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HNF4A modulates glucocorticoid action in the liver
A Louise Hunter1, Toryn M Poolman2, Donghwan Kim3
1Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
Cell Reports
|April 20, 2022
Summary
Hepatocyte nuclear factor 4A (HNF4A) dictates liver-specific glucocorticoid receptor (GR) action by influencing GR binding sites. Loss of HNF4A reshapes the GR landscape, altering gene expression in response to glucocorticoids.
Area of Science:
- Endocrinology
- Molecular Biology
- Hepatology
Background:
- The glucocorticoid receptor (GR) is a key regulator of metabolism and inflammation.
- GR's function is context-dependent, varying by cell type.
- Hepatocyte nuclear factor 4A (HNF4A) is a crucial liver-determining factor.
Purpose of the Study:
- To investigate the role of HNF4A in conferring liver specificity to GR actions.
- To understand how HNF4A influences GR binding and chromatin accessibility in the liver.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) to map GR binding sites.
- Analysis of chromatin accessibility.
- Comparison of GR cistromes in wild-type and HNF4A-deficient mouse livers.
- Assessment of transcriptional changes upon glucocorticoid treatment.
Main Results:
- HNF4A motifs are located near GR binding sites in open chromatin in mouse liver.
- HNF4A deficiency leads to significant remodeling of the liver GR cistrome.
- Loss of HNF4A results in decreased GR binding at weak response elements due to reduced chromatin accessibility.
- GR binding and chromatin accessibility increase at strong response elements, mirroring non-liver tissue patterns.
- HNF4A-regulated GR sites are functionally important, as evidenced by altered glucocorticoid-induced gene expression in HNF4a-null livers.
Conclusions:
- HNF4A is essential for establishing the liver-specific GR cistrome.
- HNF4A modulates GR binding and chromatin accessibility, thereby fine-tuning the cellular response to glucocorticoids.
- These findings highlight a mechanism for tissue-specific nuclear receptor function.
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