Abstract
Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.
Highlights
Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, there remains a lack of knowledge regarding the underlying epigenomics of PDAC
We have performed a multi-factorial integrative analysis of genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, as well as RNAsequencing (RNA-seq) and DNA methylation studies to generate, for the first time, new knowledge on epigenetic landscapes linked to the heterogeneity of PDAC grown as patient-derived tumor xenografts (PDTXs)
Super-enhancer mapping combined with transcription factor (TF) binding motif and upstream regulatory analyses reveal that these tumors populate two distinct epigenomic landscapes with classical tumors associated with TFs involved in pancreatic development, as well as metabolic regulators and Ras signaling, whereas the basal phenotype tumors utilize proliferative and epithelial-tomesenchymal transition (EMT) transcriptional nodes downstream of the MET oncogene
Summary
Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, there remains a lack of knowledge regarding the underlying epigenomics of PDAC. The functional importance of these findings is underscored by the fact that genetic inactivation of MET results in a transition from a basal to more classical transcriptomic signature Combined, this new knowledge on the PDAC epigenome, along with gene expression networks that it regulates, provides valuable and biomedically relevant mechanistic insight into this disease, offers potential new markers for PDAC, and informs the potential development of future therapeutic regimens that may help manage patients affected by this dismal malignancy. This new knowledge on the PDAC epigenome, along with gene expression networks that it regulates, provides valuable and biomedically relevant mechanistic insight into this disease, offers potential new markers for PDAC, and informs the potential development of future therapeutic regimens that may help manage patients affected by this dismal malignancy These findings bear significant mechanistic and medical importance
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