Post-transcriptional gene regulation by mRNA modifications

The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.

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

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

[3]  D T Dubin,et al.  The methylation state of poly A-containing messenger RNA from cultured hamster cells. , 1975, Nucleic acids research.

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

[5]  J. Valcárcel,et al.  Biochemical Function of Female-Lethal (2)D/Wilms' Tumor Suppressor-1-associated Proteins in Alternative Pre-mRNA Splicing* , 2003, The Journal of Biological Chemistry.

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

[7]  Spitale Robert,et al.  Structural imprints in vivo decode RNA regulatory mechanisms , 2016 .

[8]  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.

[9]  Xiaohong Zhu,et al.  Transcriptome-wide high-throughput deep m6A-seq reveals unique differential m6A methylation patterns between three organs in Arabidopsis thaliana , 2015, Genome Biology.

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

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

[12]  Samie R. Jaffrey,et al.  m6A RNA methylation promotes XIST-mediated transcriptional repression , 2016, Nature.

[13]  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.

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

[15]  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.

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

[17]  D. B. Dunn,et al.  An additional sugar component of ribonucleic acids. , 1959, Biochimica et biophysica acta.

[18]  Frank Lyko,et al.  RNA cytosine methylation analysis by bisulfite sequencing , 2008, Nucleic acids research.

[19]  R. H. Hall Method for isolation of 2′-O-methylribonucleosides and N1-methyladenosine from ribonucleic acid , 1963 .

[20]  Michael Benatar,et al.  Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS , 2013, Nature.

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

[22]  R. Desrosiers,et al.  Characterization of Novikoff hepatoma mRNA methylation and heterogeneity in the methylated 5' terminus. , 1975, Biochemistry.

[23]  A. Shatkin,et al.  Methylated simian virus 40-specific RNA from nuclei and cytoplasm of infected BSC-1 cells. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Zhen Zhang,et al.  Variant rs1421085 in the FTO gene contribute childhood obesity in Chinese children aged 3-6 years. , 2013, Obesity research & clinical practice.

[25]  M. Schaefer,et al.  Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. , 2009, Cancer research.

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

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

[28]  Samir Adhikari,et al.  Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. , 2016, Molecular cell.

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

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

[31]  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.

[32]  B. Cairns,et al.  Dnmt2 functions in the cytoplasm to promote liver, brain, and retina development in zebrafish. , 2007, Genes & development.

[33]  Y. Zhang,et al.  The Demethylase Activity of FTO (Fat Mass and Obesity Associated Protein) Is Required for Preadipocyte Differentiation , 2015, PloS one.

[34]  G. Pfeifer,et al.  Tet-Mediated Formation of 5-Hydroxymethylcytosine in RNA , 2014, Journal of the American Chemical Society.

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

[36]  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..

[37]  Bryan R. Cullen,et al.  Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression. , 2016, Cell host & microbe.

[38]  Karl-Dieter Entian,et al.  Identification of a novel methyltransferase, Bmt2, responsible for the N-1-methyl-adenosine base modification of 25S rRNA in Saccharomyces cerevisiae , 2013, Nucleic acids research.

[39]  P. Agris The importance of being modified: an unrealized code to RNA structure and function , 2015, RNA.

[40]  L. Sánchez,et al.  The gene fl(2)d is needed for the sex-specific splicing of transformer pre-mRNA but not for double-sex pre-mRNA in Drosophila melanogaster , 1996, Molecular and General Genetics MGG.

[41]  Qi Xu,et al.  An association study of the m6A genes with major depressive disorder in Chinese Han population. , 2015, Journal of affective disorders.

[42]  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.

[43]  Fei Wang,et al.  Transcriptome-wide distribution and function of RNA hydroxymethylcytosine , 2016, Science.

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

[45]  P. Blum Archaea : new models for prokaryotic biology , 2008 .

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

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

[48]  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.

[49]  R. Perry,et al.  Existence of Methylated Messenger RNA in Mouse L Cells , 1974 .

[50]  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.

[51]  Robert P. Perry,et al.  The methylated constituents of L cell messenger RNA: Evidence for an unusual cluster at the 5′ terminus , 1975, Cell.

[52]  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.

[53]  K. Matsuo,et al.  Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case–control study in Japan , 2013, BMC Cancer.

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

[55]  F. Rottman,et al.  Methylation of mRNA. , 1992, Advances in enzymology and related areas of molecular biology.

[56]  N. Jasnić,et al.  Fasting Induced Cytoplasmic Fto expression in Some Neurons of Rat Hypothalamus , 2013, PloS one.

[57]  Julian J. Emmanuel,et al.  A link between FTO, ghrelin, and impaired brain food-cue responsivity. , 2013, The Journal of clinical investigation.

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

[59]  P. Sergiev,et al.  N6-Methylated Adenosine in RNA: From Bacteria to Humans. , 2016, Journal of molecular biology.

