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

DNA and histone modifications exhibit noticeable impacts on gene expression(1). Being the most prevalent internal modification in mRNA, N(6)-Methyladenosine (m(6)A) mRNA modification emerges as an important post-transcriptional mechanism of gene regulation(2-4) and plays critical roles in various normal and pathological bioprocesses(5-12). However, how m(6)A is precisely and dynamically deposited in the transcriptome remains elusive. Here we report that H3K36me3 histone modification, a marker for transcription elongation, globally guides m(6)A modification. We found that m(6)A modifications enrich 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 critical 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, and 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 silencing, H3K36me3 depletion also induces m(6)A reduction transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the critical roles of H3K36me3 and METTL14 in determining precise and dynamic m(6)A deposition in mRNA, and uncover another layer of gene expression regulation involving crosstalk between histone modification and RNA methylation.