m 6 a RNA Methylation: The Implications for Health and Disease

The recent resurgence of interest in m6a has been spurred by some intriguing findings detailing the effects and dynamics of this epigenetic modification. The m6a modification is a highly reactive and fluid modification which can respond rapidly to a broad variety of stimuli, and translate these signals into cellular activity. The little information that has been established on its functional capacity has opened up many new avenues of research and has tremendous implications for several fields of study. Here we outline the breakthroughs which have led to the resurgence of interest in this modification and discuss the effects and potential they represent in terms of control in the immune system, viral replication and infection, as well as the occurrence and progression of cancer.

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

[2]  Jernej Ule,et al.  Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders , 2014, The EMBO journal.

[3]  T. Robak,et al.  Toll-like receptors and their role in carcinogenesis and anti-tumor treatment , 2008, Cellular & Molecular Biology Letters.

[4]  Wei Zheng,et al.  Evaluating Genome-Wide Association Study-Identified Breast Cancer Risk Variants in African-American Women , 2013, PloS one.

[5]  K. Zhu,et al.  Toll-Like Receptors in Human Papillomavirus Infection , 2013, Archivum Immunologiae et Therapiae Experimentalis.

[6]  D. Sibley,et al.  New insights into dopaminergic receptor function using antisense and genetically altered animals. , 1999, Annual review of pharmacology and toxicology.

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

[8]  C. Feierstein,et al.  Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. , 2002, Endocrinology.

[9]  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.

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

[11]  M. Tuck,et al.  Inhibition of 6-methyladenine formation decreases the translation efficiency of dihydrofolate reductase transcripts. , 1999, The international journal of biochemistry & cell biology.

[12]  J. Nevins,et al.  N-6-methyl-adenosine in adenovirus type 2 nuclear RNA is conserved in the formation of messenger RNA. , 1979, Journal of molecular biology.

[13]  J. Darnell,et al.  The methylation of adenovirus-specific nuclear and cytoplasmic RNA. , 1976, Nucleic acids research.

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

[15]  Yan Huang,et al.  Roles of dopamine receptor subtypes in mediating modulation of T lymphocyte function. , 2010, Neuro endocrinology letters.

[16]  Ruslan Medzhitov,et al.  Toll-like receptors and innate immunity , 2001, Nature Reviews Immunology.

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

[18]  Shizuo Akira,et al.  Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA , 2004, Science.

[19]  C. Amantini,et al.  T-cell subpopulations express a different pattern of dopaminergic markers in intra- and extra-thymic compartments. , 2013, Journal of biological regulators and homeostatic agents.

[20]  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.

[21]  Henri Grosjean,et al.  Fine-tuning of RNA functions by modification and editing , 2005 .

[22]  G. Brown,et al.  Methylated bases of ribosomal ribonucleic acid from HeLa cells. , 1968, Archives of biochemistry and biophysics.

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

[24]  Y. Huang,et al.  Dopamine Receptors Modulate Cytotoxicity of Natural Killer Cells via cAMP-PKA-CREB Signaling Pathway , 2013, PloS one.

[25]  R. Płoski,et al.  Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. , 2011, Addiction.

[26]  G. Yeo,et al.  FTO expression is regulated by availability of essential amino acids , 2013, International Journal of Obesity.

[27]  M. Olsen,et al.  FTO, RNA epigenetics and epilepsy , 2012, Epigenetics.

[28]  Jef Rozenski,et al.  The RNA modification database, RNAMDB: 2011 update , 2010, Nucleic Acids Res..

[29]  I. Blümcke,et al.  Epigenetic mechanisms in epilepsy. , 2014, Progress in brain research.

[30]  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.

[31]  F. Ashcroft,et al.  FTO Is Expressed in Neurones throughout the Brain and Its Expression Is Unaltered by Fasting , 2011, PloS one.

[32]  K. Miura,et al.  A blocked structure at the 5′ terminus of mRNA from cytoplasmic polyhedrosis virus , 1975, Nature.

[33]  Guifang Jia,et al.  Reversible RNA adenosine methylation in biological regulation. , 2013, Trends in genetics : TIG.

[34]  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.

[35]  M. Linnebacher,et al.  Identification of an MSI-H Tumor-Specific Cytotoxic T Cell Epitope Generated by the (−1) Frame of U79260(FTO) , 2010, Journal of biomedicine & biotechnology.

[36]  Francesca Tuorto,et al.  RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. , 2010, Genes & development.

[37]  Peter Kraft,et al.  Association of type 2 diabetes susceptibility variants with advanced prostate cancer risk in the Breast and Prostate Cancer Cohort Consortium. , 2012, American journal of epidemiology.

[38]  G. Yeo FTO and Obesity: A Problem for a Billion People , 2012, Journal of neuroendocrinology.

[39]  R. Perry,et al.  The methylated constituents of globin mRNA , 1975, FEBS letters.

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

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

[42]  Y. Hiraoka,et al.  Selective elimination of messenger RNA prevents an incidence of untimely meiosis , 2006, Nature.

[43]  Yufei Huang,et al.  Decomposition of RNA methylome reveals co-methylation patterns induced by latent enzymatic regulators of the epitranscriptome. , 2015, Molecular bioSystems.

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

[45]  D. Weissman,et al.  mRNA Is an Endogenous Ligand for Toll-like Receptor 3* , 2004, Journal of Biological Chemistry.

[46]  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.

