Exon-intron boundary inhibits m Nat Commun. 2023;14(1):4172.
JMG, Introns, RNA, Messenger, Half-Life, Exons, RNA Splicing, RNA Precursors
Nat Commun. 2023;14(1):4172.
Ke Laboratory and this research is funded by NIH/NIGMS Maximizing Investigators’ Research Award (MIRA) R35 Award (R35 GM133711 to S.K.), American Cancer Society Pilot Award (ACS-2019-Pilot-Ke/IRG-16-191-33/ IRG-21-136-36-IRG to S.K.) and the Jackson Laboratory Cancer Center New Investigator award from the NIH/NCI Cancer Center Support Grant (2 P30 CA034196-34 to S.K.).
Regional bias of N6-methyladenosine (m6A) mRNA modification avoiding splice site region, calls for an open hypothesis whether exon-intron boundary could affect m6A deposition. By deep learning modeling, we find that exon- intron boundary represses a proportion (12% to 34%) of m6A deposition at adjacent exons (~100 nt to splice site). Experiments validate that m6A signal increases once the host gene does not undergo pre-mRNA splicing to produce the same mRNA. Inhibited m6A sites have higher m6A enhancers and lower m6A silencers locally and show high heterogeneity at different exons genome- widely, with only a small proportion (12% to 15%) of exons showing strong inhibition, enabling more stable mRNAs and flexible protein coding. m6A is majorly responsible for why mRNAs with more exons be more stable. Exon junction complex (EJC) only partially contributes to this exon-intron boundary m6A inhibition in some short internal exons, highlighting additional factors yet to be identified.