Dna Methylation Reveals Alternative Promoter Usage In Genes Critical To Pediatric Tumors

Transcriptional regulation is fundamental for cell identity and function, and it9s deregulation is a defining feature for common diseases, including cancers. Besides directly modifying the canonical promoter activities, tumors frequently utilize alternative promoters to increase the isoform diversity, activate oncogenes when the canonical promoters are repressed, and to evade host immune attacks by immune-editing. However, fresh-tissue availability and technical challenges represent major obstacles in genomewide promoter activity assessment in patient tumors by ChIP-seq experiments. Here, we presented MethylToActivity (M2A), a deep-learning framework that reveals promoter activities (H3K4me3 and H3K27ac) from DNA methylation (DNAm) patterns, a relatively stable epigenetic regulatory mechanism that can be robustly and accurately profiled in various tissues, including retrospective tumor samples archived using the formalin-fixed paraffin-embedded (FFPE) method. Trained from a cohort of neuroblastomas (N = 6), we demonstrate that M2A 1) approaches the accuracies of ChIP-seq experiments in revealing promoter activities, 2) is generalizable to various pediatric and adult cancers, 3) captures changes of promoter activity associated with differentially methylated regions, and 4) faithfully recapitulates differential promoter usages among tumor subtypes. Importantly, M2A uncovers oncogenic activation of alternative promoters in genes critical for tumor survival while the canonical promoter remains inactive. These results substantiate that M2A is capable of accurately measuring promoter activities, which will be of great use not only to functionally interpret differential DNAm patterns, but to unveil alternative promoter usages in patient tumors, which will facilitate precision medicine by tailoring treatments based on both epigenetic deregulations and genetic variants. Citation Format: Justin Williams, Beisi Xu, Daniel Putnam, Xiang Chen. DNA methylation reveals alternative promoter usage in genes critical to pediatric tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6576.