N6-methyladenosine–encoded epitranscriptomics

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA. Recent discoveries of the locations, functions and mechanisms of m6A have shed light on a new layer of gene regulation at the RNA level, giving rise to the field of m6A epitranscriptomics. In this Perspective, we provide an update on the various effects of mammalian m6A modification, which affects many different stages of the RNA life cycle.

[1]  S. Kane,et al.  Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: implications for RNA processing , 1985, Molecular and cellular biology.

[2]  R. Kierzek,et al.  The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. , 2003, Nucleic acids research.

[3]  T. Pan,et al.  N(6)-Methyladenosine Modification in a Long Noncoding RNA Hairpin Predisposes Its Conformation to Protein Binding. , 2016, Journal of molecular biology.

[4]  Zhike Lu,et al.  m6A-dependent regulation of messenger RNA stability , 2013, Nature.

[5]  Christopher E. Mason,et al.  Single-nucleotide resolution mapping of m6A and m6Am throughout the transcriptome , 2015, Nature Methods.

[6]  Gerald R. Fink,et al.  RNA Methylation by the MIS Complex Regulates a Cell Fate Decision in Yeast , 2012, PLoS genetics.

[7]  Chengqi Yi,et al.  N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO , 2011, Nature chemical biology.

[8]  A. Shatkin,et al.  Sequences containing methylated nucleotides at the 5' termini of messenger RNAs: possible implications for processing. , 1974, Cell.

[9]  Perturbation of m 6 A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5 Sites Citation , 2014 .

[10]  T. Pan,et al.  RNA epigenetics. , 2015, Translational research : the journal of laboratory and clinical medicine.

[11]  S. Zhong,et al.  Adenosine Methylation in Arabidopsis mRNA is Associated with the 3′ End and Reduced Levels Cause Developmental Defects , 2012, Front. Plant Sci..

[12]  Samir Adhikari,et al.  Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase , 2014, Cell Research.

[13]  Julian König,et al.  Direct Competition between hnRNP C and U2AF65 Protects the Transcriptome from the Exonization of Alu Elements , 2013, Cell.

[14]  Yi Xing,et al.  m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. , 2014, Cell stem cell.

[15]  M. Kupiec,et al.  Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq , 2012, Nature.

[16]  R J Roberts,et al.  Sequence specificity of the human mRNA N6-adenosine methylase in vitro. , 1990, Nucleic acids research.

[17]  Alan G Hinnebusch,et al.  The scanning mechanism of eukaryotic translation initiation. , 2014, Annual review of biochemistry.

[18]  Gideon Rechavi,et al.  Gene expression regulation mediated through reversible m6A RNA methylation , 2014, Nature Reviews Genetics.

[19]  Maxwell R. Mumbach,et al.  Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA , 2014, Cell.

[20]  J. Malter,et al.  hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. , 1998, Nucleic acids research.

[21]  B. Moss,et al.  Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid. , 1977, Biochemistry.

[22]  T. Cech,et al.  RNA seeds higher-order assembly of FUS protein. , 2013, Cell reports.

[23]  Ke Liu,et al.  Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. , 2014, Nature chemical biology.

[24]  Chuan He,et al.  RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation , 2015, Genes & development.

[25]  Jihui Wu,et al.  Structure of the YTH domain of human YTHDF2 in complex with an m6A mononucleotide reveals an aromatic cage for m6A recognition , 2014, Cell Research.

[26]  W. Gilbert,et al.  Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells , 2014, Nature.

[27]  David L. Spector,et al.  Nuclear speckles: a model for nuclear organelles , 2003, Nature Reviews Molecular Cell Biology.

[28]  Kazuko Nishikura,et al.  Adenosine-to-inosine RNA editing and human disease , 2013, Genome Medicine.

[29]  Jimin Pei,et al.  Cell-free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers within Hydrogels , 2012, Cell.

[30]  S. Tavazoie,et al.  N6-methyladenosine marks primary microRNAs for processing , 2015, Nature.

[31]  O. Elemento,et al.  Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons , 2012, Cell.

[32]  Mani Ramaswami,et al.  Altered Ribostasis: RNA-Protein Granules in Degenerative Disorders , 2013, Cell.

[33]  Chris P. Ponting,et al.  The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase , 2007, Science.

[34]  Nian Liu,et al.  Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA , 2013, RNA.

[35]  Howard Y. Chang,et al.  Structural imprints in vivo decode RNA regulatory mechanisms , 2015, Nature.

