Integrative genomics outlines a biphasic glucose response and a ChREBP-RORγ axis regulating proliferation in β cells

Søren Fisker Schmidt, Jesper Grud Skat Madsen, Kari Østerli, Lars la Cour Poulsen, Sofia Salö, Michael Boergesen, Anne Loft, Bjørk Ditlev Larsen, Maria Stahl Madsen, Jens Juul Holst, Pierre Maechler, Louise Torp Dalgaard, Susanne Mandrup

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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.

Original languageEnglish
JournalCell Reports
Volume16
Issue number9
Pages (from-to)2359-2372
DOIs
Publication statusPublished - 30. Aug 2016

Keywords

  • Journal Article

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