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

Cell Rep. 2016 Aug 30;16(9):2359-72. doi: 10.1016/j.celrep.2016.07.063. Epub 2016 Aug 18.

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.

Keywords: ChIP-seq; ChREBP; RNA-seq; RORγ; glucose; metabolism; pancreatic β cells; proliferation; β cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Dose-Response Relationship, Drug
  • Enhancer Elements, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genomics
  • Glucose / metabolism
  • Glucose / pharmacology*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Promoter Regions, Genetic
  • Rats
  • Transcription, Genetic

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Cycle Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Rorc protein, rat
  • Wbscr14 protein, rat
  • Glucose