We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Downregulation of HNF4A enables transcriptomic reprogramming during the hepatic acute-phase response.
- Authors
Ehle, Charlotte; Iyer-Bierhoff, Aishwarya; Wu, Yunchen; Xing, Shaojun; Kiehntopf, Michael; Mosig, Alexander S.; Godmann, Maren; Heinzel, Thorsten
- Abstract
The hepatic acute-phase response is characterized by a massive upregulation of serum proteins, such as haptoglobin and serum amyloid A, at the expense of liver homeostatic functions. Although the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has a well-established role in safeguarding liver function and its cistrome spans around 50% of liver-specific genes, its role in the acute-phase response has received little attention so far. We demonstrate that HNF4A binds to and represses acute-phase genes under basal conditions. The reprogramming of hepatic transcription during inflammation necessitates loss of HNF4A function to allow expression of acute-phase genes while liver homeostatic genes are repressed. In a pre-clinical liver organoid model overexpression of HNF4A maintained liver functionality in spite of inflammation-induced cell damage. Conversely, HNF4A overexpression potently impaired the acute-phase response by retaining chromatin at regulatory regions of acute-phase genes inaccessible to transcription. Taken together, our data extend the understanding of dual HNF4A action as transcriptional activator and repressor, establishing HNF4A as gatekeeper for the hepatic acute-phase response. Ehle et al. show that downregulation of the liver-identity factor HNF4A facilitates inflammation-associated acute phase gene expression at the expense of homeostatic hepatic functions, to promote the acute phase response.
- Subjects
HEPATOCYTE nuclear factors; TRANSCRIPTION factors; HAPTOGLOBINS; LIVER regeneration; ACUTE phase reaction; BLOOD proteins; GENE expression
- Publication
Communications Biology, 2024, Vol 7, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-024-06288-1