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Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells.

  • Schmidt SF Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Madsen JG 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.
  • Frafjord KØ Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Poulsen Ll Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Salö S Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.
  • Boergesen M Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Loft A Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Larsen BD Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Madsen MS Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • Holst JJ NNF Center of Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark; Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
  • Maechler P Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland.
  • Dalgaard LT Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.
  • Mandrup S Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark. Electronic address: s.mandrup@bmb.sdu.dk.
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  • 2016-08-23
Published in:
  • Cell reports. - 2016
ChIP-seq
ChREBP
RNA-seq
RORγ
glucose
metabolism
pancreatic β cells
proliferation
β cells
Animals
Base Sequence
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cell Cycle
Cell Cycle Proteins
Cell Line
Cell Proliferation
Dose-Response Relationship, Drug
Enhancer Elements, Genetic
Gene Expression Profiling
Gene Expression Regulation
Genomics
Glucose
Insulin-Secreting Cells
Metabolic Networks and Pathways
Nuclear Receptor Subfamily 1, Group F, Member 3
Promoter Regions, Genetic
Rats
Transcription, Genetic
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/169574
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