[36]  Michel Herzog,et al.  MTA Is an Arabidopsis Messenger RNA Adenosine Methylase and Interacts with a Homolog of a Sex-Specific Splicing Factor[W][OA] , 2008, The Plant Cell Online.

[37]  Bing Ren,et al.  N6-methyladenosine-dependent regulation of messenger RNA stability , 2013 .

[38]  Yang Wang,et al.  N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells , 2014, Nature Cell Biology.

[39]  Howard Y. Chang,et al.  Structure and thermodynamics of N6-methyladenosine in RNA: a spring-loaded base modification. , 2015, Journal of the American Chemical Society.

[40]  C. Bouchard,et al.  FTO: the first gene contributing to common forms of human obesity , 2008, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[41]  Olivier Elemento,et al.  5′ UTR m6A Promotes Cap-Independent Translation , 2015, Cell.

[42]  Tao Pan,et al.  High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. , 2015, Angewandte Chemie.

[43]  T. Preiss,et al.  Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA , 2012, Nucleic acids research.

[44]  F. Rottman,et al.  Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. , 1994, The Journal of biological chemistry.

[45]  Erez Y. Levanon,et al.  m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation , 2015, Science.

[46]  K. Beemon,et al.  Sequence specificity of mRNA N6-adenosine methyltransferase. , 1990, The Journal of biological chemistry.

[47]  M. Ehrenberg,et al.  N6-methyladenosine in mRNA disrupts tRNA selection and translation elongation dynamics , 2016, Nature Structural &Molecular Biology.

[48]  Schraga Schwartz,et al.  High-Resolution Mapping Reveals a Conserved, Widespread, Dynamic mRNA Methylation Program in Yeast Meiosis , 2013, Cell.

[49]  C. Bugg,et al.  Conformation of N6-Methyladenine, a Base Involved in DNA Modification: Restriction Processes , 1973, Science.

[50]  Minoru Yoshida,et al.  RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock , 2013, Cell.

[51]  Chuan He,et al.  N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions , 2015, Nature.

[52]  N. Cox,et al.  Obesity-associated variants within FTO form long-range functional connections with IRX3 , 2014, Nature.

[53]  Chuan He,et al.  FTO-Mediated Formation of N6-Hydroxymethyladenosine and N6-Formyladenosine in Mammalian RNA , 2013, Nature Communications.

[54]  J. Bokar The biosynthesis and functional roles of methylated nucleosides in eukaryotic mRNA , 2005 .

[55]  Arne Klungland,et al.  ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. , 2013, Molecular cell.

[56]  Miao Yu,et al.  A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation , 2013, Nature chemical biology.

[57]  Samie R. Jaffrey,et al.  The dynamic epitranscriptome: N6-methyladenosine and gene expression control , 2014, Nature Reviews Molecular Cell Biology.

[58]  Miao Yu,et al.  A METTL 3-METTL 14 complex mediates mammalian nuclear RNA N 6-adenosine methylation , 2016 .

[59]  F. Rottman,et al.  N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA , 1990, Molecular and cellular biology.

[60]  J. Ule,et al.  iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution , 2010, Nature Structural &Molecular Biology.

[61]  T. Orr-Weaver,et al.  Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis , 2011, Proceedings of the National Academy of Sciences.

[62]  S. McKnight,et al.  Phosphorylation-Regulated Binding of RNA Polymerase II to Fibrous Polymers of Low-Complexity Domains , 2013, Cell.

[63]  Jens C. Brüning,et al.  Inactivation of the Fto gene protects from obesity , 2009, Nature.

[64]  Chuan He,et al.  N 6 -methyladenosine Modulates Messenger RNA Translation Efficiency , 2015, Cell.

[65]  Markus Blatter,et al.  Solution structure of the YTH domain in complex with N6-methyladenosine RNA: a reader of methylated RNA , 2014, Nucleic acids research.

[66]  M. Ohno,et al.  hnRNP C Tetramer Measures RNA Length to Classify RNA Polymerase II Transcripts for Export , 2012, Science.

[67]  Saeed Tavazoie,et al.  HNRNPA2B1 Is a Mediator of m6A-Dependent Nuclear RNA Processing Events , 2015, Cell.

[68]  Arne Klungland,et al.  A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation , 2015, Genes & development.

[69]  Liang Tong,et al.  Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain , 2014, Proceedings of the National Academy of Sciences.

[70]  Shu-Bing Qian,et al.  Dynamic m6A mRNA methylation directs translational control of heat shock response , 2015, Nature.

[71]  R. Desrosiers,et al.  Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[72]  Qi Zhou,et al.  m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. , 2015, Cell stem cell.