Abstract
Abnormal genetic and epigenetic modifications play a key role in esophageal cancer. By Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq), this study compared chromatin accessibility landscapes among two esophageal squamous cell carcinoma (ESCC) cell lines, KYSE-30 and KYSE-150, and a non-cancerous esophageal epithelial cell line, HET-1A. Data showed that hyper-accessible regions in ESCC cells contained genes related with cancer hallmarks, such as epidermal growth factor receptor (EGFR). Multi-omics analysis and digital-droplet PCR results demonstrated that several non-coding RNAs in EGFR upstream were upregulated in ESCC cells. Among them, one appeared to act as an enhancer RNA responsible for EGFR overexpression. Further motif analysis and pharmacological data suggested that AP-1 family transcription factors were able to bind the hyper-accessible regions and thus to regulate cancer cell proliferation and migration. This study discovered a putative enhancer RNA for EGFR gene and the reliance of ESCC on AP-1 transcription factor.
Highlights
Esophageal cancer is among the most fatal cancers and presents two main sub-types, i.e., esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC)
ATAC-seq peaks from replicates were well correlated showing a high degree of concordance, and the open chromatin structure of HET-1A cells was disparate from that of the two ESCC cell lines (Figure S1C)
These were identified as differentially accessible DNA loci of ATAC-seq peaks in each cell line and hierarchically clustered resulting in their open or closed chromatin patterns (Figures 1A, B)
Summary
Esophageal cancer is among the most fatal cancers and presents two main sub-types, i.e., esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). The development of ESCC is strongly influenced by genetic and environmental factors via epigenetic changes. Such epigenetic changes, including alterations in transcriptome and DNA methylome, have been revealed by genomewide RNA transcripts and CpG site methylation tests [1,2,3]. Hyper-Accessible Chromatin Regions in ESCC associated SNPs located at regulatory regions other than exon have been found to control target gene transcription [4]. Despite these findings, a panoramic view of deregulated genetic and epigenetic networks in ESCC cells is missing, which is essential to dissect the molecular mechanisms contributing to cancer development and progression. Given that transcription factors bind to DNA in a sequence-specific manner by removing or moving the nucleosomes to form open chromatin, mapping hyper-accessible regions in cancer cell genome provides information regarding onco-transcription and pioneering factors [5]
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