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HNF4A modulates glucocorticoid action in the liver.

Authors
  • Hunter, A Louise1
  • Poolman, Toryn M2
  • Kim, Donghwan3
  • Gonzalez, Frank J3
  • Bechtold, David A1
  • Loudon, Andrew S I1
  • Iqbal, Mudassar1
  • Ray, David W4
  • 1 Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
  • 2 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK.
  • 3 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Apr 19, 2022
Volume
39
Issue
3
Pages
110697–110697
Identifiers
DOI: 10.1016/j.celrep.2022.110697
PMID: 35443180
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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