mRNA m6A regulates gene expression via H3K4me3 shift in 5’ UTR

Abstract

N6-methyladenosine (m6A) is a prevalent and conserved RNA modification in eukaryotes. While its roles in the 3’ untranslated regions (3’ UTR) are well-studied, its role in the 5' UTR and its relationship with histone modifications remain underexplored. We demonstrate that m6A methylation in the 5’ UTR of mRNA triggers a downstream shift in H3K4me3 modification. This regulatory mechanism is conserved in Arabidopsis, rice, and chrysanthemum. The observed shift in H3K4me3 is genetically controlled by m6A modifiers and influences gene expression. MTA, the m6A methylase, preferentially binds to phosphorylated serine 5 (Ser5P)-CTD of RNA Pol II during transcription, leading to the displacement of ATX1, the H3K4me3 methylase. This dynamic binding of MTA and ATX1 to RNA Pol II ultimately results in the shift of H3K4me3 modification. Genetic evidence demonstrates that m6A in the 5' UTR controls H3K4me3 shift, thereby affecting SEDOHEPTULOSE-BISPHOSPHATASE expression and leaf senescence. Our study provides new insights into the roles of m6A modification and its crosstalk with histone modification in 5’ UTRs, shedding light on the mechanism of m6A-mediated gene expression regulation.