RNA methylation and diseases: experimental results, databases, Web servers and computational models

Ribonucleic acid (RNA) methylation is a type of posttranscriptional modifications occurring in all kingdoms of life. It is strongly related to important biological process, thus making it linked to a number of human diseases. Owing to the development of high-throughput sequencing technology, plenty of achievement had been obtained in RNA methylation research recently. Meanwhile, various computational models have been developed to analyze and mining increasing RNA methylation data. In this review, we first made a brief introduction about eight types of most popular RNA methylation, the biological functions of RNA methylation, the relationship between RNA methylation and disease and five important RNA methylation-related diseases. The research of RNA methylation is based on sequencing data processing, and effective bioinformatics techniques can benefit better understanding of RNA methylation. We further introduced seven publicly available RNA methylation-related databases, and some important publicly available RNA-methylation-related Web servers and software for RNA methylation site identification, differential analysis and so on. Furthermore, we provided detailed analysis of the state-of-the-art computational models used in these Web servers and software. We also analyzed the limitations of these models and discussed the future directions of developing computational models for RNA methylation research.

[1]  Yuan Wang,et al.  MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3′-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein* , 2017, The Journal of Biological Chemistry.

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

[3]  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.

[4]  M T Tuck,et al.  Partial purification of a 6-methyladenine mRNA methyltransferase which modifies internal adenine residues. , 1992, The Biochemical journal.

[5]  Chuan He,et al.  Dynamics of Human and Viral RNA Methylation during Zika Virus Infection. , 2016, Cell host & microbe.

[6]  Wei Chen,et al.  MethyRNA: a web server for identification of N6-methyladenosine sites , 2017, Journal of biomolecular structure & dynamics.

[7]  Wei Gu,et al.  RNA-MethylPred: A high-accuracy predictor to identify N6-methyladenosine in RNA. , 2016, Analytical biochemistry.

[8]  Uwe Ohler,et al.  RCAS: an RNA centric annotation system for transcriptome-wide regions of interest , 2017, Nucleic acids research.

[9]  Zhirong Sun,et al.  txCoords: A Novel Web Application for Transcriptomic Peak Re-Mapping , 2017, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[10]  Nian Liu,et al.  N6-methyladenosine–encoded epitranscriptomics , 2016, Nature Structural &Molecular Biology.

[11]  Oguzhan Begik,et al.  m6A Modification and Implications for microRNAs. , 2017, MicroRNA.

[12]  Yufei Huang,et al.  DRME: Count-based differential RNA methylation analysis at small sample size scenario. , 2016, Analytical biochemistry.

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

[14]  Yuk Yee Leung,et al.  HAMR: high-throughput annotation of modified ribonucleotides , 2013, RNA.

[15]  Ricardo C T Aguiar,et al.  IDH Mutation, Competitive Inhibition of FTO, and RNA Methylation. , 2017, Cancer cell.

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

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

[18]  Hongping Dong,et al.  2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members , 2010, Nature.

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

[20]  Gideon Rechavi,et al.  MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. , 2013, The Journal of clinical investigation.

[21]  Jessica M. Rusert,et al.  ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia , 2012, Proceedings of the National Academy of Sciences.

[22]  S. Elledge,et al.  The DNA damage response: making it safe to play with knives. , 2010, Molecular cell.

[23]  S. Horner,et al.  RNA modifications go viral , 2017, PLoS pathogens.

[24]  J. Manley,et al.  Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches , 2009, Nature Reviews Molecular Cell Biology.

[25]  R. Micura,et al.  Distinct 5-methylcytosine profiles in poly(A) RNA from mouse embryonic stem cells and brain , 2017, Genome Biology.

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

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

[28]  Ernesto Picardi,et al.  REDIportal: a comprehensive database of A-to-I RNA editing events in humans , 2016, Nucleic Acids Res..

