Defining the basal-like A-specific enhancer landscape in PDAC

Defining the specificity and P63-dependence of B-STEP

Supplementary Table S3 contains list of genes associated with Gö4Pdx4 super enhancers overlapping TP63.

Supplementary Table S4 contains L3.6pl TP63-dependent enhancer regions.

Verification of P63-dependence and B-STEP enhancer-gene regulations.

Supplementary Table S5 contains list of genes associated with L3.6pl TP63 dependent enhancers.

The file contains additional supplementary methods

Supplementary Table S2 contains GöPdx4 super enhancers regions overlapping TP63

Supplementary Table S6 contains list of qPCR primers used in the study.

AbstractA major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analyses revealed a Basal-like A subtype-specific transcribed enhancer program in PDAC characterized by enhancer RNA (eRNA) production that is associated with more frequent chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histologic approach for PDAC patient stratification by performing RNA-ISH analyses for subtype-specific eRNAs on pathologic tissue samples. Thus, this study provides proof-of-concept that subtype-specific epigenetic changes relevant for PDAC progression can be detected at a single-cell level in complex, heterogeneous, primary tumor material.Implications:Subtype-specific enhancer activity analysis via detection of eRNAs on a single-cell level in patient material can be used as a potential tool for treatment stratification.