The differential hormone-dependent transcriptional activation of thyroid hormone receptor isoforms is mediated by interplay of their domains

Human thyroid hormone nuclear receptor isoforms (TRα1 and TRβ1) express differentially in a tissue-specific and development-dependent manner. It is unclear whether these two isoforms have differential functions. We analyzed their interaction with a thyroid hormone response element with half- site binding motifs arranged in an everted repeat separated by six nucleotides (F2). Despite extensive sequence homologies, the two isoforms bound to F2 with different affinities and ratios of homodimer/monomer. Using F2-containing reporter gene, we found that the transcriptional activity of TRβ1 was ~6-fold higher than that of TRαI. The lower activity of TRαI was not due to differences in expression of the two isoforms because similar nuclear localization patterns were observed. To understand the structural determinants responsible for these differences, we constructed chimeric receptors in which hinge regions (domain D), hormone binding domains (domain E), and domains (D + E) were sequentially interchanged and their activities were compared. Chimeric TRs containing the domains D, E or (D + E) of TRβ1 showed increased propensities to form homodimers and mediated higher transactivation activities than TRα1. Thus, differential transactivation activities of TR isoforms are mediated by interplay of their domains and could serve as an important regulatory mechanism to achieve diversity and specificity of pleiotropic T₃ effect.