Differential Recruitment of Nuclear Coregulators Directs the Isoform-Dependent Action of Mutant Thyroid Hormone Receptors

Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TR alpha 1 and TR beta 1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TR alpha 1 (Thra1(PV) mice) or beta 1 (Thrb(PV) mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-dependent functions in vivo. Here we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that distinct 33 nuclear proteins including nuclear receptor corepressor (NCoR1) and six other proteins preferentially associated with TR alpha 1PV or TR beta 1PV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is subtype dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of Thra1PV and ThrbPV mice was further explored. NCoR1 preferentially interacted with TR alpha 1PV rather than with TR beta 1PV. NCoR1 was recruited more avidly to the thyroid hormone response element-bound TR alpha 1PV than to TR beta 1PV in the promoter of the CCAAT/enhancer-binding protein alpha gene to repress its expression in the liver of Thra1(PV) mice, but not in Thrb(PV) mice. This preferential recruitment of NCoR1 by mutant isoforms could contribute, at least in part, to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins. (Molecular Endocrinology 25: 908-921, 2011)