[29]  Hui Zhang,et al.  iTRAQ-based chromatin proteomic screen reveals CHD4-dependent recruitment of MBD2 to sites of DNA damage. , 2016, Biochemical and biophysical research communications.

[30]  Shahar Alon,et al.  Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma , 2014, Genome Biology.

[31]  Xiaodong Cui,et al.  Exome-based analysis for RNA epigenome sequencing data , 2013, Bioinform..

[32]  R Engers,et al.  DKC1 overexpression associated with prostate cancer progression , 2009, British Journal of Cancer.

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

[34]  Chris P. Ponting,et al.  The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA , 2014, Cell reports.

[35]  Ian M. Carr,et al.  m6aViewer: software for the detection, analysis, and visualization of N6-methyladenosine peaks from m6A-seq/ME-RIP sequencing data , 2017, RNA.

[36]  Nian Liu,et al.  N 6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein , 2017, Nucleic acids research.

[37]  Edwin Cuppen,et al.  Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis , 2011, Annals of neurology.

[38]  Anthony O. Olarerin-George,et al.  MetaPlotR: a Perl/R pipeline for plotting metagenes of nucleotide modifications and other transcriptomic sites , 2017, Bioinform..

[39]  Zornitza Stark,et al.  Defects in tRNA Anticodon Loop 2′‐O‐Methylation Are Implicated in Nonsyndromic X‐Linked Intellectual Disability due to Mutations in FTSJ1 , 2015, Human mutation.

[40]  Zipora Y. Fligelman,et al.  Systematic identification of abundant A-to-I editing sites in the human transcriptome , 2004, Nature Biotechnology.

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

[42]  Jie Wu,et al.  RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data , 2015, Nucleic Acids Res..

[43]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[44]  C. Allis,et al.  Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers , 2010, Nature Reviews Cancer.

[45]  Yang Shi,et al.  m6A RNA methylation regulates the UV-induced DNA damage response , 2016, Nature.

[46]  Zlatko Trajanoski,et al.  meRanTK: methylated RNA analysis ToolKit , 2016, Bioinform..

[47]  Wei Chen,et al.  Detecting N6-methyladenosine sites from RNA transcriptomes using ensemble Support Vector Machines , 2017, Scientific Reports.

[48]  Patrice Vitali,et al.  dsRNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis , 2013 .

[49]  R. Thauer Biochemistry of methanogenesis: a tribute to Marjory Stephenson. 1998 Marjory Stephenson Prize Lecture. , 1998, Microbiology.

[50]  Sailu Yellaboina,et al.  Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity , 2011, Nucleic acids research.

[51]  S. Ankri,et al.  Reviving the RNA World: An Insight into the Appearance of RNA Methyltransferases , 2016, Front. Genet..

[52]  Yi-Tao Yu,et al.  U2 snRNA is inducibly pseudouridylated at novel sites by Pus7p and snR81 RNP , 2011, The EMBO journal.

[53]  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.

[54]  Sven Rahmann,et al.  N6-Adenosine Methylation in MiRNAs , 2015, PloS one.

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

[56]  Chuan He,et al.  m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition , 2016, Nature.

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

[58]  T. Nilsen,et al.  Kaposi's Sarcoma-Associated Herpesvirus Utilizes and Manipulates RNA N6-Adenosine Methylation To Promote Lytic Replication , 2017, Journal of Virology.

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

[60]  Zhirong Sun,et al.  AthMethPre: a web server for the prediction and query of mRNA m6A sites in Arabidopsis thaliana. , 2016, Molecular bioSystems.

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

[62]  Q. Cui,et al.  SRAMP: prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features , 2016, Nucleic acids research.

[63]  Andreas Hildebrandt,et al.  CoverageAnalyzer (CAn): A Tool for Inspection of Modification Signatures in RNA Sequencing Profiles , 2016, Biomolecules.

[64]  Wei Chen,et al.  Identification and analysis of the N6-methyladenosine in the Saccharomyces cerevisiae transcriptome , 2015, Scientific Reports.

