Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone.

Brijesh Kumar Singh,Paul Michael Yen,Rohit Anthony Sinha

doi:10.3390/ijms19103284

Abstract

The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.

Highlights

Thyroid hormones (THs; triiodothyronine/T3 and thyroxine/T4) are critical regulators of the cellular and physiological metabolism
TH activation of forkhead box protein O1 (FOXO1) depended upon an increase in Sirtuin 1 (SIRT1)-mammalian target of rapamycin (MTOR) Complex 2 (MTORC2) interaction and rapamycin-insensitive companion of MTOR (RICTOR) deacetylation, which led to a decreased AKT and FOXO1 phosphorylation [9]
The direct regulation of transcription by TH receptors (THRs) has been extensively studied (Type 1 transcriptional regulation; Figure 1), there are other mechanisms that regulate transcription ranging from the THR interaction with other transcription factors bound to response elements (Type 2 transcriptional regulation), the TH activation of THRs to mediate effects that do not involve DNA-binding (Type 3 transcriptional regulation), and the TH binding to proteins other than THRs (Type 4 transcriptional regulation) [23]

Summary

Introduction

Thyroid hormones (THs; triiodothyronine/T3 and thyroxine/T4) are critical regulators of the cellular and physiological metabolism. Only a limited number of transcriptionally-regulated genes have been identified which have direct THR binding to the conserved hexamer nucleotide sequences that comprise TREs [2,3]. It appears that TH can activate cellular pathways and physiological responses without THR binding to DNA or through the direct modulation of gene expression [4]. These discrepancies raise the possibility for alternative mechanisms of metabolic regulation by TH. We will describe some of these alternative mechanisms as well as examine new examples in which TH can modulate the transcription of subsets of target genes via the induction of metabolic changes that can lead to activation of other nuclear receptors/transcription factors, THR cross-talk with other cellular and nuclear proteins, and miRNAs [5,6,7,8,9,10,11]

Direct Regulation of Transcription by TH

Major Alternative Types of Transcriptional Regulation

Additional Mechanisms of Transcriptional Regulation by TH

New Mechanisms of Transcriptional Regulation by TH

Findings

Future Directions and Conclusions