C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements

Lars Grøntved, Sam John, Songjoon Baek, Ying Liu, John R Buckley, Charles Vinson, Greti Aguilera, Gordon L Hager

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocorticoid injection. Upon activation of the glucocorticoid receptor (GR), proximal regions of activated and repressed genes are remodelled, and these remodelling events correlate with RNA polymerase II occupancy of regulated genes. GR is exclusively associated with accessible chromatin and 62% percent of GR-binding sites are occupied by C/EBPβ. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBPβ for GR recruitment. Disruption of C/EBPβ binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin remodelling specifically at sites co-occupied by GR and C/EBPβ. Collectively, we demonstrate a highly cooperative mechanism by which C/EBPβ regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodellers.

Original languageEnglish
JournalE M B O Journal
Volume32
Issue number11
Pages (from-to)1568-83
ISSN0261-4189
DOIs
Publication statusPublished - 2013

Fingerprint

Glucocorticoid Receptors
Response Elements
Liver
Chromatin
Steroids
Tissue
Genes
Glucocorticoids
Chromatin Assembly and Disassembly
RNA Polymerase II
Transcription Factors
Chemical activation
Binding Sites

Keywords

  • Animals
  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-beta
  • Cell Line
  • Chromatin
  • Chromatin Assembly and Disassembly
  • Dexamethasone
  • Gene Expression Regulation
  • Glucocorticoids
  • Humans
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Nucleosomes
  • Nucleotide Motifs
  • Organ Specificity
  • Protein Binding
  • Receptors, Glucocorticoid
  • Regulatory Elements, Transcriptional
  • Response Elements

Cite this

Grøntved, Lars ; John, Sam ; Baek, Songjoon ; Liu, Ying ; Buckley, John R ; Vinson, Charles ; Aguilera, Greti ; Hager, Gordon L. / C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. In: E M B O Journal. 2013 ; Vol. 32, No. 11. pp. 1568-83.
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abstract = "Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocorticoid injection. Upon activation of the glucocorticoid receptor (GR), proximal regions of activated and repressed genes are remodelled, and these remodelling events correlate with RNA polymerase II occupancy of regulated genes. GR is exclusively associated with accessible chromatin and 62{\%} percent of GR-binding sites are occupied by C/EBPβ. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBPβ for GR recruitment. Disruption of C/EBPβ binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin remodelling specifically at sites co-occupied by GR and C/EBPβ. Collectively, we demonstrate a highly cooperative mechanism by which C/EBPβ regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodellers.",
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C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. / Grøntved, Lars; John, Sam; Baek, Songjoon; Liu, Ying; Buckley, John R; Vinson, Charles; Aguilera, Greti; Hager, Gordon L.

In: E M B O Journal, Vol. 32, No. 11, 2013, p. 1568-83.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements

AU - Grøntved, Lars

AU - John, Sam

AU - Baek, Songjoon

AU - Liu, Ying

AU - Buckley, John R

AU - Vinson, Charles

AU - Aguilera, Greti

AU - Hager, Gordon L

PY - 2013

Y1 - 2013

N2 - Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocorticoid injection. Upon activation of the glucocorticoid receptor (GR), proximal regions of activated and repressed genes are remodelled, and these remodelling events correlate with RNA polymerase II occupancy of regulated genes. GR is exclusively associated with accessible chromatin and 62% percent of GR-binding sites are occupied by C/EBPβ. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBPβ for GR recruitment. Disruption of C/EBPβ binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin remodelling specifically at sites co-occupied by GR and C/EBPβ. Collectively, we demonstrate a highly cooperative mechanism by which C/EBPβ regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodellers.

AB - Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocorticoid injection. Upon activation of the glucocorticoid receptor (GR), proximal regions of activated and repressed genes are remodelled, and these remodelling events correlate with RNA polymerase II occupancy of regulated genes. GR is exclusively associated with accessible chromatin and 62% percent of GR-binding sites are occupied by C/EBPβ. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBPβ for GR recruitment. Disruption of C/EBPβ binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin remodelling specifically at sites co-occupied by GR and C/EBPβ. Collectively, we demonstrate a highly cooperative mechanism by which C/EBPβ regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodellers.

KW - Animals

KW - Binding Sites

KW - CCAAT-Enhancer-Binding Protein-beta

KW - Cell Line

KW - Chromatin

KW - Chromatin Assembly and Disassembly

KW - Dexamethasone

KW - Gene Expression Regulation

KW - Glucocorticoids

KW - Humans

KW - Liver

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Models, Molecular

KW - Nucleosomes

KW - Nucleotide Motifs

KW - Organ Specificity

KW - Protein Binding

KW - Receptors, Glucocorticoid

KW - Regulatory Elements, Transcriptional

KW - Response Elements

U2 - 10.1038/emboj.2013.106

DO - 10.1038/emboj.2013.106

M3 - Journal article

C2 - 23665916

VL - 32

SP - 1568

EP - 1583

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

IS - 11

ER -