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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Resumé

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.

OriginalsprogEngelsk
TidsskriftCell Reports
Vol/bind16
Udgave nummer9
Sider (fra-til)2359-2372
DOI
StatusUdgivet - 30. aug. 2016

Fingeraftryk

Cell Proliferation
Glucose
Genes
cdc Genes
Transcription Factors
Cells
Gene expression
Insulin
Rats
Cell Line
Chemical activation
Genomics

Citer dette

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title = "Integrative genomics outlines a biphasic glucose response and a ChREBP-RORγ axis regulating proliferation in β cells",
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.",
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author = "Schmidt, {S{\o}ren Fisker} and Madsen, {Jesper Grud Skat} and Kari {\O}sterli and Poulsen, {Lars la Cour} and Sofia Sal{\"o} and Michael Boergesen and Anne Loft and Larsen, {Bj{\o}rk Ditlev} and Madsen, {Maria Stahl} and Holst, {Jens Juul} and Pierre Maechler and Dalgaard, {Louise Torp} and Susanne Mandrup",
note = "Copyright {\circledC} 2016 The Author(s). Published by Elsevier Inc. All rights reserved.",
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Integrative genomics outlines a biphasic glucose response and a ChREBP-RORγ axis regulating proliferation in β cells. / Schmidt, Søren Fisker; Madsen, Jesper Grud Skat; Østerli, Kari; 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.

I: Cell Reports, Bind 16, Nr. 9, 30.08.2016, s. 2359-2372.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Integrative genomics outlines a biphasic glucose response and a ChREBP-RORγ axis regulating proliferation in β cells

AU - Schmidt, Søren Fisker

AU - Madsen, Jesper Grud Skat

AU - Østerli, Kari

AU - Poulsen, Lars la Cour

AU - Salö, Sofia

AU - Boergesen, Michael

AU - Loft, Anne

AU - Larsen, Bjørk Ditlev

AU - Madsen, Maria Stahl

AU - Holst, Jens Juul

AU - Maechler, Pierre

AU - Dalgaard, Louise Torp

AU - Mandrup, Susanne

N1 - Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2016/8/30

Y1 - 2016/8/30

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.celrep.2016.07.063

DO - 10.1016/j.celrep.2016.07.063

M3 - Journal article

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VL - 16

SP - 2359

EP - 2372

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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