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

ABSTRACT: Glucose is an important regulator of pancreatic β-cell function. In addition to the acute stimulation of insulin secretion, glucose stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β-cells. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to promote both β-cell proliferation and dysfunction; however, the molecular mechanisms underlying these pleiotropic effects of ChREBP and glucose are not well understood. 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 wave during which metabolic genes are activated, and a second wave where cell cycle genes are induced and β-cell identity genes are repressed. We show that ChREBP directly activates first wave genes, whereas repression and activation of second wave genes by ChREBP is indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we identify multiple putative regulators of the second wave, including RAR-related orphan receptor (ROR) γ, which we demonstrate is a novel direct ChREBP target gene. Importantly, we show that RORγ activity is necessary for full glucose-induced proliferation of both INS-1E and primary rat β-cells.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE81628 | GEO | 2016/09/06

SECONDARY ACCESSION(S): PRJNA322158

REPOSITORIES: GEO

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Integrative genomics outlines a biphasic glucose response and a ChREBP-RORÎ³ axis regulating proliferation in Î²-cells

Project description:Glucose is an important regulator of pancreatic Î²-cell function. In addition to the acute stimulation of insulin secretion, glucose stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of Î²-cells. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to promote both Î²-cell proliferation and dysfunction; however, the molecular mechanisms underlying these pleiotropic effects of ChREBP and glucose are not well understood. Here, we have generated time-resolved profiles of enhancer and transcriptional activity in response to glucose in the INS-1E pancreatic Î²-cell line. Our data outline a biphasic response with a first wave during which metabolic genes are activated, and a second wave where cell cycle genes are induced and Î²-cell identity genes are repressed. We show that ChREBP directly activates first wave genes, whereas repression and activation of second wave genes by ChREBP is indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we identify multiple putative regulators of the second wave, including RAR-related orphan receptor (ROR) Î³, which we demonstrate is a novel direct ChREBP target gene. Importantly, we show that RORÎ³ activity is necessary for full glucose-induced proliferation of both INS-1E and primary rat Î²-cells. Genome-wide assesment of the transcriptional response to glucose in INS-1E Î²-cells using RNA- ChIP- and DNase-seq

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