HNF4A modulates glucocorticoid action in the liver

Louise Hunter; Toryn Poolman; Donghwan Kim; Frank Gonzalez; David Bechtold; Andrew Loudon; Mudassar Iqbal; David Ray

doi:10.1016/j.celrep.2022.110697

HNF4A modulates glucocorticoid action in the liver

Louise Hunter, Toryn Poolman, Donghwan Kim, Frank Gonzalez, David Bechtold, Andrew Loudon, Mudassar Iqbal, David Ray

The University of Oxford

Research output: Contribution to journal › Article › peer-review

Abstract

The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

Original language	English
Article number	110697
Journal	Cell Reports
Volume	39
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.110697
Publication status	Published - 19 Apr 2022

Keywords

mouse
glucocorticoid receptor
cistrome
liver
HNF4A
tissue specificity
CP: Molecular biology
nuclear receptor
ChIP
chromatin
Hepatocyte Nuclear Factors/metabolism
Receptors, Glucocorticoid/metabolism
Chromatin/metabolism
Glucocorticoids/metabolism
Animals
Liver/metabolism
Mice
Hepatocyte Nuclear Factor 4/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2022.110697Licence: CC BY

HNF4A is required to specify glucocorticoid action in the liver
Hunter, A. L. (Contributor) & Ray, D. W. (Contributor), Mendeley Data, 13 Apr 2021
DOI: 10.17632/k8d386ndz6.2, https://data.mendeley.com/datasets/k8d386ndz6
Dataset

Determinants of nuclear receptor action in circadian and metabolic regulation
Hunter, A. L. (Author), Ray, D. (Supervisor), Loudon, A. (Supervisor), Bechtold, D. (Supervisor) & Iqbal, M. (Supervisor), 31 Dec 2019
Student thesis: Phd

File

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title = "HNF4A modulates glucocorticoid action in the liver",

abstract = "The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.",

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author = "Louise Hunter and Toryn Poolman and Donghwan Kim and Frank Gonzalez and David Bechtold and Andrew Loudon and Mudassar Iqbal and David Ray",

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AU - Hunter, Louise

AU - Poolman, Toryn

AU - Kim, Donghwan

AU - Gonzalez, Frank

AU - Bechtold, David

AU - Loudon, Andrew

AU - Iqbal, Mudassar

AU - Ray, David

PY - 2022/4/19

Y1 - 2022/4/19

N2 - The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

AB - The glucocorticoid receptor (GR) is a nuclear receptor critical to the regulation of energy metabolism and inflammation. The actions of GR are dependent on cell type and context. Here, we demonstrate the role of liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver specificity of GR action. In mouse liver, the HNF4A motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodeled, with loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites associates with loss of GR binding at weak GRE motifs. GR binding and chromatin accessibility are gained at sites characterized by strong GRE motifs, which show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is indicated by an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

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KW - glucocorticoid receptor

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KW - HNF4A

KW - tissue specificity

KW - CP: Molecular biology

KW - nuclear receptor

KW - ChIP

KW - chromatin

KW - Hepatocyte Nuclear Factors/metabolism

KW - Receptors, Glucocorticoid/metabolism

KW - Chromatin/metabolism

KW - Glucocorticoids/metabolism

KW - Animals

KW - Liver/metabolism

KW - Mice

KW - Hepatocyte Nuclear Factor 4/genetics

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DO - 10.1016/j.celrep.2022.110697

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SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

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M1 - 110697

ER -

HNF4A modulates glucocorticoid action in the liver

Abstract

Keywords

UN SDGs

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Datasets

HNF4A is required to specify glucocorticoid action in the liver

Student theses

Determinants of nuclear receptor action in circadian and metabolic regulation

Cite this