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

• Published in: Cell reports (Cambridge) 2016-08, Vol.16 (9), p.2359-2372
• Main Authors: Schmidt, Søren Fisker, Madsen, Jesper Grud Skat, Frafjord, Kari Østerli, Poulsen, Lars la Cour, Salö, Sofia, Boergesen, Michael, Loft, Anne, Larsen, Bjørk Ditlev, Madsen, Maria Stahl, Holst, Jens Juul, Maechler, Pierre, Dalgaard, Louise Torp, Mandrup, Susanne
• Format: Article
• Language: English
• Subjects: 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; ChIP-seq; ChREBP; Dose-Response Relationship, Drug; Enhancer Elements, Genetic; Gene Expression Profiling; Gene Expression Regulation; Genomics; glucose; 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; metabolism; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; pancreatic β cells; proliferation; Promoter Regions, Genetic; Rats; RNA-seq; RORγ; Transcription, Genetic; β cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.07.063

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. [Display omitted] •Glucose reprograms the transcriptional network of INS-1E β cells in a biphasic manner•ChREBP is a central regulator of the first wave of the glucose response•Induction of cell-cycle genes requires ChREBP-induced transcription factors•RORγ is required for full glucose-induced proliferation of INS-1E and primary β cells Schmidt et al. characterize the transcriptional reprogramming of the β cell enhancer and gene landscape by glucose and outline a ChREBP-initiated, biphasic response. Delayed induction of cell-cycle genes is mediated by secondary transcription factors including RORγ, which is required for full induction of β cell proliferation by glucose.