[47]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[48]  Mitsutoshi Nakamura,et al.  A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. , 2009, Cancer research.

[49]  Donald Grierson,et al.  Yeast targets for mRNA methylation , 2010, Nucleic acids research.

[50]  A. Shatkin,et al.  Blocked, methylated 5′-terminal sequence in avian sarcoma virus RNA , 1975, Nature.

[51]  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.

[52]  X. Wang,et al.  Wilms' tumor 1 as a novel target for immunotherapy of leukemia. , 2010, Transplantation proceedings.

[53]  Robert J. McDonald,et al.  Neuroscience and Biobehavioral Reviews the Trouble with Circadian Clock Dysfunction: Multiple Deleterious Effects on the Brain and Body , 2022 .

[54]  Chuan He,et al.  Grand challenge commentary: RNA epigenetics? , 2010, Nature chemical biology.

[55]  A. Gintsburg,et al.  Toll-Like Receptors (TLRs): The Role in Tumor Progression , 2010, Acta naturae.

[56]  Michael Hiller,et al.  The YTH Domain Is a Novel RNA Binding Domain* , 2010, The Journal of Biological Chemistry.

[57]  Tao Pan,et al.  Identification of recognition residues for ligation-based detection and quantitation of pseudouridine and N6-methyladenosine , 2007, Nucleic acids research.

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

[59]  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.

[60]  J. A. Steitz,et al.  HuR and mRNA stability , 2001, Cellular and Molecular Life Sciences CMLS.

[61]  Clement T Y Chan,et al.  A Quantitative Systems Approach Reveals Dynamic Control of tRNA Modifications during Cellular Stress , 2010, PLoS genetics.

[62]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

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

[64]  M. Cosentino,et al.  Expression of Dopaminergic Receptors on Human CD4+ T Lymphocytes: Flow Cytometric Analysis of Naive and Memory Subsets and Relevance for the Neuroimmunology of Neurodegenerative Disease , 2014, Journal of Neuroimmune Pharmacology.

[65]  R. Colonno,et al.  Methylation of messenger RNA of Newcastle disease virus in vitro by a virion-associated enzyme. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

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

[67]  T. Nilsen,et al.  Mapping of N6-methyladenosine residues in bovine prolactin mRNA. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[68]  S. Akira,et al.  Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7 , 2005, Nature Medicine.

[69]  Yufei Huang,et al.  A protocol for RNA methylation differential analysis with MeRIP-Seq data and exomePeak R/Bioconductor package. , 2014, Methods.

[70]  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.

[71]  B. A. Ballif,et al.  ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage , 2007, Science.

[72]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

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

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

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

[76]  K. Beemon,et al.  Localization of N6-methyladenosine in the Rous sarcoma virus genome. , 1977, Journal of molecular biology.

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

[78]  Michael W. Weiner,et al.  A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly , 2010, Proceedings of the National Academy of Sciences.

[79]  P. Sergiev,et al.  The ybiN gene of Escherichia coli encodes adenine-N6 methyltransferase specific for modification of A1618 of 23 S ribosomal RNA, a methylated residue located close to the ribosomal exit tunnel. , 2008, Journal of molecular biology.

[80]  Nengjun Yi,et al.  The role of the fat mass and obesity associated gene (FTO) in breast cancer risk , 2011, BMC Medical Genetics.

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

[82]  K. Shimada,et al.  ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression , 2013, Cancer science.

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

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

[85]  M. Guo,et al.  Inhibitory effect of S-adenosylmethionine on the growth of human gastric cancer cells in vivo and in vitro. , 2010, Chinese journal of cancer.

[86]  R. Borchardt,et al.  S-Adenosylmethionine and its analogs. Structural features correlated with synthesis and methylation of mRNAs of cytoplasmic polyhedrosis virus. , 1980, The Journal of biological chemistry.

[87]  Radhika Das,et al.  Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease. , 2015, Briefings in functional genomics.

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

[89]  S. Nishimura,et al.  Isolation and characterization of N6-methyladenosine from Escherichia coli valine transfer RNA. , 1969, Biochimica et biophysica acta.

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

[91]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[92]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[93]  A. Canellada,et al.  Dopamine Agonists Upregulate IL-6 and IL-8 Production in Human Keratinocytes , 2012, Neuroimmunomodulation.

[94]  F. Ashcroft,et al.  Changes in Gene Expression Associated with FTO Overexpression in Mice , 2014, PloS one.

[95]  H. Ueno,et al.  Long-term administration of Wilms tumor-1 peptide vaccine in combination with gemcitabine causes severe local skin inflammation at injection sites. , 2010, Japanese journal of clinical oncology.

[96]  B. Pierce,et al.  Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data , 2011, Cancer Causes & Control.

[97]  W. Shao,et al.  Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin , 2012, Nature.

[98]  R. Gainetdinov,et al.  The Physiology, Signaling, and Pharmacology of Dopamine Receptors , 2011, Pharmacological Reviews.

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

[100]  Yanhong Zhang,et al.  LPS-induced inflammation in the chicken is associated with CCAAT/enhancer binding protein beta-mediated fat mass and obesity associated gene down-regulation in the liver but not hypothalamus , 2013, BMC Veterinary Research.

[101]  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.

[102]  F. Rottman,et al.  N6-adenosine methylation in mRNA: substrate specificity and enzyme complexity. , 1994, Biochimie.

[103]  R. Joober,et al.  Association between obesity‐related gene FTO and ADHD , 2013, Obesity.