Differential control of growth and identity by HNF4α isoforms in pancreatic ductal adenocarcinoma

Abstract

BackgroundAlthough 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 HNF4 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. ObjectiveThe objective of this study is to investigate the role of HNF4 P1 and P2 isoforms in regulating growth and differentiation. DesignWe performed functional, transcriptomic, and epigenetic analysis after exogenous expression in HNF4-negative models or CRISPRi-mediated knockdown of endogenous isoforms. ResultsWe characterized the variable expression of P1 isoforms in HNF4-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. ConclusionsOur study characterizes the functional roles of HNF4 P1 and P2 isoforms in PDAC and highlights the necessity of considering different isoforms when studying molecular regulators.