[65]  Shabana,et al.  Role of a common variant of Fat Mass and Obesity associated (FTO) gene in obesity and coronary artery disease in subjects from Punjab, Pakistan: a case control study , 2016, Lipids in Health and Disease.

[66]  Ke Liu,et al.  RNAMethPre: A Web Server for the Prediction and Query of mRNA m6A Sites , 2016, PloS one.

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

[68]  Guang Peng,et al.  Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. , 2010, Cancer research.

[69]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[70]  F. Davis,et al.  Ribonucleic acids from yeast which contain a fifth nucleotide. , 1957, The Journal of biological chemistry.

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

[72]  M. Jantsch,et al.  The dynamic epitranscriptome: A to I editing modulates genetic information , 2015, Chromosoma.

[73]  Philippe Marin,et al.  Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia , 2012, The Journal of Neuroscience.

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

[75]  Florante A. Quiocho,et al.  Insertion of an N7-methylguanine mRNA Cap between Two Coplanar Aromatic Residues of a Cap-binding Protein Is Fast and Selective for a Positively Charged Cap* , 2003, Journal of Biological Chemistry.

[76]  Xuemei Chen,et al.  Methylation Protects miRNAs and siRNAs from a 3′-End Uridylation Activity in Arabidopsis , 2005, Current Biology.

[77]  Wei Chen,et al.  RAMPred: identifying the N1-methyladenosine sites in eukaryotic transcriptomes , 2016, Scientific Reports.

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

[79]  Peter A. Jones Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[80]  Eli Eisenberg,et al.  A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes , 2014, Genome research.

[81]  M. Green,et al.  Multiple methylated cap sequences in adenovirus type 2 early mRNA , 1976, Journal of virology.

[82]  M B Sporn,et al.  2'-O-methylation of adenosine, guanosine, uridine, and cytidine in RNA of isolated rat liver nuclei. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

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

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

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

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

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

[88]  Artur Jarmolowski,et al.  MicroRNA biogenesis: Epigenetic modifications as another layer of complexity in the microRNA expression regulation. , 2016, Acta biochimica Polonica.

[89]  Ran Elkon,et al.  Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation , 2017, Cell.

[90]  Yan-Hui Li,et al.  PPUS: a web server to predict PUS-specific pseudouridine sites , 2015, Bioinform..

[91]  Wei Chen,et al.  Identifying N6-methyladenosine sites in the Arabidopsis thaliana transcriptome , 2016, Molecular Genetics and Genomics.

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

[93]  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.

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

[95]  G. Church,et al.  Genome-Wide Identification of Human RNA Editing Sites by Parallel DNA Capturing and Sequencing , 2009, Science.

[96]  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.

[97]  V. Narry Kim,et al.  Emerging Roles of RNA Modification: m6A and U-Tail , 2014, Cell.

[98]  Miguel A. Andrade-Navarro,et al.  m6A modulates neuronal functions and sex determination in Drosophila , 2016, Nature.

[99]  Nathan Archer,et al.  m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination , 2016, Nature.

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

[101]  Michaela Frye,et al.  Genomic gain of 5p15 leads to over-expression of Misu (NSUN2) in breast cancer. , 2010, Cancer letters.

[102]  Yan Li,et al.  Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. , 2014, Cancer research.

[103]  Gideon Rechavi,et al.  Hippocampus-specific deficiency in RNA editing of GluA2 in Alzheimer's disease , 2014, Neurobiology of Aging.

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

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

[106]  M. Biel,et al.  Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates , 2010, PloS one.

[107]  Justin L Cotney,et al.  Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness. , 2009, Human molecular genetics.

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

[109]  K. Chou,et al.  iRNA-PseColl: Identifying the Occurrence Sites of Different RNA Modifications by Incorporating Collective Effects of Nucleotides into PseKNC , 2017, Molecular therapy. Nucleic acids.

[110]  Wei Chen,et al.  iRNA-PseU: Identifying RNA pseudouridine sites , 2016, Molecular therapy. Nucleic acids.

