title: NF-Y behaves as a bifunctional transcription factor that can stimulate or repress the FGF-4 promoter in an enhancer-dependent manner.
abstract: NF-Y is a bifunctional transcription factor capable of activating or repressing transcription. NF-Y specifically recognizes CCAAT box motifs present in many eukaryotic promoters. The mechanisms involved in regulating its activity are poorly understood. Previous studies have shown that the FGF-4 promoter is regulated positively by its CCAAT box and NF-Y in embryonal carcinoma (EC) cells where the distal enhancer of the FGF-4 gene is active. Here, we demonstrate that the CCAAT box functions as a negative cis-regulatory element when cis-regulatory elements of the FGF-4 enhancer are disrupted, or after EC cells differentiate and the FGF-4 enhancer is inactivated. We also demonstrate that NF-Y mediates the repression of the CCAAT box and that NF-Y associates with the endogenous FGF-4 gene in both EC cells and EC-differentiated cells. Importantly, we also determined that the orientation and the position of the CCAAT box are critical for its role in regulating the FGF-4 promoter. Together, these studies demonstrate that the distal enhancer of the FGF-4 gene determines whether the CCAAT box of the FGF-4 promoter functions as a positive or a negative cis-regulatory element. In addition, these studies are consistent with NF-Y playing an architectural role in its regulation of the FGF-4 promoter.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA.
authors.forename: Cory T
authors.initials: CT
authors.lastname: Bernadt
authors.forename: Tamara
authors.initials: T
authors.lastname: Nowling
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Wiebe
authors.forename: Angie
authors.initials: A
authors.lastname: Rizzino
mesh_terms: D000818:Animals; D023081:CCAAT-Binding Factor / Q000502:physiology*; D018236:Carcinoma, Embryonal / Q000378:metabolism; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D047468:Immunoprecipitation; D051379:Mice; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D023081:CCAAT-Binding Factor; C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D014157:Transcription Factors