HNF4A modulates glucocorticoid action in the liver

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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Article number110697
JournalCell Reports
Issue number3
Publication statusPublished - 19 Apr 2022


  • 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


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