Thyroid hormone response element organization dictates the composition of active receptor

Area of Science:

• Molecular Biology
• Endocrinology
• Gene Regulation

Background:

• Thyroid hormone (T3) signaling involves thyroid hormone receptors (TRs) and retinoid X receptors (RXRs) binding to T3 response elements (TREs).
• TRs typically function as heterodimers with RXRs, binding to direct repeat TREs (DR-4).
• Alternative TRE arrangements, including inverted palindromes (F2) and palindromes (Pal), exist but their TR binding partners are less understood.

Purpose of the Study:

• To investigate the role of TR homodimers and monomers in transcriptional activation from different TREs.
• To determine the TRE-selective activity of TR alpha and TR beta isoforms.
• To elucidate the functional significance of TR oligomerization in mediating T3 action.

Main Methods:

• In vitro analysis of TR homodimer formation at F2 TREs.
• Reconstruction of TR transcription complexes in yeast.
• Analysis of TR beta mutations affecting dimer formation in mammalian cells.

Main Results:

• TR homodimers and monomers activate transcription from TREs with varied half-site arrangements.
• TR beta homodimers show preferential formation and activity at F2 TREs compared to TR alpha.
• Yeast and mammalian cell studies confirm TRE-selective activity: TR beta homodimers at F2, RXR-TRs at DR-4, and TR monomers at Pal.
• TR beta requires higher T3 levels for F2 activation, linked to TR.TRE complex composition.

Conclusions:

• TRs can form homodimers and monomers that are transcriptionally active on specific TREs.
• TRE-selective binding and activation by different TR oligomeric forms (homodimers, heterodimers, monomers) contribute to the nuanced regulation of gene expression by thyroid hormone.
• These findings highlight the underappreciated role of TR oligomerization in vivo T3 signaling.