Differential recruitment of nuclear coregulators directs the isoform-dependent action of mutant thyroid hormone...

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Thyroid hormone receptors (TR) exist as distinct isoforms (TRα1 and TRβ1) with both overlapping and unique biological functions.
• Dominant-negative mutations in TRα1 (Thra1(PV)) and TRβ1 (Thrb(PV)) lead to different phenotypes in mice, suggesting isoform-specific roles.
• Understanding the molecular basis of these isoform-dependent functions is crucial for elucidating thyroid hormone action.

Purpose of the Study:

• To test the hypothesis that distinct functions of TR mutant isoforms are directed by specific nuclear regulatory proteins.
• To identify nuclear proteins that preferentially associate with TRα1PV or TRβ1PV.
• To investigate the role of nuclear receptor corepressor 1 (NCoR1) in mediating the distinct liver phenotypes observed in Thra1(PV) and Thrb(PV) mice.

Main Methods:

• Tandem-affinity chromatography of HeLa nuclear extracts to identify interacting proteins.
• Analysis of protein-DNA interactions at the CCAAT/enhancer-binding protein α (C/EBPα) gene promoter.
• Comparison of NCoR1 recruitment and gene expression in the liver of Thra1(PV) and Thrb(PV) mice.

Main Results:

• Distinct sets of 33 nuclear proteins, including NCoR1, preferentially associated with either TRα1PV or TRβ1PV.
• NCoR1 showed preferential interaction with TRα1PV over TRβ1PV.
• NCoR1 was recruited more avidly to the TRα1PV-bound C/EBPα promoter, repressing its expression in the liver of Thra1(PV) mice but not Thrb(PV) mice.

Conclusions:

• TR isoforms direct selective functions through preferential recruitment of specific nuclear coregulatory proteins.
• Preferential recruitment of NCoR1 by TRα1PV contributes to the distinct liver lipid phenotype in Thra1(PV) mice.
• This study reveals a novel mechanism underlying TR isoform-specific gene regulation and function.