Multi-omics analysis reveals divergent epigenetic regulation of gene expression and drivers of esophageal squamous cell carcinoma

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in regions with the heterochromatin marker (H3K9me3, H3K27me3) binding, while hyper-methylated regions are enriched in polycomb repressive complex (EZH2,SUZ12) recognizing regions. Methylation alteration in promoters, enhancers, and gene bodies, as well as polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. This analysis uncovers epigenetics-mediated activation of non-canonical WNT/beta-catenin/MMP signaling and a YY1-lncRNA ESCCAL-1-ribosomal protein network, which are validated as potential ESCC driver alterations. This study advances the understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery.