title: Binding of serum response factor to cystic fibrosis transmembrane conductance regulator CArG-like elements, as a new potential CFTR transcriptional regulation pathway.
abstract: CFTR expression is tightly controlled by a complex network of ubiquitous and tissue-specific cis-elements and trans-factors. To better understand mechanisms that regulate transcription of CFTR, we examined transcription factors that specifically bind a CFTR CArG-like motif we have previously shown to modulate CFTR expression. Gel mobility shift assays and chromatin immunoprecipitation analyses demonstrated the CFTR CArG-like motif binds serum response factor both in vitro and in vivo. Transient co-transfections with various SRF expression vector, including dominant-negative forms and small interfering RNA, demonstrated that SRF significantly increases CFTR transcriptional activity in bronchial epithelial cells. Mutagenesis studies suggested that in addition to SRF other co-factors, such as Yin Yang 1 (YY1) previously shown to bind the CFTR promoter, are potentially involved in the CFTR regulation. Here, we show that functional interplay between SRF and YY1 might provide interesting perspectives to further characterize the underlying molecular mechanism of the basal CFTR transcriptional activity. Furthermore, the identification of multiple CArG binding sites in highly conserved CFTR untranslated regions, which form specific SRF complexes, provides direct evidence for a considerable role of SRF in the CFTR transcriptional regulation into specialized epithelial lung cells.
authors.affiliation: Laboratoire de Génétique Moléculaire et Chromosomique, Institut Universitaire de Recherche Clinique, Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: René
authors.forename: Magali
authors.initials: M
authors.lastname: Taulan
authors.forename: Florence
authors.initials: F
authors.lastname: Iral
authors.forename: Julien
authors.initials: J
authors.lastname: Doudement
authors.forename: Aurore
authors.initials: A
authors.lastname: L'Honoré
authors.forename: Catherine
authors.initials: C
authors.lastname: Gerbon
authors.forename: Jacques
authors.initials: J
authors.lastname: Demaille
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Romey
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000378:metabolism*; D027602:Serum Response Element; D026362:Serum Response Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050986:YY1 Transcription Factor
chemical_list: C505032:CFTR protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D026362:Serum Response Factor; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator