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Cited by 49Estrogen and related hormone effectsGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

HNF4A modulates glucocorticoid action in the liver

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Hunter, A. Louise, Poolman, Toryn M., Kim, Donghwan, Gonzalez, Frank J., Bechtold, David A., Loudon, Andrew S.I., Iqbal, Mudassar, Ray, David W.·2022·Cell Reports
DOI 10.1016/j.celrep.2022.110697PMC PMC9380254
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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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  • HNF4A depletion in adult mouse liver reduces H3K4me1 at locations normally occupied by HNF4A.

    “In agreement with recent papers50,53, we observed reduced levels of H3K4me1 in cKO livers at locations normally occupied by HNF4A (Fig. 1b).”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [53]

    The Results section on chromatin accessibility reports that HNF4A loss reduces accessibility at sites usually marked by HNF4A. The Results section on chromatin state reports H3K4me1 levels at GR sites in normal liver, but does not show that H3K4me1 decreases after HNF4A depletion. Page numbers were not available in our copy. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Hunter, A. L., Poolman, T. M., Kim, D., Gonzalez, F. J., Bechtold, D. A., Loudon, A. S. I., Iqbal, M., & Ray, D. W.
Affiliations
  • University of Oxford (GB)
  • National Institutes of Health (US)
  • University of Manchester (GB)
  • John Radcliffe Hospital (GB)
Corresponding author
Ray, David W.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2022-04
Volume
39
Issue
3
Pages
110697
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2022.110697
PMC
PMC9380254
OpenAlex
W4224217744
Cited by
49
References
7
Citations by year
2026: 16 · 2025: 12 · 2024: 12 · 2023: 7 · 2022: 1 · 2021: 1
FWCI
4.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
Funders
  • Wellcome Trust (107849/Z/15/Z, 107851/Z/15/Z)
  • Medical Research Council (MR/N021479/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
HNF4α, glucocorticoid receptor, glucocorticoid response element, chromatin accessibility, open chromatin, transcriptional regulation, tissue-specific gene regulation
MeSH terms
Animals, Chromatin, Glucocorticoids, Liver, Receptors, Glucocorticoid, Mice, Hepatocyte Nuclear Factors, Hepatocyte Nuclear Factor 4

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