title: Feedback on hypothalamic TRH transcription is dependent on thyroid hormone receptor N terminus.
abstract: The beta thyroid hormone receptor (TRbeta), but not TRalpha1, plays a specific role in mediating T(3)-dependent repression of hypothalamic TRH transcription. To investigate the structural basis of isoform specificity, we compared the transcriptional regulation and DNA binding obtained with chimeric and N-terminally deleted TRs. Using in vivo transfection assays to follow hypothalamic TRH transcription in the mouse brain, we found that TRbeta1 and chimeras with the TRbeta1 N terminus did not affect either transcriptional activation or repression from the rat TRH promoter, whereas N-terminally deleted TRbeta1 impaired T(3)-dependent repression. TRalpha1 or chimeras with the TRalpha1 N terminus reduced T(3)-independent transcriptional activation and blocked T(3)-dependent repression of transcription. Full deletion of the TRalpha1 N terminus restored ligand-independent activation of transcription. No TR isoform specificity was seen after transcription from a positive thyroid hormone response element. Gel mobility assays showed that all TRs tested bound specifically to the main negative thyroid hormone response element in the TRH promoter (site 4). Addition of neither steroid receptor coactivator 1 nor nuclear extracts from the hypothalamic paraventricular nuclei revealed any TR isoform specificity in binding to site 4. Thus N-terminal sequences specify TR T(3)-dependent repression of TRH transcription but not DNA recognition, emphasizing as yet unknown neuron-specific contributions to protein-promoter interactions in vivo.
authors.affiliation: Laboratoire de Physiologie Générale et Comparée, Unité Mixte de Recherche 8572, Centre Nationale de la Recherche Scientifique, Muséum National d'Histoire Naturelle, 75231 Paris, cedex 5, France.
authors.forename: Hajer
authors.initials: H
authors.lastname: Guissouma
authors.forename: Sandrine M
authors.initials: SM
authors.lastname: Dupré
authors.forename: Nathalie
authors.initials: N
authors.lastname: Becker
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jeannin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Seugnet
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Demeneix
mesh_terms: D000818:Animals; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D025461:Feedback, Physiological; D051548:Histone Acetyltransferases; D007031:Hypothalamus / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D056920:Nuclear Receptor Coactivator 1; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013379:Substrate Specificity; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1