title: The Glucocorticoid Receptor Regulates the ANGPTL4 Gene in a CTCF-Mediated Chromatin Context in Human Hepatic Cells.
abstract: Glucocorticoid signaling through the glucocorticoid receptor (GR) plays essential roles in the response to stress and in energy metabolism. This hormonal action is integrated to the transcriptional control of GR-target genes in a cell type-specific and condition-dependent manner. In the present study, we found that the GR regulates the angiopoietin-like 4 gene (ANGPTL4) in a CCCTC-binding factor (CTCF)-mediated chromatin context in the human hepatic HepG2 cells. There are at least four CTCF-enriched sites and two GR-binding sites within the ANGPTL4 locus. Among them, the major CTCF-enriched site is positioned near the ANGPTL4 enhancer that binds GR. We showed that CTCF is required for induction and subsequent silencing of ANGPTL4 expression in response to dexamethasone (Dex) and that transcription is diminished after long-term treatment with Dex. Although the ANGPTL4 locus maintains a stable higher-order chromatin conformation in the presence and absence of Dex, the Dex-bound GR activated transcription of ANGPTL4 but not that of the neighboring three genes through interactions among the ANGPTL4 enhancer, promoter, and CTCF sites. These results reveal that liganded GR spatiotemporally controls ANGPTL4 transcription in a chromosomal context.
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.|Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamoto
authors.affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.|Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Hirosue
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hino
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.|Core Research for Evolutionary Science and Technology (CREST), Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000076246:CCCTC-Binding Factor; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D003907:Dexamethasone