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Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally
Open accessAbstract
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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“Indeed, several reports identified specific crosstalk between m6A RNA modifications and histone modifications, including H3K36me3 (Huang et al., 2019), H3K9me2 (Li et al., 2020a), H3K9me3 (Liu et al., 2021a; 2021b), and K3K27Ac (Huang et al., 2025).”
From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Huang et al., 2019
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Metadata
- Authors
- Huang, H., Weng, H., Zhou, K., Wu, T., Zhao, B. S., Sun, M., Chen, Z., Deng, X., Xiao, G., Auer, F., Klemm, L., Wu, H., Zuo, Z., Qin, X., Dong, Y., Zhou, Y., Qin, H., Tao, S., Du, J., Liu, J., Lu, Z., Yin, H., Mesquita, A., Yuan, C. L., Hu, Y.-C., Sun, W., Su, R., Dong, L., Shen, C., Li, C., Qing, Y., Jiang, X., Wu, X., Sun, M., Guan, J.-L., Qu, L., Wei, M., Müschen, M., Huang, G., He, C., Yang, J., & Chen, J.
- Affiliations
- City of Hope (US)
- Sun Yat-sen University (CN)
- Howard Hughes Medical Institute (US)
- Cincinnati Children's Hospital Medical Center (US)
- Sun Yat-sen University Cancer Center (CN)
- University of Cincinnati (US)
- China Medical University (CN)
- City Of Hope National Medical Center (US)
- Corresponding author
- Huang, Gang
- He, Chuan
- Yang, Jianhua
- Chen, Jianjun
- ORCID
- Huang, Huilin
- Weng, Hengyou
- Zhou, Keren
- Wu, Tong
- Zhao, Boxuan Simen
- Sun, Mingli
- Chen, Zhenhua
- Deng, Xiaolan
- Xiao, Gang
- Auer, Franziska
- Wu, Huizhe
- Zuo, Zhixiang
- Qin, Xi
- Dong, Yunzhu
- Qin, Hanjun
- Tao, Shu
- Du, Juan
- Liu, Jun
- Lu, Zhike
- Yin, Hang
- Hu, Yueh-Chiang
- Sun, Wenju
- Su, Rui
- Dong, Lei
- Shen, Chao
- Li, Chenying
- Qing, Ying
- Jiang, Xi
- Wu, Xiwei
- Sun, Miao
- Guan, Jun-Lin
- Wei, Minjie
- Müschen, Markus
- Huang, Gang
- He, Chuan
- Yang, Jianhua
- Chen, Jianjun
- Venue
- Nature
- Published
- 2019-03
- Volume
- 567
- Issue
- 7748
- Pages
- 414-419
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6438714
- OpenAlex
- W2921763102
- Cited by
- 677
- References
- 33
- Citations by year
- 2026: 48 · 2025: 93 · 2024: 99 · 2023: 114 · 2022: 103 · 2021: 114 · 2020: 76 · 2019: 30
- FWCI
- 27.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (RM1HG008935)
- National Cancer Institute (R01CA214965, R21CA187276, R01CA243386, R01CA163493, R01CA236399, R01CA178454, R01CA213138, R01CA182528, R01CA172558, U10CA180827, R01CA139032, R01CA137060, R01CA157644, R35CA197628, P30CA033572, R01CA211066, R01CA211614)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK120282)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- H3K36me3, N6-methyladenosine, m6A RNA methylation, METTL14, m6A methyltransferase complex, RNA polymerase II, nascent RNA, pluripotency, mouse embryonic stem cells, gene expression regulation
- MeSH terms
- Adenosine, Animals, Cell Differentiation, Cell Line, Histones, Humans, Lysine, Methylation, Methyltransferases, RNA Polymerase II, RNA, Messenger, Transcription, Genetic, Mice, Embryonic Stem Cells, Transcriptome, Transcription Elongation, Genetic
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