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

Abstract

Both pre-mRNA splicing and N6-methyladenosine (m6A) mRNA modification occur during transcription, enabling the potential crosstalk regulation between these two fundamental processes. The regional m6A location bias of avoiding splice site region, calls for an open hypothesis whether pre-mRNA splicing could affect m6A deposition. By deep learning modeling, we find that pre-mRNA splicing represses a proportion (4% to 32%) of m6A deposition at nearby exons. Experimental validation confirms such an inhibition as the m6A signal increases in mRNA once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Pre-mRNA splicing inhibited m6A sites tend to have higher m6A enhancers and lower m6A silencers locally than the m6A sites that are not inhibited. Moreover, this m6A 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.