Journal
NATURE
Volume 567, Issue 7748, Pages 414-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1016-7
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Funding
- National Institutes of Health (NIH) from National Nature Science Foundation of China [R01 CA214965, R01 CA211614, R01 CA178454, R01 CA182528, R01 CA236399, RM1 HG008935, R21 CA187276, R01 CA163493, R35 CA197628, U10 CA180827, R01 CA137060, R01 CA157644, R01 CA172558, R01 CA213138, 2017YFA0504400, 91440110, 31671349]
- Cancer Center Support Grant from City of Hope National Medical Center [P30CA33572]
- Deutsche Forschungsgemeinschaft (DFG) fellowship [AU 525/1-1]
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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.
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