Thyroid hormone T3 (triiodothyronine) exerts its genomic effects by acting as a ligand for nuclear thyroid hormone receptors (TR). Before ligand binding, the unliganded TR/RXR heterodimer on thyroid hormone response elements (TREs) typically:

• A Acts as a transcriptional activator in the absence of T3, and T3 binding represses transcription
• B Is sequestered in the cytoplasm until T3 binding causes nuclear translocation
• C Binds DNA constitutively without corepressors; T3 causes DNA dissociation
• D Actively represses transcription by recruiting histone deacetylase (HDAC)-containing corepressors; T3 binding causes corepressor release and coactivator (HAT) recruitment ✓

Explanation

The unliganded TR/RXR heterodimer binds TREs on DNA and recruits corepressor complexes containing NCoR (nuclear corepressor) or SMRT, which in turn recruit histone deacetylases (HDACs). HDACs deacetylate histone tails, compacting chromatin and repressing transcription — this is why hypothyroid states can have paradoxically repressed metabolic genes. Upon T3 binding, the receptor undergoes conformational change (helix 12 repositioning in the ligand-binding domain), releasing corepressors and recruiting coactivators (SRC-1, p300/CBP with histone acetyltransferase/HAT activity), which acetylate histones and activate transcription. This nuclear receptor mechanism (ligand-induced switch from repressor to activator) distinguishes TRs from many other transcription factors.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.