Thyroid hormones (T3) exert their genomic effects by binding to thyroid hormone receptor (TR). Before T3 binding, TR bound to thyroid response elements (TRE) on DNA is associated with co-repressors. This pre-ligand complex actively represses transcription by:

• A Phosphorylating RNA polymerase II to prevent promoter clearance
• B Acetylating histone H3K27 to form constitutive heterochromatin
• C Methylating CpG islands at the TSS of thyroid-responsive genes
• D Recruiting histone deacetylases (HDACs) via SMRT/NCoR co-repressors to compact chromatin ✓

Explanation

Unliganded thyroid hormone receptor (TR) bound to TRE recruits co-repressor complexes containing SMRT (silencing mediator of retinoid and thyroid receptors) or NCoR (nuclear receptor co-repressor). These co-repressors in turn recruit histone deacetylase (HDAC) complexes that remove acetyl groups from histone tails, compacting chromatin and repressing basal transcription of T3-responsive genes. When T3 binds TR, the co-repressor complex dissociates and is replaced by co-activator complexes containing CBP/p300 with histone acetyltransferase activity, activating transcription. H3K27 acetylation is an activating mark, not a repressive mechanism.

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

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Written and medically reviewed by the StethoPrep medical team.