DNA and histone modifications have notable effects on gene expression1. Being the most prevalent internal modification in mRNA, the N6-methyladenosine (m6A) mRNA modification is as an important post-transcriptional mechanism of gene regulation2,3,4 and has crucial roles in various normal and pathological processes5,6,7,8,9,10,11,12. However, it is unclear how m6A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6A deposition globally. We show that m6A 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 m6A methyltransferase complex (MTC), which in turn facilitates the binding of the m6A MTC to adjacent RNA polymerase II, thereby delivering the m6A MTC to actively transcribed nascent RNAs to deposit m6A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m6A 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 m6A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.
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Code used for data analysis including cutadapt v.1.13 (adapter remove), Bowtie v.1.1.2 (ChIP–seq, CLIP sequencing and miCLIP sequencing alignment), TopHat version v.2.1.1 (m6A-seq and ribosome-profiling alignment), featureCounts v.1.6.0 (reads count), HTSeq v.0.6.1p1 (reads count), RSEM v.1.2.31 (gene expression quantification), DEGseq v.1.28.0 (differential gene expression analysis), MACS v.1.4.2 (peak calling of H3K36me3 ChIP–seq), SICER v.1.1 (peak calling of METTL14 ChIP–seq), exomePeak v.2.8.0 (peak calling of m6A-seq), HOMER v.3.12 (motif analysis) and RiboDiff v.0.2.1 (differential translation efficiency analysis) are publicly available from the indicated references.
All sequencing data that support the findings of this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE110323. Previous published ChIP–seq data and m6A-seq data of HepG2 cells were re-analysed and are available under GEO accession codes GSE51334 and GSE37003. Previously published ENCODE data that were re-analysed here are available under accession codes ENCFF533JQH, ENCSR000ATD (H3K9me3) and ENCFF042EDV, ENCSR000DUE (H3K27me3) for heterochromatin and window correlation analysis. The expression data of SETD2 and MTC genes were derived from the TCGA Research Network (http://cancergenome.nih.gov/), GTEx program (https://www.gtexportal.org/), and CCLE project (https://portals.broadinstitute.org/ccle). The dataset derived from this resource that supports the findings of this study is available in the ChIPbase (http://rna.sysu.edu.cn/chipbase/)29,30 and CCLE (https://portals.broadinstitute.org/ccle) websites.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This work was supported in part by the National Institutes of Health (NIH) grants R01 CA214965 (J.C.), R01 CA211614 (J.C.), R01 CA178454 (J.C.), R01 CA182528 (J.C.), R01 CA236399 (J.C.), RM1 HG008935 (C.H.), R21 CA187276 (G.H.), R01 CA163493 (J.G.), R35 CA197628 (M.M.), U10 CA180827 (M.M.), R01 CA137060 (M.M.), R01 CA157644 (M.M.), R01 CA172558 (M.M.) and R01 CA213138 (M.M.), and grants 2017YFA0504400 (J.Y.), 91440110 (J.Y.) and 31671349 (L.Q.) from National Nature Science Foundation of China, and Cancer Center Support Grant (P30CA33572) from City of Hope National Medical Center. J.C. is a Leukemia & Lymphoma Society (LLS) Scholar. C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). M.M. is an HHMI Faculty Scholar. B.S.Z. is an HHMI International Student Research Fellow. F.A. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship (AU 525/1-1).
Nature thanks Abid Khan, Brian Strahl and the other anonymous reviewer(s) for their contribution to the peer review of this work.