Dynamic control of chromatin-associated m 6 A methylation regulates nascent RNA synthesis.

Autor:	Xu W; 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., He C; 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., Kaye EG; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Li J; 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., Mu M; 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., Nelson GM; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Dong L; 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., Wang J; 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., Wu F; 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., Shi YG; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Adelman K; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: karen_adelman@hms.harvard.edu., Lan F; 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., Shi Y; Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford OX3 7DQ, UK. Electronic address: yang.shi@ludwig.ox.ac.uk., Shen H; 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.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2022 Mar 17; Vol. 82 (6), pp. 1156-1168.e7. Date of Electronic Publication: 2022 Feb 25.
DOI:	10.1016/j.molcel.2022.02.006
Abstrakt:	N 6 -methyladenosine (m 6 A) methylation is co-transcriptionally deposited on mRNA, but a possible role of m 6 A on transcription remains poorly understood. Here, we demonstrate that the METTL3/METTL14/WTAP m 6 A methyltransferase complex (MTC) is localized to many promoters and enhancers and deposits the m 6 A 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 m 6 A binders. Taken together, our findings suggest that MTC-mediated m 6 A modification protects nascent RNAs from Integrator-mediated termination and promotes productive transcription, thus unraveling an unexpected layer of gene regulation imposed by RNA m 6 A modification. Competing Interests: Declaration of interests Y.S. is a co-founder of and holds equity in K36 Therapeutics. Y.S. is a consultant for Active Motif, a member of the Scientific Advisory Board of the College of Life Sciences, West Lake University, and a member of the MD Anderson External Advisory Board. K.A. received research funding from Novartis not related to this work, is a consultant for Syros Pharmaceuticals, is on the SAB of CAMP4 Therapeutics, and is a member of the Advisory Board of Molecular Cell. All other authors declare no competing interests. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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