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.
Bibliographical noteFunding Information:
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.
© 2016 Macmillan Publishers Limited. All rights reserved.