Transcriptome profiling reveals HNF4A as the gatekeeper of the hepatic acute-phase response

Liver-specific genes regulating homeostatic functions are markedly repressed following an inflammatory stimulus. Conversely, transcriptional resources are reallocated to boost acute-phase genes, driving the systemic immune reaction termed the acute phase response (APR). While the liver-enriched transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) directs expression of more than 50% of hepatic genes, its role in the APR is poorly investigated.

To analyze inflammatory gene profile in hepatocytes, we adopted an in vitro APR model of LPS-treated differentiated HepaRG (dHepaRG) cells. RNA sequencing and transcription factor enrichment of the downregulated gene set directed our research focus to HNF4A. The APR resulted in a rapid repression of HNF4A RNA and protein levels. Consequently, reduced binding of HNF4A to regulatory regions of acute-phase genes serum amyloid A (SAA) and haptoglobin (HP) was followed by a chromatin-opening and derepression of these genes. Vice versa, HNF4A overexpression potently inhibited activation of acute-phase genes by maintaining a repressive chromatin state. This result was reproducible in a liver organoid model, where HNF4A overexpression protected from severe loss of liver function while limiting the APR.

We demonstrate that a rapid repression of HNF4A levels and activity is required to enable a transcriptomic switch during the hepatic acute-phase response. HNF4A overexpression impaired acute-phase gene expression while preserving liver functionality, offering potential for the treatment of liver dysfunction during systemic inflammation or sepsis.

Author and article information

Conference

Publisher: ScienceOpen

Publication date (Electronic, pub): 9 October 2023

Affiliations

[1 ] Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany;

[2 ] School of Basic Medical Sciences, Shenzhen University, Shenzhen, China;

[3 ] The First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China;

[4 ] Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Jena, Germany;

[5 ] Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena, Jena University Hospital, Member of the Leibniz Center for Photonics in Infection Research (LPI), Jena, Germany;

[6 ] Institute of Biochemistry II, Jena University Hospital, Jena, Germany;

[7 ] Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany;

Author information

Charlotte Ehle https://orcid.org/0009-0008-5415-3770

Aishwarya Iyer-Bierhoff https://orcid.org/0009-0003-6662-4852

Shaojun Xing https://orcid.org/0000-0003-0777-2196

Alexander S Mosig https://orcid.org/0000-0002-5687-2444

Maren Godmann https://orcid.org/0000-0002-0214-8012

Thorsten Heinzel https://orcid.org/0009-0003-8937-6089

Article

DOI: 10.14293/GOF.23.46

SO-VID: 74813be6-b9c7-4827-bd62-816a11902975

License:

Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

Conference name: Genetoberfest 2023

Conference date: 16-18 October 2023

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ScienceOpen