Pre-mRNA splicing inhibits m6A deposition, allowing longer mRNA half-life and flexible protein coding

Both pre-mRNA splicing and N 6 -methyladenosine (m 6 A) mRNA modification occur during transcription, enabling the potential crosstalk regulation between these two fundamental processes. The regional m 6 A location bias of avoiding splice site region, calls for an open hypothesis whether pre-mRNA splicing could affect m 6 A deposition. By deep learning modeling, we find that pre-mRNA splicing represses a proportion (4% to 32%) of m 6 A deposition at nearby exons. Experimental validation confirms such an inhibition as the m 6 A signal increases in mRNA once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Pre-mRNA splicing inhibited m 6 A sites tend to have higher m 6 A enhancers and lower m 6 A silencers locally than the m 6 A sites that are not inhibited. Moreover, this m 6 A deposition inhibition by pre-mRNA splicing shows high heterogeneity at different exons of mRNAs at genome-widely, with only a small proportion (12% to 15%) of exons showing strong inhibition, enabling stable mRNAs and flexible protein coding for important biological functions.