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Nature. 2019 Mar;567(7748):414-419. doi: 10.1038/s41586-019-1016-7. Epub 2019 Mar 13.

Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally.

Huang H1,2, Weng H1,2, Zhou K3,4, Wu T5,6,7,8, Zhao BS5,6,7,8, Sun M1,9, Chen Z1, Deng X1,2,9, Xiao G1, Auer F1, Klemm L1, Wu H1,2,9, Zuo Z2,10, Qin X1,2, Dong Y11,12, Zhou Y11,12, Qin H13, Tao S13, Du J13, Liu J5,6,7,8, Lu Z5,6,7,8, Yin H5,6,7,8, Mesquita A2, Yuan CL14, Hu YC14, Sun W3,4, Su R1,2, Dong L1,2, Shen C1,2, Li C1,2, Qing Y1,2, Jiang X1,2,15,16, Wu X13, Sun M17,18, Guan JL2, Qu L3,4, Wei M9, Müschen M1, Huang G19,20, He C21,22,23,24, Yang J25,26, Chen J27,28.

Author information

1
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
2
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
3
Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, China.
4
State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
5
Department of Chemistry, University of Chicago, Chicago, IL, USA.
6
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
7
Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
8
Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
9
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.
10
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
11
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
12
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
13
Intergrative Genomics Core, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
14
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
15
Department of Pharmacology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
16
Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
17
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
18
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
19
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. gang.huang@cchmc.org.
20
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. gang.huang@cchmc.org.
21
Department of Chemistry, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
22
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
23
Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
24
Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
25
Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, China. yangjh7@mail.sysu.edu.cn.
26
State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China. yangjh7@mail.sysu.edu.cn.
27
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA. jianchen@coh.org.
28
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. jianchen@coh.org.

Abstract

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 regulation2-4 and has crucial roles in various normal and pathological processes5-12. 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.

PMID:
30867593
DOI:
10.1038/s41586-019-1016-7

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