title: Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells.
abstract: Glucose is an important inducer of insulin secretion, but it also stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β cells. Here, we have generated time-resolved profiles of enhancer and transcriptional activity in response to glucose in the INS-1E pancreatic β cell line. Our data outline a biphasic response with a first transcriptional wave during which metabolic genes are activated, and a second wave where cell-cycle genes are activated and β cell identity genes are repressed. The glucose-sensing transcription factor ChREBP directly activates first wave enhancers, whereas repression and activation of second wave enhancers are indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we have identified multiple putative regulators of the second wave. These include RORγ, the activity of which is important for glucose-induced proliferation of both INS-1E and primary rat β cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Søren Fisker
authors.initials: SF
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; NNF Center of Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Jesper Grud Skat
authors.initials: JG
authors.lastname: Madsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Kari Østerli
authors.initials: KØ
authors.lastname: Frafjord
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Lars la Cour
authors.initials: Ll
authors.lastname: Poulsen
authors.affiliation: Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.
authors.forename: Sofia
authors.initials: S
authors.lastname: Salö
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Boergesen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Loft
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Bjørk Ditlev
authors.initials: BD
authors.lastname: Larsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Maria Stahl
authors.initials: MS
authors.lastname: Madsen
authors.affiliation: NNF Center of Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
authors.affiliation: Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.
authors.forename: Louise Torp
authors.initials: LT
authors.lastname: Dalgaard
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark. Electronic address: s.mandrup@bmb.sdu.dk.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023281:Genomics; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; C442825:Mlxipl protein, rat; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539902:Rorc protein, rat; D005947:Glucose
keywords: ChIP-seq; ChREBP; RNA-seq; RORγ; glucose; metabolism; pancreatic β cells; proliferation; β cells