CREB Promotes Beta Cell Gene Expression by Targeting Its Coactivators to Tissue-Specific Enhancers

Sam Van de Velde, Ezra Wiater, Melissa Tran, You Sang Hwang, Philip A. Cole, Marc Montminy

Research output: Contribution to journalArticle

Abstract

CREB mediates effects of cyclic AMP on cellular gene expression. Ubiquitous CREB target genes are induced following recruitment of CREB and its coactivators to promoter proximal binding sites. We found that CREB stimulates the expression of pancreatic beta cell-specific genes by targeting CBP/p300 to promoter-distal enhancer regions. Subsequent increases in histone acetylation facilitate recruitment of the coactivators CRTC2 and BRD4, leading to release of RNA polymerase II over the target gene body. Indeed, CREB-induced hyperacetylation of chromatin over superenhancers promoted beta cell-restricted gene expression, which is sensitive to inhibitors of CBP/p300 and BRD4 activity. Neurod1 appears critical in establishing nucleosome-free regions for recruitment of CREB to beta cell-specific enhancers. Deletion of a CREB-Neurod1-bound enhancer within the Lrrc10b-Syt7 superenhancer disrupted the expression of both genes and decreased beta cell function. Our results demonstrate how cross talk between signal-dependent and lineage-determining factors promotes the expression of cell-type-specific gene programs in response to extracellular cues.

Original languageEnglish (US)
JournalMolecular and cellular biology
Volume39
Issue number17
DOIs
StatePublished - Sep 1 2019

Fingerprint

Gene Targeting
Gene Expression
Genes
Nucleosomes
RNA Polymerase II
Insulin-Secreting Cells
Acetylation
Cyclic AMP
Histones
Chromatin
Cues
Binding Sites

Keywords

  • beta cell
  • BRD4
  • cAMP
  • CBP
  • CREB
  • CRTC2
  • insulin
  • NeuroD1
  • PKA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

CREB Promotes Beta Cell Gene Expression by Targeting Its Coactivators to Tissue-Specific Enhancers. / Van de Velde, Sam; Wiater, Ezra; Tran, Melissa; Hwang, You Sang; Cole, Philip A.; Montminy, Marc.

In: Molecular and cellular biology, Vol. 39, No. 17, 01.09.2019.

Research output: Contribution to journalArticle

Van de Velde, Sam ; Wiater, Ezra ; Tran, Melissa ; Hwang, You Sang ; Cole, Philip A. ; Montminy, Marc. / CREB Promotes Beta Cell Gene Expression by Targeting Its Coactivators to Tissue-Specific Enhancers. In: Molecular and cellular biology. 2019 ; Vol. 39, No. 17.
@article{882c7ee47b6a4e3e89bc68c4ddbb4a3c,
title = "CREB Promotes Beta Cell Gene Expression by Targeting Its Coactivators to Tissue-Specific Enhancers",
abstract = "CREB mediates effects of cyclic AMP on cellular gene expression. Ubiquitous CREB target genes are induced following recruitment of CREB and its coactivators to promoter proximal binding sites. We found that CREB stimulates the expression of pancreatic beta cell-specific genes by targeting CBP/p300 to promoter-distal enhancer regions. Subsequent increases in histone acetylation facilitate recruitment of the coactivators CRTC2 and BRD4, leading to release of RNA polymerase II over the target gene body. Indeed, CREB-induced hyperacetylation of chromatin over superenhancers promoted beta cell-restricted gene expression, which is sensitive to inhibitors of CBP/p300 and BRD4 activity. Neurod1 appears critical in establishing nucleosome-free regions for recruitment of CREB to beta cell-specific enhancers. Deletion of a CREB-Neurod1-bound enhancer within the Lrrc10b-Syt7 superenhancer disrupted the expression of both genes and decreased beta cell function. Our results demonstrate how cross talk between signal-dependent and lineage-determining factors promotes the expression of cell-type-specific gene programs in response to extracellular cues.",
keywords = "beta cell, BRD4, cAMP, CBP, CREB, CRTC2, insulin, NeuroD1, PKA",
author = "{Van de Velde}, Sam and Ezra Wiater and Melissa Tran and Hwang, {You Sang} and Cole, {Philip A.} and Marc Montminy",
year = "2019",
month = "9",
day = "1",
doi = "10.1128/MCB.00200-19",
language = "English (US)",
volume = "39",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "17",

}

TY - JOUR

T1 - CREB Promotes Beta Cell Gene Expression by Targeting Its Coactivators to Tissue-Specific Enhancers

AU - Van de Velde, Sam

AU - Wiater, Ezra

AU - Tran, Melissa

AU - Hwang, You Sang

AU - Cole, Philip A.

AU - Montminy, Marc

PY - 2019/9/1

Y1 - 2019/9/1

N2 - CREB mediates effects of cyclic AMP on cellular gene expression. Ubiquitous CREB target genes are induced following recruitment of CREB and its coactivators to promoter proximal binding sites. We found that CREB stimulates the expression of pancreatic beta cell-specific genes by targeting CBP/p300 to promoter-distal enhancer regions. Subsequent increases in histone acetylation facilitate recruitment of the coactivators CRTC2 and BRD4, leading to release of RNA polymerase II over the target gene body. Indeed, CREB-induced hyperacetylation of chromatin over superenhancers promoted beta cell-restricted gene expression, which is sensitive to inhibitors of CBP/p300 and BRD4 activity. Neurod1 appears critical in establishing nucleosome-free regions for recruitment of CREB to beta cell-specific enhancers. Deletion of a CREB-Neurod1-bound enhancer within the Lrrc10b-Syt7 superenhancer disrupted the expression of both genes and decreased beta cell function. Our results demonstrate how cross talk between signal-dependent and lineage-determining factors promotes the expression of cell-type-specific gene programs in response to extracellular cues.

AB - CREB mediates effects of cyclic AMP on cellular gene expression. Ubiquitous CREB target genes are induced following recruitment of CREB and its coactivators to promoter proximal binding sites. We found that CREB stimulates the expression of pancreatic beta cell-specific genes by targeting CBP/p300 to promoter-distal enhancer regions. Subsequent increases in histone acetylation facilitate recruitment of the coactivators CRTC2 and BRD4, leading to release of RNA polymerase II over the target gene body. Indeed, CREB-induced hyperacetylation of chromatin over superenhancers promoted beta cell-restricted gene expression, which is sensitive to inhibitors of CBP/p300 and BRD4 activity. Neurod1 appears critical in establishing nucleosome-free regions for recruitment of CREB to beta cell-specific enhancers. Deletion of a CREB-Neurod1-bound enhancer within the Lrrc10b-Syt7 superenhancer disrupted the expression of both genes and decreased beta cell function. Our results demonstrate how cross talk between signal-dependent and lineage-determining factors promotes the expression of cell-type-specific gene programs in response to extracellular cues.

KW - beta cell

KW - BRD4

KW - cAMP

KW - CBP

KW - CREB

KW - CRTC2

KW - insulin

KW - NeuroD1

KW - PKA

UR - http://www.scopus.com/inward/record.url?scp=85071350965&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071350965&partnerID=8YFLogxK

U2 - 10.1128/MCB.00200-19

DO - 10.1128/MCB.00200-19

M3 - Article

C2 - 31182641

AN - SCOPUS:85071350965

VL - 39

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 17

ER -