title: Transcription of the Geminin gene is regulated by a negative-feedback loop.
abstract: Geminin performs a central function in regulating cellular proliferation and differentiation in development and also in stem cells. Of interest, down-regulation of Geminin induces gene transcription regulated by E2F, indicating that Geminin is involved in regulation of E2F-mediated transcriptional activity. Because transcription of the Geminin gene is reportedly regulated via an E2F-responsive region (E2F-R) located in the first intron, we first used a reporter vector to examine the effect of Geminin on E2F-mediated transcriptional regulation. We found that Geminin transfection suppressed E2F1- and E2F2-mediated transcriptional activation and also mildly suppressed such activity in synergy with E2F5, 6, and 7, suggesting that Geminin constitutes a negative-feedback loop for the Geminin promoter. Of interest, Geminin also suppressed nuclease accessibility, acetylation of histone H3, and trimethylation of histone H3 at lysine 4, which were induced by E2F1 overexpression, and enhanced tri-methylation of histone H3 at lysine 27 and monoubiquitination of histone H2A at lysine 119 in E2F-R. However, Geminin5EQ, which does not interact with Brahma or Brg1, did not suppress accessibility to nuclease digestion or transcription but had an overall dominant-negative effect. These findings suggest that E2F-mediated activation of Geminin transcription is negatively regulated by Geminin through the inhibition of chromatin remodeling.
authors.affiliation: Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita 562-0025, Japan Department of Life Sciences, Meiji University School of Agriculture, Kawasaki 214-8571, Japan Department of Molecular Genetics, Maastricht University Medical Centre, 6229ER Maastricht, Netherlands Department of Food and Fermentation Science, Faculty of Food Science and Nutrition, Beppu University, Beppu 874-0915, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohno
authors.forename: Keita
authors.initials: K
authors.lastname: Saeki
authors.forename: Shin'ichiro
authors.initials: S
authors.lastname: Yasunaga
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kurogi
authors.forename: Kyoko
authors.initials: K
authors.lastname: Suzuki-Takedachi
authors.forename: Manabu
authors.initials: M
authors.lastname: Shirai
authors.forename: Keichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: J Willem
authors.initials: JW
authors.lastname: Voncken
authors.forename: Motoaki
authors.initials: M
authors.lastname: Ohtsubo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
mesh_terms: D016475:3T3 Cells; D000107:Acetylation; D000818:Animals; D000906:Antibodies / Q000276:immunology; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D025461:Feedback, Physiological; D064248:Geminin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006657:Histones / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics*; D054875:Ubiquitination
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D064248:Geminin; D006657:Histones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases