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Updated: May 13, 2025

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Differential control of growth and identity by HNF4α isoforms in pancreatic ductal adenocarcinoma
Background:
Although transcriptomic studies have stratified pancreatic ductal adenocarcinoma (PDAC) into clinically relevant subtypes, classical or basal-like, further research is needed to identify the transcriptional regulators of each subtype. Previous studies identified HNF4α as a key regulator of the classical subtype, but the distinct contributions of its isoforms (P1 and P2), which display dichotomous functions in normal development and gastrointestinal malignancies, remain unexplored.
Objective:
The objective of this study is to investigate the role of HNF4α P1 and P2 isoforms in regulating growth and differentiation.
Design:
We performed functional, transcriptomic, and epigenetic analysis after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms.
Results:
We characterized the variable expression of P1 isoforms in HNF4α-positive tumors. We demonstrate that P1 isoforms are less compatible with growth than P2 isoforms. Despite sharing a common DNA binding domain, we show that P1 isoforms are stronger transcriptional regulators.
Conclusions:
Our study characterizes the functional roles of HNF4α P1 and P2 isoforms in PDAC and highlights the necessity of considering different isoforms when studying molecular regulators.
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