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Gene expression is spatially and temporally regulated at multiple levels. N 6-methyladenosine (m 6 A) is the most prevalent internal modification in messenger RNA (mRNA) and long noncoding RNA (lncRNAs). m 6 A plays important roles in multiple cellular processes including stem cell pluripotency, adipogenesis, spermatogenesis, neurogenesis, circadian rhythm and development by modulating RNA splicing, export, stability, degradation and translation. Although aberrant m 6 A methylation has been reported in various types of cancer, the underlying molecular functions of METTL3, the solely catalytic subunit of the m 6 A-methylase complex, has yet to be defined.

m 6 A has been recently identified in nascent pre-mRNA, and more specifically intronic m 6 A has been linked to exon skipping events. The occurrence of impaired alternative splicing (AS) is frequently found during the development of cancer. We performed transcriptome wide analysis in breast cancer cell lines and explored AS events. Our results define an AS signature for breast tumorigenesis. We found that METTL3 modulates AS directly through m 6 A deposition at the intron-exon junctions or indirectly by the m 6 A deposition in transcripts encoding for splicing factors and transcription factors. In particular, we show that MYC mRNA harbours the m 6 A mark, suggesting that METTL3 regulates AS indirectly via the regulation of MYC expression. Indeed, the targets of MYC overlapped with METTL3-associated AS events. Importantly, five of the AS events identified and validated in vitro, are linked to a worse prognosis in breast cancer patients. Additionally, we show that METTL3 …