First functional polymorphism in CFTR promoter that results in decreased transcriptional activity and Sp1/USF binding.
Growing evidences show that functionally relevant polymorphisms in various promoters alter both transcriptional activity and affinities of existing protein-DNA interactions, and thus influence disease progression in humans. We previously reported the -94G>T CFTR promoter variant in a female CF patient in whom any known disease-causing mutation has been detected. To investigate whether the -94G>T could be a regulatory variant, we have proceeded to in silico analyses and functional studies including EMSA and reporter gene assays. Our data indicate that the promoter variant decreases basal CFTR transcriptional activity in different epithelial cells and alters binding affinities of both Sp1 and USF nuclear proteins to the CFTR promoter. The present report provides evidence for the first functional polymorphism that negatively affects the CFTR transcriptional activity and demonstrates a cooperative role of Sp1 and USF transcription factors in transactivation of the CFTR gene promoter.
INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France. magali.taulan@montp.inserm.fr
M
M
Taulan
E
E
Lopez
C
C
Guittard
C
C
René
D
D
Baux
J P
JP
Altieri
M
M
DesGeorges
M
M
Claustres
M C
MC
Romey
D001665:Binding Sites; D018938:Caco-2 Cells; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D024721:E-Box Elements; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
C505032:CFTR protein, human; D016329:Sp1 Transcription Factor; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator