Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus

John R. Pooley*, Ben P. Flynn, Lars Grøntved, Songjoon Baek, Michael J. Guertin, Yvonne M. Kershaw, Matthew T. Birnie, Annie Pellatt, Caroline A. Rivers, R. Louis Schiltz, Gordon L. Hager, Stafford L. Lightman, Becky L. Conway-Campbell

*Corresponding author for this work

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Abstract

Glucocorticoids regulate hippocampal function in part by modulating gene expression through the glucocorticoid receptor (GR). GR binding is highly cell type specific, directed to accessible chromatin regions established during tissue differentiation. Distinct classes of GR binding sites are dependent on the activity of additional signal-activated transcription factors that prime chromatin toward context-specific organization. We hypothesized a stress context dependency for GR binding in hippocampus as a consequence of rapidly induced stress mediators priming chromatin accessibility. Using chromatin immunoprecipitation sequencing to interrogate GR binding, we found no effect of restraint stress context on GR binding, although analysis of sequences underlying GR binding sites revealed mechanistic detail for hippocampal GR function. We note enrichment of GR binding sites proximal to genes linked to structural and organizational roles, an absence of major tethering partners for GRs, and little or no evidence for binding at negative glucocorticoid response elements. A basic helix-loop-helix motif closely resembling a NeuroD1 or Olig2 binding site was found underlying a subset of GR binding sites and is proposed as a candidate lineage-determining transcription factor directing hippocampal chromatin access for GRs. Of our GR binding sites, 54% additionally contained half-sites for nuclear factor (NF)-1 that we propose as a collaborative or general transcription factor involved in hippocampal GR function. Our findings imply a dosedependent and context-independent action of GRs in the hippocampus. Alterations in the expression or activity of NF-1/basic helix-loop-helix factors may play an as yet undetermined role in glucocorticoid-related disease susceptibility and outcome by altering GR access to hippocampal binding sites. Copyright for this article is retained by the author(s).

Original languageEnglish
JournalEndocrinology
Volume158
Issue number5
Pages (from-to)1486-1501
ISSN0013-7227
DOIs
Publication statusPublished - 2017

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Glucocorticoid Receptors
Glucocorticoids
Chromatin Immunoprecipitation
Sequence Analysis
Organizations

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Pooley, J. R., Flynn, B. P., Grøntved, L., Baek, S., Guertin, M. J., Kershaw, Y. M., ... Conway-Campbell, B. L. (2017). Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus. Endocrinology, 158(5), 1486-1501. https://doi.org/10.1210/en.2016-1929
Pooley, John R. ; Flynn, Ben P. ; Grøntved, Lars ; Baek, Songjoon ; Guertin, Michael J. ; Kershaw, Yvonne M. ; Birnie, Matthew T. ; Pellatt, Annie ; Rivers, Caroline A. ; Schiltz, R. Louis ; Hager, Gordon L. ; Lightman, Stafford L. ; Conway-Campbell, Becky L. / Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus. In: Endocrinology. 2017 ; Vol. 158, No. 5. pp. 1486-1501.
@article{2c5e5fac720c4ea99acc2f1a633d36e5,
title = "Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus",
abstract = "Glucocorticoids regulate hippocampal function in part by modulating gene expression through the glucocorticoid receptor (GR). GR binding is highly cell type specific, directed to accessible chromatin regions established during tissue differentiation. Distinct classes of GR binding sites are dependent on the activity of additional signal-activated transcription factors that prime chromatin toward context-specific organization. We hypothesized a stress context dependency for GR binding in hippocampus as a consequence of rapidly induced stress mediators priming chromatin accessibility. Using chromatin immunoprecipitation sequencing to interrogate GR binding, we found no effect of restraint stress context on GR binding, although analysis of sequences underlying GR binding sites revealed mechanistic detail for hippocampal GR function. We note enrichment of GR binding sites proximal to genes linked to structural and organizational roles, an absence of major tethering partners for GRs, and little or no evidence for binding at negative glucocorticoid response elements. A basic helix-loop-helix motif closely resembling a NeuroD1 or Olig2 binding site was found underlying a subset of GR binding sites and is proposed as a candidate lineage-determining transcription factor directing hippocampal chromatin access for GRs. Of our GR binding sites, 54{\%} additionally contained half-sites for nuclear factor (NF)-1 that we propose as a collaborative or general transcription factor involved in hippocampal GR function. Our findings imply a dosedependent and context-independent action of GRs in the hippocampus. Alterations in the expression or activity of NF-1/basic helix-loop-helix factors may play an as yet undetermined role in glucocorticoid-related disease susceptibility and outcome by altering GR access to hippocampal binding sites. Copyright for this article is retained by the author(s).",
author = "Pooley, {John R.} and Flynn, {Ben P.} and Lars Gr{\o}ntved and Songjoon Baek and Guertin, {Michael J.} and Kershaw, {Yvonne M.} and Birnie, {Matthew T.} and Annie Pellatt and Rivers, {Caroline A.} and Schiltz, {R. Louis} and Hager, {Gordon L.} and Lightman, {Stafford L.} and Conway-Campbell, {Becky L.}",
year = "2017",
doi = "10.1210/en.2016-1929",
language = "English",
volume = "158",
pages = "1486--1501",
journal = "Endocrinology",
issn = "0013-7227",
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}

