Recent advances in dynamic m6A RNA modification

The identification of m6A demethylases and high-throughput sequencing analysis of methylated transcriptome corroborated m6A RNA epigenetic modification as a dynamic regulation process, and reignited its investigation in the past few years. Many basic concepts of cytogenetics have been revolutionized by the growing understanding of the fundamental role of m6A in RNA splicing, degradation and translation. In this review, we summarize typical features of methylated transcriptome in mammals, and highlight the ‘writers’, ‘erasers’ and ‘readers’ of m6A RNA modification. Moreover, we emphasize recent advances of biological functions of m6A and conceive the possible roles of m6A in the regulation of immune response and related diseases.

[1]  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.

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

[3]  H. Spits,et al.  The biology of innate lymphoid cells , 2015, Nature.

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

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

[6]  Ye Fu,et al.  Sprouts of RNA epigenetics , 2013, RNA biology.

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

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

[9]  S. Perlman,et al.  Mitochondrial protein synthesis: RNA with the properties of Eukaryotic messenger RNA. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

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

[11]  N. Friedman,et al.  Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells , 2011, Nature Biotechnology.

[12]  Simon Hess,et al.  The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry , 2013, Nature Neuroscience.

[13]  N. Little,et al.  Identification of WTAP, a novel Wilms' tumour 1-associating protein. , 2000, Human molecular genetics.

[14]  B. Moss,et al.  Methylated nucleotides block 5′ terminus of HeLa cell messenger RNA , 1975, Cell.

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

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

[17]  Roger D. Cox,et al.  Overexpression of Fto leads to increased food intake and results in obesity , 2010, Nature Genetics.

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

[19]  F. Rottman,et al.  Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. , 1997, RNA.

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

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

[22]  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..

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

[24]  Boris Lenhard,et al.  Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3 , 2009, Proceedings of the National Academy of Sciences.

[25]  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.

[26]  F. Rottman,et al.  An in vitro system for accurate methylation of internal adenosine residues in messenger RNA. , 1988, Science.

[27]  Arne Klungland,et al.  Dynamic RNA modifications in disease. , 2014, Current opinion in genetics & development.

[28]  Paul Ryvkin,et al.  Global analysis of RNA secondary structure in two metazoans. , 2012, Cell reports.

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

[30]  B. Moss,et al.  5'-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA. , 1976, Biochemistry.

[31]  Jonathan Hall,et al.  Structural and mechanistic insights into poly(uridine) tract recognition by the hnRNP C RNA recognition motif. , 2014, Journal of the American Chemical Society.

[32]  R. Krug,et al.  Influenza viral mRNA contains internal N6-methyladenosine and 5'-terminal 7-methylguanosine in cap structures , 1976, Journal of virology.

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

[34]  Suzanne Cory,et al.  Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA , 1975, Nature.

[35]  C. Timpte,et al.  Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene. , 2002, Nucleic acids research.

[36]  Rong Wang,et al.  Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. , 2015, Cell stem cell.

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

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

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

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

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

[42]  U. Schibler,et al.  Comparison of methylated sequences in messenger RNA and heterogeneous nuclear RNA from mouse L cells. , 1977, Journal of molecular biology.

[43]  James Strait,et al.  Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits , 2007, PLoS genetics.

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

[45]  D. Spector,et al.  Nuclear organization of pre-mRNA processing. , 1993, Current opinion in cell biology.

[46]  J. Bujnicki,et al.  MODOMICS: a database of RNA modification pathways—2013 update , 2012, Nucleic Acids Res..

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

[48]  Dan Xie,et al.  Variation and Genetic Control of Protein Abundance in Humans , 2013, Nature.

[49]  Michaela Frye,et al.  Role of RNA methyltransferases in tissue renewal and pathology , 2014, Current opinion in cell biology.

[50]  Yuri Motorin,et al.  RNA nucleotide methylation , 2011, Wiley interdisciplinary reviews. RNA.

[51]  Richard Bonneau,et al.  The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. , 2012, Molecular cell.

