The dynamic N1 -methyladenosine methylome in eukaryotic messenger RNA

Dan Dominissini; Sigrid Nachtergaele; Sharon Moshitch-Moshkovitz; Eyal Peer; Nitzan Kol; Moshe Shay Ben-Haim; Qing Dai; Ayelet Di Segni; Mali Salmon-Divon; Wesley C. Clark; Guanqun Zheng; Tao Pan; Oz Solomon; Eran Eyal; Vera Hershkovitz; Dali Han; Louis C. Doré; Ninette Amariglio; Gideon Rechavi; Chuan He

doi:10.1038/nature16998

The dynamic N¹ -methyladenosine methylome in eukaryotic messenger RNA

Dan Dominissini, Sigrid Nachtergaele, Sharon Moshitch-Moshkovitz, Eyal Peer, Nitzan Kol, Moshe Shay Ben-Haim, Qing Dai, Ayelet Di Segni, Mali Salmon-Divon, Wesley C. Clark, Guanqun Zheng, Tao Pan, Oz Solomon, Eran Eyal, Vera Hershkovitz, Dali Han, Louis C. Doré, Ninette Amariglio, Gideon Rechavi, Chuan He

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

777 Scopus citations

Abstract

Gene expression can be regulated post-transcriptionally through dynamic and reversible RNA modifications. A recent noteworthy example is N⁶ -methyladenosine (m⁶ A), which affects messenger RNA (mRNA) localization, stability, translation and splicing. Here we report on a new mRNA modification, N¹-methyladenosine (m¹ A), that occurs on thousands of different gene transcripts in eukaryotic cells, from yeast to mammals, at an estimated average transcript stoichiometry of 20% in humans. Employing newly developed sequencing approaches, we show that m¹ A is enriched around the start codon upstream of the first splice site: it preferentially decorates more structured regions around canonical and alternative translation initiation sites, is dynamic in response to physiological conditions, and correlates positively with protein production. These unique features are highly conserved in mouse and human cells, strongly indicating a functional role for m¹ A in promoting translation of methylated mRNA.

Original language	English
Pages (from-to)	441-446
Number of pages	6
Journal	Nature
Volume	530
Issue number	7591
DOIs	https://doi.org/10.1038/nature16998
State	Published - 25 Feb 2016

Bibliographical note

Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.

Funding

Acknowledgements The work was supported by the National Institutes of Health HG008688 and GM71440 grants to C.H., GM113194 grant to T.P. and C.H. and grants from the Flight Attendant Medical Research Institute (FAMRI), Israel Science Foundation (ISF grant no. 1667/12), Israeli Centers of Excellence (I-CORE) Program (ISF grants no. 41/11 and no. 1796/12), Ernest and Bonnie Beutler Research Program and Kahn Family Foundation to G.R. A part of this work was funded by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (to D.D. and C.H.). C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). G.R. is a member of the Sagol Neuroscience Network and holds the Djerassi Chair for Oncology at the Sackler Faculty of Medicine, Tel-Aviv University, Israel. D.D. is supported by a Human Frontier Science Program (HFSP) long-term fellowship. S.N. is an HHMI Fellow of the Damon Runyon Cancer Research Foundation (DRG-2215-15), previously supported by a Yen post-doctoral fellowship in interdisciplinary research. Q.D. is supported by the National Institutes of Health grant HG006699. We wish to thank S. Farage-Barhom, K. Cesarkas and E. Glick-Saar for help with deep sequencing.

Funders	Funder number
Searle Funds at The Chicago Community Trust
National Institutes of Health	HG008688, GM71440
National Institute of General Medical Sciences	R01GM113194
Damon Runyon Cancer Research Foundation	DRG-2215-15, HG006699
Human Frontier Science Program
Flight Attendant Medical Research Institute
Iowa Science Foundation	1667/12
Israel Science Foundation
Israeli Centers for Research Excellence	41/11, 1796/12

Access to Document

10.1038/nature16998

Cite this

Dominissini, D., Nachtergaele, S., Moshitch-Moshkovitz, S., Peer, E., Kol, N., Ben-Haim, M. S., Dai, Q., Di Segni, A., Salmon-Divon, M., Clark, W. C., Zheng, G., Pan, T., Solomon, O., Eyal, E., Hershkovitz, V., Han, D., Doré, L. C., Amariglio, N., Rechavi, G., & He, C. (2016). The dynamic N¹ -methyladenosine methylome in eukaryotic messenger RNA. Nature, 530(7591), 441-446. https://doi.org/10.1038/nature16998

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title = "The dynamic N1 -methyladenosine methylome in eukaryotic messenger RNA",

abstract = "Gene expression can be regulated post-transcriptionally through dynamic and reversible RNA modifications. A recent noteworthy example is N6 -methyladenosine (m6 A), which affects messenger RNA (mRNA) localization, stability, translation and splicing. Here we report on a new mRNA modification, N1-methyladenosine (m1 A), that occurs on thousands of different gene transcripts in eukaryotic cells, from yeast to mammals, at an estimated average transcript stoichiometry of 20% in humans. Employing newly developed sequencing approaches, we show that m1 A is enriched around the start codon upstream of the first splice site: it preferentially decorates more structured regions around canonical and alternative translation initiation sites, is dynamic in response to physiological conditions, and correlates positively with protein production. These unique features are highly conserved in mouse and human cells, strongly indicating a functional role for m1 A in promoting translation of methylated mRNA.",

author = "Dan Dominissini and Sigrid Nachtergaele and Sharon Moshitch-Moshkovitz and Eyal Peer and Nitzan Kol and Ben-Haim, {Moshe Shay} and Qing Dai and {Di Segni}, Ayelet and Mali Salmon-Divon and Clark, {Wesley C.} and Guanqun Zheng and Tao Pan and Oz Solomon and Eran Eyal and Vera Hershkovitz and Dali Han and Dor{\'e}, {Louis C.} and Ninette Amariglio and Gideon Rechavi and Chuan He",

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Dominissini, D, Nachtergaele, S, Moshitch-Moshkovitz, S, Peer, E, Kol, N, Ben-Haim, MS, Dai, Q, Di Segni, A, Salmon-Divon, M, Clark, WC, Zheng, G, Pan, T, Solomon, O, Eyal, E, Hershkovitz, V, Han, D, Doré, LC, Amariglio, N, Rechavi, G & He, C 2016, 'The dynamic N¹ -methyladenosine methylome in eukaryotic messenger RNA', Nature, vol. 530, no. 7591, pp. 441-446. https://doi.org/10.1038/nature16998

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AU - Zheng, Guanqun

AU - Pan, Tao

AU - Solomon, Oz

AU - Eyal, Eran

AU - Hershkovitz, Vera

AU - Han, Dali

AU - Doré, Louis C.

AU - Amariglio, Ninette

AU - Rechavi, Gideon

AU - He, Chuan

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