title: Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8.
abstract: Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4alpha (HNF4alpha) in the ABCG5/ABCG8 intergenic promoter, through which HNF4alpha strongly activated the expression of a reporter gene in both directions. The HNF4alpha-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4alpha. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4alpha leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4alpha and GATA were essential for maximal synergism. We also show that HNF4alpha, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4alpha and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4alpha acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.
authors.affiliation: Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sumi
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Aoi
authors.initials: A
authors.lastname: Uchida
authors.forename: Kenta
authors.initials: K
authors.lastname: Magoori
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Urashima
authors.forename: Riuko
authors.initials: R
authors.lastname: Ohashi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Okamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kudo
authors.forename: Kenji
authors.initials: K
authors.lastname: Daigo
authors.forename: Takashi
authors.initials: T
authors.lastname: Maejima
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kojima
authors.forename: Iori
authors.initials: I
authors.lastname: Sakakibara
authors.forename: Shuying
authors.initials: S
authors.lastname: Jiang
authors.forename: Go
authors.initials: G
authors.lastname: Hasegawa
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D017124:Conserved Sequence; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D017930:Genes, Reporter; D051557:Hepatocyte Nuclear Factor 4 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
chemical_list: C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D051557:Hepatocyte Nuclear Factor 4; D008074:Lipoproteins; D008156:Luciferases