Thyroid hormone receptors (TR) act as activators of transcription in the presence of the thyroid hormone (T 3 ) and as repressors in its absence. While many in vitro approaches have been used to study the molecular mechanisms of TR action, their physiological relevance has not been addressed. Here we investigate how TR regulates gene expression during vertebrate postembryonic development by using T 3 -dependent amphibian metamorphosis as a model. Earlier studies suggest that TR acts as a repressor during premetamorphosis when T 3 is absent. We hypothesize that corepressor complexes containing the nuclear receptor corepressor (N-CoR) are key factors in this TR-dependent gene repression, which is important for premetamorphic tadpole growth. To test this hypothesis, we isolated Xenopus laevis N-CoR (xN-CoR) and showed that it was present in pre-and metamorphic tadpoles. Using a chromatin immunoprecipitation assay, we demonstrated that xN-CoR was recruited to the promoters of T 3 response genes during premetamorphosis and released upon T 3 treatment, accompanied by a local increase in histone acetylation. Furthermore, overexpression of a dominant-negative N-CoR in tadpole tail muscle led to increased transcription from a T 3 -dependent promoter. Our data indicate that N-CoR is recruited by unliganded TR to repress target gene expression during premetamorphic animal growth, an important process that prepares the tadpole for metamorphosis.Combinatorial actions of transcription factors are critical for coordinating development, cell homeostasis, and physiology (31). Nuclear receptors represent a large class of transcription factors implicated in the control of many important biological processes (29,31). This superfamily includes receptors for thyroid hormone (T 3 , or 3,5,3Ј-triiodothyronine), vitamin D, retinoids, steroids, and components of lipid metabolism, as well as a number of orphan receptors (29). One of the most striking developmental processes involving nuclear receptors is amphibian metamorphosis.The metamorphic transformation involves degeneration of larval tissues through apoptosis with concurrent proliferation and differentiation of adult cell types (6, 48). Metamorphosis requires the induction of a number of gene cascades at a precise developmental time point (47, 49). In Xenopus laevis, the switch to the metamorphic program is entirely T 3 dependent (6, 48) but only occurs when the tadpole has grown to a suitable size and stage. This suggests that a molecular repressor mechanism must be in place during the growth period to repress metamorphosis-inducing genes.Our working hypothesis was that this repressor mechanism, vital to correct physiological development, would involve certain corepressors. This hypothesis was derived from the results of a series of elegant in vitro and ex vivo experiments that show liganded as well as unliganded thyroid hormone receptors (TRs) to be capable of binding to target genes through cisacting DNA sequences known as thyroid hormone response elements (T 3 REs). In the absen...
Transcriptional regulation by many diverse groups of transcription factors, including nuclear hormone receptors, involves coactivator and corepressor complexes (reviewed in Refs.
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