Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

Ki-Jun Yoon; Francisca Rojas Ringeling; Caroline Vissers; Fadi Jacob; Michael Pokrass; Dennisse Jimenez-Cyrus; Yijing Su; Nam-Shik Kim; Yunhua Zhu; Lily Zheng; Sunghan Kim; Xinyuan Wang; Louis C Doré; Peng Jin; Sergi Regot; Xiaoxi Zhuang; Stefan Canzar; Chuan He; Guo-Li Ming; Hongjun Song

doi:10.1016/j.cell.2017.09.003

Temporal Control of Mammalian Cortical Neurogenesis by m⁶A Methylation

Cell. 2017 Nov 2;171(4):877-889.e17. doi: 10.1016/j.cell.2017.09.003. Epub 2017 Sep 28.

Authors

Ki-Jun Yoon¹, Francisca Rojas Ringeling², Caroline Vissers³, Fadi Jacob⁴, Michael Pokrass³, Dennisse Jimenez-Cyrus⁵, Yijing Su⁶, Nam-Shik Kim⁷, Yunhua Zhu⁸, Lily Zheng², Sunghan Kim⁸, Xinyuan Wang⁶, Louis C Doré⁹, Peng Jin¹⁰, Sergi Regot¹¹, Xiaoxi Zhuang¹², Stefan Canzar¹³, Chuan He⁹, Guo-Li Ming¹⁴, Hongjun Song¹⁵

Affiliations

¹ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² The Pre-doctoral Human Genetic Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Departments of Chemistry and Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
¹⁰ Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
¹¹ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹² Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
¹³ Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
¹⁴ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.
¹⁵ Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Pre-doctoral Human Genetic Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@pennmedicine.upenn.edu.

Abstract

N⁶-methyladenosine (m⁶A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m⁶A regulates mammalian brain development is unknown. Here, we show that m⁶A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m⁶A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m⁶A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m⁶A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m⁶A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m⁶A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m⁶A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

Keywords: Mettl14; RNA methylation; autism; epitranscriptomics; human organoid; m(6)A; neurogenesis; radial glia cell; schizophrenia; transcriptional prepatterning.

MeSH terms

Animals
Cell Cycle
Gene Expression Regulation
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Humans
Methylation
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Mice, Knockout
Neural Stem Cells / metabolism
Neurogenesis*
Organoids / metabolism
Prosencephalon / cytology
Prosencephalon / embryology*
Prosencephalon / metabolism
RNA Processing, Post-Transcriptional*
RNA Stability
RNA, Messenger / metabolism*

Substances

RNA, Messenger
METTL14 protein, human
Methyltransferases
Mettl14 protein, mouse
Mettl3 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding