SHI, Y.B.: Mechanism and developmental function of gene regulation by thyroid hormone receptors in Xenopus laevis.

Thyroid hormone (T3) receptors (TRs) are the presumed mediators of the effects of T3 during metamorphosis. Interestingly, these receptors are expressed not only during metamorphosis but also in premetamorphic tadpoles when there is no T3. To investigate the roles of TRs during Xenopus laevis development, we have taken several approaches. First, using an oocyte transcription system, we have demonstrated that TR/RXR heterodimers can alternatively activate or repress a T3-dependent promoter in chromatin in the presence or absence of T3, respectively. Furthermore, transcriptional regulation by TR/RXR appears to involve histone acetylases/deacetylases and transcriptional activation is accompanied by drastic chromatin disruption. Second, we have analyzed the expression of TR and RXR (9-cis retinoic acid receptor, the heterodimerization partner of TR) genes during development, which suggests that TR/RXR heterodimers have dual roles during frog development. Third, by introducing TRs and/or RXRs into Xenopus embryos, We have shown that TR/RXR heterodimers, but not TRs or RXRs alone, can precociously activate endogenous genes in the presence of T3, while repressing these genes in the absence of T3. Finally, we demonstrate by chromatin immunoprecipitation (ChIP) assay that TR/RXR heterodimers are bound to T3 target genes in premetamorphic tadpoles. We further show that histone acetylation changes correlate with T3 target gene expression in some but not all tadpole organs. These results suggest that TR/RXR heterodimers have dual functions during frog development, in part by modifying histone acetylation.