[52]  N. Proudfoot,et al.  HUMAN NUCLEAR DICER RESTRICTS THE DELETERIOUS ACCUMULATION OF ENDOGENOUS DOUBLE STRAND RNA , 2014, Nature Structural &Molecular Biology.

[53]  Beverley Balkau,et al.  Variation in FTO contributes to childhood obesity and severe adult obesity , 2007, Nature Genetics.

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

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

[56]  B. Gregory,et al.  Global analysis of the RNA-protein interaction and RNA secondary structure landscapes of the Arabidopsis nucleus. , 2015, Molecular cell.

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

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

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

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

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

[62]  Shizuo Akira,et al.  Toll‐like Receptor and RIG‐1‐like Receptor Signaling , 2008, Annals of the New York Academy of Sciences.

[63]  M. Selbach,et al.  Global quantification of mammalian gene expression control , 2011, Nature.

[64]  A. Iwasaki,et al.  Control of adaptive immunity by the innate immune system , 2015, Nature Immunology.

[65]  Zhike Lu,et al.  Unique Features of the m6A Methylome in Arabidopsis thaliana , 2014, Nature Communications.

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

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

[68]  Olivier Elemento,et al.  5 0 UTR m 6 A Promotes Cap-Independent Translation Graphical , 2022 .

[69]  Tsutomu Suzuki,et al.  Polyadenylation in mammalian mitochondria: insights from recent studies. , 2008, Biochimica et biophysica acta.

[70]  Philippe Froguel,et al.  Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. , 2009, American journal of human genetics.

[71]  Houping Ni,et al.  Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. , 2005, Immunity.

[72]  Neville E. Sanjana,et al.  Perturbation of m 6 AWriters Reveals Two Distinct Classes of mRNA Methylation at Internal and 5 0 Sites , 2014 .

[73]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

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

[75]  K. Dimock,et al.  Sequence specificity of internal methylation in B77 avian sarcoma virus RNA subunits. , 1977, Biochemistry.

[76]  Chuan He,et al.  FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis , 2014, Cell Research.

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

[78]  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.

[79]  F. Ashcroft,et al.  Role for the obesity-related FTO gene in the cellular sensing of amino acids , 2013, Proceedings of the National Academy of Sciences.

[80]  Jonathan K. Pritchard,et al.  Primate Transcript and Protein Expression Levels Evolve Under Compensatory Selection Pressures , 2013, Science.

[81]  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.

[82]  R. Desrosiers,et al.  Nucleotide methylation patterns in eukaryotic mRNA. , 1976, Progress in nucleic acid research and molecular biology.

[83]  C. Kahana,et al.  Identification and mapping of N6-methyladenosine containing sequences in simian virus 40 RNA. , 1979, Nucleic acids research.

[84]  Marcin Feder,et al.  Structure Prediction and Phylogenetic Analysis of a Functionally Diverse Family of Proteins Homologous to the MT-A70 Subunit of the Human mRNA:m6A Methyltransferase , 2002, Journal of Molecular Evolution.

[85]  Schraga Schwartz,et al.  Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites. , 2014, Cell reports.

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

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

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

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

[90]  A. Rudensky,et al.  Interactions between innate and adaptive lymphocytes , 2014, Nature Reviews Immunology.

[91]  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.

[92]  Bin Zhang,et al.  Biogenesis and function of nuclear bodies. , 2011, Trends in genetics : TIG.

[93]  L. Trinkle-Mulcahy,et al.  Nuclear bodies: new insights into assembly/dynamics and disease relevance. , 2014, Current opinion in cell biology.

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

[95]  D. Spector,et al.  Nuclear neighborhoods and gene expression. , 2009, Current opinion in genetics & development.

[96]  D. Geiger,et al.  Polyadenylation of ribosomal RNA in human cells , 2006 .

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

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

[99]  B. Moss,et al.  Methylated nucleotides block 5'-terminus of vaccinia virus messenger RNA. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[100]  J E Darnell,et al.  Methylated, blocked 5 termini in HeLa cell mRNA. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[101]  J. Hurwitz,et al.  Messenger RNA. , 1962, Scientific American.

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