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.