[60]  Tsutomu Suzuki,et al.  Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. , 2015, Cell metabolism.

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

[62]  Liang-Hu Qu,et al.  RTL-P: a sensitive approach for detecting sites of 2′-O-methylation in RNA molecules , 2012, Nucleic acids research.

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

[64]  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.

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

[66]  Xin Deng,et al.  Widespread occurrence of N6-methyladenosine in bacterial mRNA , 2015, Nucleic acids research.

[67]  Li Wang,et al.  Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine , 2014, Cell Research.

[68]  I. Craig,et al.  The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression , 2013, Molecular Psychiatry.

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

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

[71]  C. Mantzoros,et al.  Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer , 2012, British Journal of Cancer.

[72]  B. Lane Historical Perspectives on RNA Nucleoside Modifications , 1998 .

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

[74]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[75]  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.

[76]  D. B. Dunn,et al.  The occurrence of 1-methyladenine in ribonucleic acid. , 1961, Biochimica et biophysica acta.

[77]  R. Haugland,et al.  Post-transcriptional modifications of oat coleoptile ribonucleic acids. 5'-Terminal capping and methylation of internal nucleosides in poly(A)-rich RNA. , 1980, European journal of biochemistry.

[78]  F. Ashcroft,et al.  FTO influences adipogenesis by regulating mitotic clonal expansion , 2015, Nature Communications.

[79]  R. Loos,et al.  The bigger picture of FTO—the first GWAS-identified obesity gene , 2014, Nature Reviews Endocrinology.

[80]  M. Lentze,et al.  Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias , 2003, Scandinavian journal of urology and nephrology.

[81]  Xiaoyu Zhang,et al.  Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2 , 2006, Science.

[82]  J. Kowalak,et al.  The role of posttranscriptional modification in stabilization of transfer RNA from hyperthermophiles. , 1994, Biochemistry.

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

[84]  Qiangfeng Cliff Zhang,et al.  Landscape and variation of RNA secondary structure across the human transcriptome , 2014, Nature.

[85]  R. Gregory,et al.  The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. , 2016, Molecular cell.

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

[87]  Jernej Ule,et al.  NSun2-Mediated Cytosine-5 Methylation of Vault Noncoding RNA Determines Its Processing into Regulatory Small RNAs , 2013, Cell reports.

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

[89]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

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

[91]  F. Rottman,et al.  Context effects on N6-adenosine methylation sites in prolactin mRNA. , 1994, Nucleic acids research.

[92]  Gideon Rechavi,et al.  The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA , 2016, Nature.

[93]  J. Takahashi,et al.  Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals , 2012, Science.

[94]  V. Ramakrishnan,et al.  Unusual base pairing during the decoding of a stop codon by the ribosome , 2013, Nature.

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

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

[97]  Andreas Marx,et al.  Direct and site-specific quantification of RNA 2′-O-methylation by PCR with an engineered DNA polymerase , 2016, Nucleic acids research.

[98]  Albert Jeltsch,et al.  Human DNMT2 methylates tRNA(Asp) molecules using a DNA methyltransferase-like catalytic mechanism. , 2008, RNA.

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

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

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

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

[103]  C. Stoltzfus,et al.  Accumulation of Spliced Avian Retrovirus mRNA Is Inhibited in S-Adenosylmethionine-Depleted Chicken Embryo Fibroblasts , 1982, Journal of virology.

[104]  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.

[105]  Ligang Wu,et al.  YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex , 2016, Nature Communications.

[106]  Shiqing Ma,et al.  Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. , 2015, Nature chemical biology.

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

[108]  R. Perry,et al.  Methylated constituents of heterogeneous nuclear RNA: Presence in blocked 5′ terminal structures , 1975, Cell.

[109]  H. Grosjean Modification and editing of RNA: historical overview and important facts to remember , 2005 .

[110]  Chuanzhao Zhang,et al.  Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA , 2016, Proceedings of the National Academy of Sciences.

[111]  A. Busch,et al.  Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns , 2016, RNA biology.

[112]  B. Cullen,et al.  Posttranscriptional m6A Editing of HIV-1 mRNAs Enhances Viral Gene Expression. , 2017, Cell host & microbe.

[113]  Gianmarc Grazioli,et al.  m1A and m1G Potently Disrupt A-RNA Structure Due to the Intrinsic Instability of Hoogsteen Base Pairs , 2016, Nature Structural &Molecular Biology.

[114]  J. L. Nichols,et al.  in maize poly(A)-containing RNA , 1979 .

[115]  A. Hüttenhofer,et al.  Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[116]  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.

[117]  Shang Gao,et al.  Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells , 2016, Nature Microbiology.

[118]  Y. Hong,et al.  FTO Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women , 2014, Diabetes & metabolism journal.

