The DOI matches its Crossref record; 32 of the 33 references it cites were found in a registry or an index.
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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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
High-Resolution Profiling of Histone Methylations in the Human Genome
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Chen, X., Xiu, M., Xing, J., Yu, S., Min, D., & Guo, F. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479439 · Cited by 5,760
Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq
Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., Cesarkas, K., Jacob-Hirsch, J., Amariglio, N., Kupiec, M., et al. (2012) · Nature · doi:10.1038/nature11112 · Cited by 4,884
N6-methyladenosine-dependent regulation of messenger RNA stability
Wang, X., Lu, Z., Gomez, A., Hon, G. C., Yue, Y., Han, D., Fu, Y., Parisien, M., Dai, Q., Jia, G., et al. (2014) · Nature · doi:10.1038/nature12730 · Cited by 4,558
Self-citationComprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons
Meyer, K. D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C. E., & Jaffrey, S. R. (2012) · Cell · doi:10.1016/j.cell.2012.05.003 · Cited by 4,223
N6-methyladenosine Modulates Messenger RNA Translation Efficiency
Wang, X., Zhao, B. S., Roundtree, I. A., Lu, Z., Han, D., Ma, H., Weng, X., Chen, K., Shi, H., & He, C. (2015) · Cell · doi:10.1016/j.cell.2015.05.014 · Cited by 3,483
Self-citationA METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation
Liu, J., Yue, Y., Han, D., Wang, X., Fu, Y., Zhang, L., Jia, G., Yu, M., Lu, Z., Deng, X., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1432 · Cited by 3,433
Self-citationEpigenetics in human disease and prospects for epigenetic therapy
Egger, G., Liang, G., Aparicio, A., & Jones, P. A. (2004) · Nature · doi:10.1038/nature02625 · Cited by 3,232
Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation
Huang, H., Weng, H., Sun, W., Qin, X., Shi, H., Wu, H., Zhao, B. S., Mesquita, A., Liu, C., Yuan, C. L., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0045-z · Cited by 2,997
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Reading, writing and erasing mRNA methylation
Zaccara, S., Ries, R. J., & Jaffrey, S. R. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0168-5 · Cited by 2,597
Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers
Shi, H., Wei, J., & He, C. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.04.025 · Cited by 1,943
Self-citationFunctions of N6-methyladenosine and its role in cancer
He, L., Li, H., Wu, A., Peng, Y., Shu, G., & Yin, G. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1109-9 · Cited by 1,410
m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer
Huang, H., Weng, H., & Chen, J. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.02.004 · Cited by 1,238
Self-citationHistone post-translational modifications - cause and consequence of genome function
Millán-Zambrano, G., Burton, A., Bannister, A. J., & Schneider, R. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00468-7 · Cited by 1,116
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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