Mechanisms that mediate negative regulation of the thyroid-stimulating hormone alpha gene by the thyroid hormone...

Area of Science:

• Molecular Biology
• Gene Regulation
• Endocrinology

Background:

• Nuclear hormone receptors regulate gene expression via cofactors like corepressors (CoRs) and coactivators (CoAs).
• CoRs recruit histone deacetylases (HDACs) for silencing, while CoAs recruit histone acetyltransferases (HATs) for activation.
• Gene regulation by nuclear receptors can be complex, with some genes activated in the absence of ligand and repressed upon ligand binding.

Purpose of the Study:

• To investigate the novel mechanism of negative regulation of the thyroid-stimulating hormone alpha (TSHalpha) promoter by the thyroid hormone receptor (TR).
• To elucidate the role of corepressors, histone acetylation, and ligand binding in TR-mediated gene regulation.

Main Methods:

• Analysis of TSHalpha promoter activity in response to TR, CoRs, and HDAC expression.
• Assessment of histone acetylation levels under various experimental conditions.
• Investigation of the effect of ligand (T3) binding on TR-mediated gene regulation.
• Examination of the impact of cAMP response element binding protein phosphorylation and HDAC inhibition.

Main Results:

• TR recruitment of CoRs stimulated TSHalpha promoter activity and histone acetylation.
• Excess HDAC reversed the TR-CoR-mediated stimulation, highlighting acetylation's role.
• T3 ligand binding induced repression of the TSHalpha promoter, associated with decreased histone acetylation.
• T3-dependent repression was blocked by maneuvers that increase histone acetylation.

Conclusions:

• Negative regulation of a subset of genes by TR involves an active exchange between CoRs and CoAs.
• This exchange impacts histone acetylation and transcriptional activation of target genes.
• The findings reveal a novel mechanism where corepressor recruitment by TR stimulates transcription and histone acetylation, which is reversed by ligand binding.