Histone H3 trimethylation at lysine 36 guides m 6 A RNA modification co-transcriptionally.

DNA and histone modifications have notable effects on gene expression ¹ . Being the most prevalent internal modification in mRNA, the N ⁶ -methyladenosine (m ⁶ A) mRNA modification is as an important post-transcriptional mechanism of gene regulation ^2-4 and has crucial roles in various normal and pathological processes ^5-12 . However, it is unclear how m ⁶ A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m ⁶ A deposition globally. We show that m ⁶ A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m ⁶ A methyltransferase complex (MTC), which in turn facilitates the binding of the m ⁶ A MTC to adjacent RNA polymerase II, thereby delivering the m ⁶ A MTC to actively transcribed nascent RNAs to deposit m ⁶ A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m ⁶ A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m ⁶ A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.