title: FoxA1 binding to the MMTV LTR modulates chromatin structure and transcription.
abstract: Novel binding sites for the forkhead transcription factor family member Forkhead box A (FoxA), previously referred to as Hepatocyte Nuclear Factor 3 (HNF3), were found within the mouse mammary tumor virus long terminal repeat (MMTV LTR). The effect of FoxA1 on MMTV LTR chromatin structure, and expression was evaluated in Xenopus laevis oocytes. Mutagenesis of either of the two main FoxA binding sites showed that the distal site, -232/-221, conferred FoxA1-dependent partial inhibition of glucocorticoid receptor (GR) driven MMTV transcription. The proximal FoxA binding segment consisted of two individual FoxA sites at -57/-46 and -45/-34, respectively, that mediated an increased basal MMTV transcription. FoxA1 binding altered the chromatin structure of both the inactive- and the hormone-activated MMTV LTR. Hydroxyl radical foot printing revealed FoxA1-mediated changes in the nucleosome arrangement. Micrococcal nuclease digestion showed the hormone-dependent sub-nucleosome complex, containing approximately 120 bp of DNA, to be expanded by FoxA1 binding to the proximal segment into a larger complex containing approximately 200 bp. The potential function of the FoxA1-mediated expression of the MMTV provirus for maintenance of expression in different tissues is discussed.
authors.affiliation: Department of Cell and Molecular Biology, The Medical Nobel Institute, Box 285, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Holmqvist
authors.forename: Sergey
authors.initials: S
authors.lastname: Belikov
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Zaret
authors.forename: Orjan
authors.initials: O
authors.lastname: Wrange
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology; D051541:Hepatocyte Nuclear Factor 3-alpha; D017665:Hydroxyl Radical / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D009865:Oocytes; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020079:Terminal Repeat Sequences / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016662:Virus Integration / Q000235:genetics; D014779:Virus Replication / Q000502:physiology; D014981:Xenopus
chemical_list: D002843:Chromatin; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D009687:Nuclear Proteins; D009707:Nucleosomes; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D017665:Hydroxyl Radical