Abstract

Thyroid hormone controls a wide range of physiological processes through thyroid hormone receptor (TR) isoforms. Classically, TRs are proposed to function as T3-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by thyroid hormone have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review will discuss data obtained in various mouse models with manipulated function of nuclear receptor co-repressor NCoR and silencing mediator of retinoid and thyroid receptor (SMRT), and family of steroid receptor co-activators (SRC) in the context of thyroid hormone action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.