title: Novel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2.
abstract: ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene.
authors.affiliation: Laboratory of Biochemistry, Department of Basic Sciences, University of Crete Medical School, Heraklion 71110, Greece; Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology of Hellas, Heraklion 71110, Greece.
authors.forename: Efstathia
authors.initials: E
authors.lastname: Thymiakou
authors.affiliation: Laboratory of Biochemistry, Department of Basic Sciences, University of Crete Medical School, Heraklion 71110, Greece; Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology of Hellas, Heraklion 71110, Greece. Electronic address: kardasis@imbb.forth.gr.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kardassis
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012176:Retinoids / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; C496502:FOXA2 protein, human; D006888:Hydroxycholesterols; D012333:RNA, Messenger; D012176:Retinoids; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: ABCA1; FOXA2; TATA box; Transcriptional repression