Downregulation of HNF4A enables transcriptomic reprogramming during the hepatic acute-phase response

• DOI: 10.1038/s42003-024-06288-1
• Publication Date: 2024-05-16T17:01:57Z
• Authors: Charlotte Ehle; Aishwarya Iyer-Bi...; Yunchen Wu; Shaojun Xing; Michael Kiehntopf; Alexander S. Mosig; Maren Godmann; Thorsten Heinzel
• Keywords: Reprogramming

The hepatic acute-phase response is characterized by a massive upregulation of serum proteins, such as haptoglobin and amyloid A, at the expense liver homeostatic functions. Although transcription factor hepatocyte nuclear 4 alpha (HNF4A) has well-established role in safeguarding function its cistrome spans around 50% liver-specific genes, received little attention so far. We demonstrate that HNF4A binds to represses genes under basal conditions. reprogramming during inflammation necessitates loss allow expression while are repressed. In pre-clinical organoid model overexpression maintained functionality spite inflammation-induced cell damage. Conversely, potently impaired retaining chromatin regulatory regions inaccessible transcription. Taken together, our data extend understanding dual action transcriptional activator repressor, establishing gatekeeper for response.