR and SMRT. Finally, it has recently been shown that repression by thyroid hormone receptor involves methylation of histone H3 lysine 9. Summary: Repression by apo-thyroid hormone receptor is a complicated process that may involve many cofactor complexes. The many corepressors involved may allow the apo-thyroid hormone receptor a good degree of flexibility in transcriptional repression. All the corepressors for thyroid hormone receptor appear to associate with histone deacetylase activity; therefore, histone deacetylation is the major mechanism through which apo-thyroid hormone receptor represses transcription.