Nuclear receptor corepressor recruitment by unliganded thyroid hormone receptor in gene repression during Xenopus laevis development.
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.
Sachs
Laurent M
LM
Unit on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-5431, USA. sachs@mnhn.fr
Jones
Peter L
PL
Havis
Emmanuelle
E
Rouse
Nicole
N
Demeneix
Barbara A
BA
Shi
Yun-Bo
YB
D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006614:Hindlimb / Q000502:physiology; D006801:Humans; D007422:Intestines / Q000502:physiology; D007814:Larva / Q000033:anatomy & histology / Q000502:physiology; D008024:Ligands; D008675:Metamorphosis, Biological / Q000502:physiology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D009865:Oocytes / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013623:Tail / Q000502:physiology; D014284:Triiodothyronine / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics / Q000254:growth & development*
D008024:Ligands; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D029867:Xenopus Proteins; C470195:nuclear receptor corepressor, Xenopus; D014284:Triiodothyronine