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

[112]  Jakub Pas,et al.  Molecular phylogenetics of the RrmJ/fibrillarin superfamily of ribose 2'-O-methyltransferases. , 2003, Gene.

[113]  G E Tomlinson,et al.  WTAP is a novel oncogenic protein in acute myeloid leukemia , 2014, Leukemia.

[114]  Dagmar Wieczorek,et al.  Mutations in NSUN2 cause autosomal-recessive intellectual disability. , 2012, American journal of human genetics.

[115]  Jun Yu,et al.  MeRIP-PF: An Easy-to-use Pipeline for High-resolution Peak-finding in MeRIP-Seq Data , 2013, Genom. Proteom. Bioinform..

[116]  Ran Su,et al.  Identifying N6-methyladenosine sites using multi-interval nucleotide pair position specificity and support vector machine , 2017, Scientific Reports.

[117]  Alexa B. R. McIntyre,et al.  N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection , 2016, Cell host & microbe.

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

[119]  Leilei Chen,et al.  Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma , 2013, Nature Medicine.

[120]  Gang Chen,et al.  Overexpression of the fat mass and obesity associated gene (FTO) in breast cancer and its clinical implications. , 2015, International journal of clinical and experimental pathology.

[121]  Cristina Bertolotto,et al.  Mitochondrial Myopathy and Sideroblastic Anemia (MLASA) , 2005, Journal of Biological Chemistry.

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

[123]  K. Chou,et al.  pRNAm-PC: Predicting N(6)-methyladenosine sites in RNA sequences via physical-chemical properties. , 2016, Analytical biochemistry.

[124]  Wengong Wang,et al.  Proteinase-activated Receptor 2 Promotes Cancer Cell Migration through RNA Methylation-mediated Repression of miR-125b* , 2015, The Journal of Biological Chemistry.

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

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

[127]  K. Chou,et al.  iRNA-Methyl: Identifying N(6)-methyladenosine sites using pseudo nucleotide composition. , 2015, Analytical biochemistry.

[128]  P. Seeburg,et al.  A mammalian RNA editing enzyme , 1996, Nature.

[129]  H. Ropers,et al.  Genetics of intellectual disability. , 2008, Current opinion in genetics & development.

[130]  Jin Billy Li,et al.  RADAR: a rigorously annotated database of A-to-I RNA editing , 2013, Nucleic Acids Res..

[131]  Yang Zhang,et al.  Extensive translation of circular RNAs driven by N6-methyladenosine , 2017, Cell Research.

[132]  Nahum Sonenberg,et al.  Cap and cap‐binding proteins in the control of gene expression , 2011, Wiley interdisciplinary reviews. RNA.

[133]  Xiaodong Cui,et al.  A novel algorithm for calling mRNA m6A peaks by modeling biological variances in MeRIP-seq data , 2016, Bioinform..

[134]  Arne Klungland,et al.  Sequencing of FTO and ALKBH5 in men undergoing infertility work-up identifies an infertility-associated variant and two missense mutations. , 2016, Fertility and sterility.

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

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

[137]  Sae-Ock Oh,et al.  WTAP regulates migration and invasion of cholangiocarcinoma cells , 2013, Journal of Gastroenterology.

[138]  Qi Ma,et al.  Gene Polymorphism Association with Type 2 Diabetes and Related Gene-Gene and Gene-Environment Interactions in a Uyghur Population , 2016, Medical science monitor : international medical journal of experimental and clinical research.

[139]  Wei Chen,et al.  iRNA-AI: identifying the adenosine to inosine editing sites in RNA sequences , 2016, Oncotarget.

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

[141]  John S Witte,et al.  Hypospadias and genes related to genital tubercle and early urethral development. , 2013, The Journal of urology.

[142]  Hui Liu,et al.  MeT-DB: a database of transcriptome methylation in mammalian cells , 2014, Nucleic Acids Res..