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Differential control of growth and identity by HNF4α isoforms in pancreatic ductal adenocarcinoma [ChIP-Seq]

ABSTRACT: 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. Here we show that HNF4α-positive human PDAC tumors exhibit uniform expression of P2-isoforms but variable expression of P1 isoforms. To dissect the roles of each isoform in PDAC, we performed functional, transcriptomic, and epigenetic analysis after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms. We demonstrated that P1 isoforms are less compatible with growth and stronger transcriptional regulators than P2. Despite both isoforms sharing a common DNA binding domain, P1 isoforms displayed stronger binding at HNF4α target genes, resulting in increased transcriptional activity. These findings provide a detailed characterization of HNF4α P1 and P2 isoforms and their distinct roles in PDAC biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284700 | GEO | 2024/12/25

REPOSITORIES: GEO

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Project description:HNF4α is a nuclear receptor regulating the transcription of genes involved mainly in development, cell differentiation and metabolism. Opposite functions for the two classes of P1 and P2 isoforms of HNF4α have recently been highlighted. These classes include 12 variants of HNF4α that can be expressed by the use of two promoters and by alternative splicing. Until now, the characterization of this transcription factor has ignored this diversity and has remained confined to the study of a fraction of the isoforms. We therefore wanted to clarify the situation by specifically characterizing the transcriptional functions of the 12 isoforms of HNF4α. We have generated for this purpose stable lines expressing each isoform of HNF4α in HCT 116 cells. We analyzed the whole transcriptome associated with each isoform by sequencing RNA, as well as their proteome by a BioID approach coupled to quantitative mass spectrometry. We noted major differences in the transcriptional function of the 12 isoforms. The α4, α5 and α6 isoforms have been characterized for the first time, and show a greatly reduced transcriptional potential. We have shown that these isoforms are unable to recognize the consensus response element of HNF4α. The α1 and α2 isoforms are the most potent regulators of gene expression, while the α3 isoform exhibits significantly reduced activity. Several transcription factors and coregulators have been identified as potential specific partners for certain HFH4α isoforms. The IRF-2BP2 co-repressor interacts specifically with isoforms which include the long form of the F domain of HNF4α. This specific interaction could explain the large number of genes modulated negatively by α1 and α2 compared to α3. The analysis integrating the vast amount of transcriptomic and proteomic data allows the identification of transcriptional regulatory mechanisms specific to certain isoforms, demonstrating the importance of considering all isoforms which can have diverse functions.

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Differential control of growth and identity by HNF4α isoforms in pancreatic ductal adenocarcinoma [ChIP-Seq]

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