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

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.