(A) m6A writer complex installs m6A co-transcriptionally in the nucleus. The recruitment of the writer complex to specific genomic loci by transcription factors (TFs) or histone marks may contribute to the gene- or region-specificity in m6A installation. Examples include ① TF SMAD2/3 interacts with m6A writer complex in response to TGFβ signaling; ② In acute myeloid leukemia (AML) cells, METTL3 is recruited to TSS (transcription start sites) regions with dependence on TF CEBPZ, which subsequently mediates methylation of transcripts important for cancer maintenance; ③ Gene-body enriched histone mark H3K36me3 recruits the m6A writer complex by interacting with METTL14, a process contributing to preferential m6A installation at CDS and 3’UTR of nascent transcripts.
(B) In the cytoplasm, METTL3 itself recognizes 3’UTR m6A sites on mRNA and promotes protein translation from the transcript by facilitating translation loop formation through interaction with eIF3h.