[119]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[120]  V. de Crécy-Lagard,et al.  Biosynthesis and function of posttranscriptional modifications of transfer RNAs. , 2012, Annual review of genetics.

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

[122]  R. Levis,et al.  5'-terminal structures of poly(A)+ cytoplasmic messenger RNA and of poly(A)+ and poly(A)- heterogeneous nuclear RNA of cells of the dipteran Drosophila melanogaster. , 1978, Journal of molecular biology.

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

[124]  Sang Weon Lee,et al.  Expression and roles of Wilms' tumor 1‐associating protein in glioblastoma , 2012, Cancer science.

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

[126]  B. Lane,et al.  Wheat embryo ribonucleates. XIII. Methyl-substituted nucleoside constituents and 5'-terminal dinucleotide sequences in bulk poly(AR)-rich RNA from imbibing wheat embryos. , 1979, Canadian journal of biochemistry.

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

[128]  A. Hüttenhofer,et al.  The expanding snoRNA world. , 2002, Biochimie.

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

[130]  Vihandha O. Wickramasinghe,et al.  Control of mammalian gene expression by selective mRNA export , 2015, Nature Reviews Molecular Cell Biology.

[131]  H. Lipshitz,et al.  Transcript clearance during the maternal-to-zygotic transition. , 2011, Current opinion in genetics & development.

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

[133]  Y. Motorin,et al.  Multisite-specific tRNA:m5C-methyltransferase (Trm4) in yeast Saccharomyces cerevisiae: identification of the gene and substrate specificity of the enzyme. , 1999, RNA.

[134]  R Giegé,et al.  A Watson-Crick base-pair-disrupting methyl group (m1A9) is sufficient for cloverleaf folding of human mitochondrial tRNALys. , 1999, Biochemistry.

[135]  L. Sánchez,et al.  The Drosophila melanogaster fl(2)d gene is needed for the female‐specific splicing of Sex‐lethal RNA. , 1990, The EMBO journal.

[136]  David A. Rand,et al.  Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth , 2015, Front. Neurol..

[137]  Chuan He,et al.  N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression , 2016, eLife.

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

[139]  Horst Zitzelsberger,et al.  Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice. , 2012, Endocrine-related cancer.

[140]  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.

[141]  Thomas J. Begley,et al.  tRNA modifications regulate translation during cellular stress , 2014, FEBS letters.

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

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

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

[145]  Bradley R. Cairns,et al.  Identification of direct targets and modified bases of RNA cytosine methyltransferases , 2013, Nature Biotechnology.

[146]  Izabela Makałowska,et al.  Identification of human tRNA:m5C methyltransferase catalysing intron-dependent m5C formation in the first position of the anticodon of the pre-tRNA(CAA)Leu , 2006, Nucleic acids research.

[147]  Shankar Balasubramanian,et al.  Formation and Abundance of 5-Hydroxymethylcytosine in RNA , 2015, Chembiochem : a European journal of chemical biology.

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

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

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

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

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

[153]  M. Rietschel,et al.  Depressive disorder moderates the effect of the FTO gene on body mass index , 2012, Molecular Psychiatry.

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

[155]  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.

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

[157]  Erlan Ramanculov,et al.  Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer. , 2013, Anticancer research.

[158]  W. Jelinek,et al.  Methyl labeling of HeLa cell hnRNA: a comparison with mRNA , 1976, Cell.

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

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

[161]  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.

[162]  Jan Gorodkin,et al.  Profiling of ribose methylations in RNA by high-throughput sequencing. , 2014, Angewandte Chemie.

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

[164]  Bifeng Yuan,et al.  The existence of 5-hydroxymethylcytosine and 5-formylcytosine in both DNA and RNA in mammals. , 2016, Chemical communications.

[165]  Yi Xing,et al.  m6A-LAIC-seq reveals the census and complexity of the m6A epitranscriptome , 2016, Nature Methods.

[166]  Y. Milaneschi,et al.  The effect of FTO rs9939609 on major depression differs across MDD subtypes , 2014, Molecular Psychiatry.

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

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

[169]  M. Assanah,et al.  HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer , 2010, Nature.

[170]  M. Helm,et al.  Detection of RNA modifications , 2010, RNA biology.

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

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

[173]  John Karijolich,et al.  Modifying the genetic code: Converting nonsense codons into sense codons by targeted pseudouridylation , 2011, Nature.

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

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

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

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

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

[179]  L. Zaharenko,et al.  Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes. , 2013, Gene.

[180]  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.

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

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

[183]  Chengqi Yi,et al.  Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. , 2016, Nature chemical biology.

[184]  Michaela Frye,et al.  Characterizing 5-methylcytosine in the mammalian epitranscriptome , 2013, Genome Biology.

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

[186]  A. Hopper,et al.  tRNA processing, modification, and subcellular dynamics: past, present, and future , 2015, RNA.

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