Pooley, JR, Flynn, BP, Grøntved, L, Baek, S, Guertin, MJ, Kershaw, YM, Birnie, MT, Pellatt, A, Rivers, CA, Schiltz, RL, Hager, GL, Lightman, SL & Conway-Campbell, BL 2017, 'Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus', Endocrinology, vol. 158, no. 5, pp. 1486-1501. https://doi.org/10.1210/en.2016-1929

Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus. / Pooley, John R.; Flynn, Ben P.; Grøntved, Lars; Baek, Songjoon; Guertin, Michael J.; Kershaw, Yvonne M.; Birnie, Matthew T.; Pellatt, Annie; Rivers, Caroline A.; Schiltz, R. Louis; Hager, Gordon L.; Lightman, Stafford L.; Conway-Campbell, Becky L.

In: Endocrinology, Vol. 158, No. 5, 2017, p. 1486-1501.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Genome-wide identification of basic helix-loop-helix and NF-1 motifs underlying GR binding sites in male rat hippocampus

AU - Pooley, John R.

AU - Flynn, Ben P.

AU - Grøntved, Lars

AU - Baek, Songjoon

AU - Guertin, Michael J.

AU - Kershaw, Yvonne M.

AU - Birnie, Matthew T.

AU - Pellatt, Annie

AU - Rivers, Caroline A.

AU - Schiltz, R. Louis

AU - Hager, Gordon L.

AU - Lightman, Stafford L.

AU - Conway-Campbell, Becky L.

PY - 2017

Y1 - 2017

N2 - Glucocorticoids regulate hippocampal function in part by modulating gene expression through the glucocorticoid receptor (GR). GR binding is highly cell type specific, directed to accessible chromatin regions established during tissue differentiation. Distinct classes of GR binding sites are dependent on the activity of additional signal-activated transcription factors that prime chromatin toward context-specific organization. We hypothesized a stress context dependency for GR binding in hippocampus as a consequence of rapidly induced stress mediators priming chromatin accessibility. Using chromatin immunoprecipitation sequencing to interrogate GR binding, we found no effect of restraint stress context on GR binding, although analysis of sequences underlying GR binding sites revealed mechanistic detail for hippocampal GR function. We note enrichment of GR binding sites proximal to genes linked to structural and organizational roles, an absence of major tethering partners for GRs, and little or no evidence for binding at negative glucocorticoid response elements. A basic helix-loop-helix motif closely resembling a NeuroD1 or Olig2 binding site was found underlying a subset of GR binding sites and is proposed as a candidate lineage-determining transcription factor directing hippocampal chromatin access for GRs. Of our GR binding sites, 54% additionally contained half-sites for nuclear factor (NF)-1 that we propose as a collaborative or general transcription factor involved in hippocampal GR function. Our findings imply a dosedependent and context-independent action of GRs in the hippocampus. Alterations in the expression or activity of NF-1/basic helix-loop-helix factors may play an as yet undetermined role in glucocorticoid-related disease susceptibility and outcome by altering GR access to hippocampal binding sites. Copyright for this article is retained by the author(s).

AB - Glucocorticoids regulate hippocampal function in part by modulating gene expression through the glucocorticoid receptor (GR). GR binding is highly cell type specific, directed to accessible chromatin regions established during tissue differentiation. Distinct classes of GR binding sites are dependent on the activity of additional signal-activated transcription factors that prime chromatin toward context-specific organization. We hypothesized a stress context dependency for GR binding in hippocampus as a consequence of rapidly induced stress mediators priming chromatin accessibility. Using chromatin immunoprecipitation sequencing to interrogate GR binding, we found no effect of restraint stress context on GR binding, although analysis of sequences underlying GR binding sites revealed mechanistic detail for hippocampal GR function. We note enrichment of GR binding sites proximal to genes linked to structural and organizational roles, an absence of major tethering partners for GRs, and little or no evidence for binding at negative glucocorticoid response elements. A basic helix-loop-helix motif closely resembling a NeuroD1 or Olig2 binding site was found underlying a subset of GR binding sites and is proposed as a candidate lineage-determining transcription factor directing hippocampal chromatin access for GRs. Of our GR binding sites, 54% additionally contained half-sites for nuclear factor (NF)-1 that we propose as a collaborative or general transcription factor involved in hippocampal GR function. Our findings imply a dosedependent and context-independent action of GRs in the hippocampus. Alterations in the expression or activity of NF-1/basic helix-loop-helix factors may play an as yet undetermined role in glucocorticoid-related disease susceptibility and outcome by altering GR access to hippocampal binding sites. Copyright for this article is retained by the author(s).

U2 - 10.1210/en.2016-1929

DO - 10.1210/en.2016-1929

M3 - Journal article

C2 - 28200020

AN - SCOPUS:85019150109

VL - 158

SP - 1486

EP - 1501

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 5

ER -