Dynamic control of chromatin-associated m6A methylation regulates nascent RNA synthesis

Wenqi Xu; Chenxi He; Emily G Kaye; Jiahui Li; Mandi Mu; Geoffrey M Nelson; Li Dong; Jiahua Wang; Feizhen Wu; Yujiang Geno Shi; Karen Adelman; Fei Lan; Yang Shi; Hongjie Shen

doi:10.1016/j.molcel.2022.02.006

Dynamic control of chromatin-associated m⁶A methylation regulates nascent RNA synthesis

Mol Cell. 2022 Mar 17;82(6):1156-1168.e7. doi: 10.1016/j.molcel.2022.02.006. Epub 2022 Feb 25.

Authors

Wenqi Xu¹, Chenxi He¹, Emily G Kaye², Jiahui Li¹, Mandi Mu¹, Geoffrey M Nelson², Li Dong¹, Jiahua Wang¹, Feizhen Wu¹, Yujiang Geno Shi³, Karen Adelman⁴, Fei Lan⁵, Yang Shi⁶, Hongjie Shen⁷

Affiliations

¹ Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 201399, China.
² Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
³ Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: karen_adelman@hms.harvard.edu.
⁵ Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 201399, China. Electronic address: fei_lan@fudan.edu.cn.
⁶ Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford OX3 7DQ, UK. Electronic address: yang.shi@ludwig.ox.ac.uk.
⁷ Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 201399, China. Electronic address: hongjieshen@fudan.edu.cn.

Abstract

N⁶-methyladenosine (m⁶A) methylation is co-transcriptionally deposited on mRNA, but a possible role of m⁶A on transcription remains poorly understood. Here, we demonstrate that the METTL3/METTL14/WTAP m⁶A methyltransferase complex (MTC) is localized to many promoters and enhancers and deposits the m⁶A modification on nascent transcripts, including pre-mRNAs, promoter upstream transcripts (PROMPTs), and enhancer RNAs. PRO-seq analyses demonstrate that nascent RNAs originating from both promoters and enhancers are significantly decreased in the METTL3-depleted cells. Furthermore, genes targeted by the Integrator complex for premature termination are depleted of METTL3, suggesting a potential antagonistic relationship between METTL3 and Integrator. Consistently, we found the Integrator complex component INTS11 elevated at promoters and enhancers upon loss of MTC or nuclear m⁶A binders. Taken together, our findings suggest that MTC-mediated m⁶A modification protects nascent RNAs from Integrator-mediated termination and promotes productive transcription, thus unraveling an unexpected layer of gene regulation imposed by RNA m⁶A modification.

Keywords: ALKBH5; INTS11; METTL3; chromatin; enhancer; hnRNP G; m(6)A; nascent RNA; promoter.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Chromatin* / genetics
Methylation
Methyltransferases* / genetics
Methyltransferases* / metabolism
RNA / genetics
RNA / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

Chromatin
RNA, Messenger
RNA
Methyltransferases

Grants and funding

R01 GM134539/GM/NIGMS NIH HHS/United States