Figure 1.

Transcriptional regulation by TH signaling. (A) Four major categories of gene regulation by TH. TH regulates gene transcription by a classical direct mechanism (Type 1 regulation), where liganded THRs heterodimerize with other nuclear receptors such as RXR, and recruit co-activators or co-repressors to directly activate or repress gene transcription, respectively. However, in Type 2 regulation, THRs do not bind directly to DNA and tether onto DNA by protein-protein interaction with other transcription factors. In Type 3 regulation, THRs do not require any binding to DNA and activate other transcription factors via non-genomic actions. In Type 4 regulation, TH binds to protein receptors other than THRs and activates gene transcription by other transcription factors. (B) Alternative mechanisms for gene regulation by TH. THR interaction with other proteins (such as SIRT1) leads to its post-translational modification and activation of gene transcription (subtypes of Type 1, 3). Metabolic activation of upstream regulator proteins such as SIRT1 by TH leads to the activation of other downstream transcription factors such as FOXO1 (subtype of Type 1). The TH-PGC1α-ERRα pathway that regulates mitochondrial turnover can be considered a special subset of Type 1 transcriptional regulation with the addition of secondary (PGC1α) and tertiary (ERRα) transcription factors and nuclear hormone receptors serving as the primary, secondary, and tertiary mediators of transcription. THR-mediated regulation of microRNAs shows post-transcriptional regulation and comes under Types 1, 2, or 3 depending on whether the mechanism involves the direct or indirect regulation of miRNA transcription.