The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs
- Valentina V. Ignatova1,
- Paul Stolz2,
- Steffen Kaiser3,
- Tobias H. Gustafsson4,
- Palma Rico Lastres1,
- Adrián Sanz-Moreno5,
- Yi-Li Cho5,
- Oana V. Amarie5,
- Antonio Aguilar-Pimentel5,
- Tanja Klein-Rodewald5,
- Julia Calzada-Wack5,
- Lore Becker5,
- Susan Marschall5,
- Markus Kraiger5,
- Lillian Garrett5,6,
- Claudia Seisenberger6,
- Sabine M. Hölter5,6,
- Kayla Borland3,
- Erik Van De Logt3,
- Pascal W.T.C. Jansen7,
- Marijke P. Baltissen7,
- Magdalena Valenta1,
- Michiel Vermeulen7,
- Wolfgang Wurst6,8,9,10,
- Valerie Gailus-Durner5,
- Helmut Fuchs5,
- Martin Hrabe de Angelis5,11,12,
- Oliver J. Rando4,
- Stefanie M. Kellner3,
- Sebastian Bultmann2 and
- Robert Schneider1,12,13
- 1Institute of Functional Epigenetics, Helmholtz Zentrum München (HMGU), Neuherberg 85764, Germany;
- 2Department of Biology II, Human Biology, and BioImaging, Ludwig-Maximilians Universität München, Munich 81377, Germany;
- 3Chemical Faculty, Ludwig-Maximilians Universität München, Munich 81377, Germany;
- 4University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
- 5German Mouse Clinic, Institute of Experimental Genetics, HMGU, Neuherberg 85764, Germany;
- 6Institute of Developmental Genetics, HMGU, Neuherberg 85764, Germany;
- 7Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, GA Nijmegen 6525, the Netherlands;
- 8Chair of Developmental Genetics, Technische Universität München, Freising-Weihenstephan 85354, Germany;
- 9Deutsches Institut für Neurodegenerative Erkrankungen (DZNE), Munich 81377, Germany;
- 10Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Munich 81377, Germany;
- 11Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 85354, Germany;
- 12German Center for Diabetes Research (DZD), Neuherberg 85764, Germany;
- 13Faculty of Biology, Ludwig-Maximilians Universität München, Planegg-Martinsried 82152, Germany
- Corresponding author: robert.schneider{at}helmholtz-muenchen.de
Abstract
Covalent chemical modifications of cellular RNAs directly impact all biological processes. However, our mechanistic understanding of the enzymes catalyzing these modifications, their substrates and biological functions, remains vague. Amongst RNA modifications N6-methyladenosine (m6A) is widespread and found in messenger (mRNA), ribosomal (rRNA), and noncoding RNAs. Here, we undertook a systematic screen to uncover new RNA methyltransferases. We demonstrate that the methyltransferase-like 5 (METTL5) protein catalyzes m6A in 18S rRNA at position A1832. We report that absence of Mettl5 in mouse embryonic stem cells (mESCs) results in a decrease in global translation rate, spontaneous loss of pluripotency, and compromised differentiation potential. METTL5-deficient mice are born at non-Mendelian rates and develop morphological and behavioral abnormalities. Importantly, mice lacking METTL5 recapitulate symptoms of patients with DNA variants in METTL5, thereby providing a new mouse disease model. Overall, our biochemical, molecular, and in vivo characterization highlights the importance of m6A in rRNA in stemness, differentiation, development, and diseases.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.333369.119.
- Received October 1, 2019.
- Accepted March 5, 2020.
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