Identification of DNA methylation of distal regulatory regions with causal effect on tumorigenesis

Abstract

Aberrant promoter methylation is a common mechanism for tumor-suppressor inactivation in cancer. However, the exact role of DNA methylation at enhancers remains to be elucidated. We have developed a set of tools to genome-wide identify DNA methylation in distal regions with causal effect on tumorigenesis. Novel oncogenes/tumor-suppressors and their putative enhancers can be identified together based on this strategy. Many predictions were directly demonstrated by dCas9-based epigenetic editing with strong evidence to support the accuracy and efficiency of our tool. Our study reveals the prevalent regulation of genomewide putative enhancers by DNA-methylation with causal effect on cellular malignancy and patient survival. Mechanistically, oncogenic and lineage-specific transcriptional-factors aberrantly shaped the methylation landscape with diverged tumor-subtype core regulatory circuitry. Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types converged on a common architecture, highlighting general organization principle for such networks regulated by DNA methylation of distal regulatory regions.