Abstract N 6 -Methyladenosine (m 6 A) is the most abundant internal modification of eukaryotic mRNAs and regulates target transcripts throughout the mRNA life cycle. Although changes in m 6 A have been reported in human cancers, technical limitations have hindered a comprehensive understanding of the cancer-associated m 6 A landscape. Here, we use GLORI-sequencing to establish the first transcriptome-wide, single-nucleotide resolution maps of m 6 A in bladder cancer. Comparing bladder cancer and healthy bladder samples, we discover two key m 6 A signatures: a global dilution of methylation and a focal hypermethylation at 3′-UTRs. The global methylation dilution results from an increased expression of unmethylated transcripts and a decreased expression of methylated transcripts. In contrast, focal 3’-UTR hypermethylation is associated with the overexpression of VIRMA, a component of the m 6 A writer complex. A functional role of VIRMA is confirmed in knockdown experiments that reveal reduced 3’-UTR methylation and oncogenic phenotypes of bladder cancer cells. Our study is the first to describe the m 6 A epitranscriptomic landscape of cancer at single-base resolution and provides first insights into the processes that generate its characteristic signatures.
Koch et al. (Mon,) studied this question.