Role of co-regulators in metabolic and transcriptional actions of thyroid hormone
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Figure 1
Schematic representation of the structure of wt SRC family members (A), wt NCoR and SMRT (B), and various genetically modified co-repressor mutants discussed in this review (C). Locations of bHLH/PAS domain, activating domains (AD), receptor-interacting domains (RID), repression domains (RD), and deacetylase activation domain (DAD) are indicated by boxes within the co-regulator molecules. Interactions between co-regulators and NRs, and co-repressors and HDAC3 are shown. Regions of other cofactor recruitment are indicated by arrows. RID3 of SMRT is shown in lighter color to reflect the fact that the predominantly expressed SMRT isoform contains only RID2 and RID1.
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Figure 2
Models of TR-mediated regulation of transcription based on the insights obtained from TR ChIP-seq experiments. Possible roles of co-regulators are hypothesized based on in vitro binding data, animal models with altered co-regulator function, and a limited number of ChIP-PCR experiments. (A) Positively and negatively regulated genes, where TR is recruited to an open chromatin region independently of T3 (based on classic bimodal switch model). On a positively regulated target gene, with a consensus DR-4 TR-binding site, in the absence of TH RXR/TR heterodimer or TR/TR homodimer preferentially recruits co-repressor complex to repress transcription. Upon binding of T3, a conformational change occurs that favors recruitment of co-activators to activate transcription. On negatively regulated targets, with yet undetermined consensus binding site, co-repressor complexes are recruited in the absence of hormone to activate transcription, while co-activators recruited to the liganded TR, mediate transcriptional repression. (B) Positively and negatively regulated genes, where TR binding to open chromatin is affected by T3. On a positive target gene containing a DR-4-binding site, there is weak TR recruitment in the absence of hormone. In the presence of T3, TR strongly binds to the response element and brings co-activator complexes to activate transcription. On a negatively regulated gene, TR is recruited to DR-0 response element in the absence of hormone to activate transcription either through ligand-independent recruitment of co-activators or by recruitment of co-repressors, which act as functional co-activators. Binding of T3 leads to dissociation of TR from DNA and diminished transcription of the target gene. (C) A positively regulated gene located within a region of inaccessible chromatin and containing a strong DR-4 TR-binding motif. TR can only be recruited in the presence of T3 to initiate chromatin remodeling and bring co-activator complex to activate transcription. (D) Negative TH-dependent regulation mediated by indirect recruitment of TR and co-regulators through yet unidentified transcription factors (TF).
- © 2016 Society for Endocrinology
