Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover novel regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications. Total RNA of PDPCOs (n=84) and NPOs (n=3) with enough amount (3 μg) and high quality were used to prepare the transcriptome library. RNA-seq libraries were generated following the manufacturer’s instructions (NEBNext Ultra RNA Library Prep Kit, New England Biolabs, E7530L). Library quality was measured on an Qxcel Bioanalyzer for product size. Paired-end libraries were sequenced by the Illumina HiSeq X Ten platform. TopHat were used to map the sequencing reads to the human reference genome hg19. The fragments per kilobase of exon per million mapped reads (FPKM) values were determined using Cufflinks. Genes with FPKM values <1 in all 87 samples were filtered out. Finally, 15,819 protein-coding genes remained for further analysis. Raw data are not available for this Series due to human genetic resources policy in China.