Thyroid hormone (T3) exerts its genomic effects by binding nuclear thyroid hormone receptors (TRα/TRβ). The key sequence of events between T3 binding and target gene transcription is:

• A T3 binds membrane integrin αvβ3 → PI3K/Akt signaling → nuclear translocation of TRα → chromatin remodeling independent of TRE sequences
• B T3 binds cytoplasmic TRβ → TR-T3 complex translocates to nucleus → heterodimerizes with glucocorticoid receptor → recognizes composite response elements
• C T3 enters cell → binds TRβ in nucleus → corepressor (NCoR/SMRT) is displaced and coactivator (SRC/p300) recruited → RNA polymerase II complex assembles → positive TRE gene transcription ✓
• D T3 activates deiodinase D2 in nucleus → local T4 to T3 conversion → allosteric activation of pre-formed TR-RXR dimers without coactivator exchange

Explanation

Thyroid hormone receptors (TRα1, TRβ1, TRβ2) are nuclear transcription factors that reside on DNA (bound to thyroid response elements, TREs) even in the absence of T3, usually as heterodimers with RXR (retinoid X receptor). In the unliganded state, TR-RXR recruits corepressor complexes (NCoR, SMRT) that possess histone deacetylase (HDAC) activity, silencing transcription. When T3 binds the TR ligand-binding domain, corepressors are displaced, coactivators (SRC-1, CBP/p300 with histone acetyltransferase activity) are recruited, chromatin decondenses, and RNA polymerase II is recruited to the promoter. This process explains why hypothyroidism (no T3) leads to transcriptional silencing and why hyperthyroidism (excess T3) leads to overexpression of T3-responsive genes.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.