RNA modifications: what have we learned and where are we headed?

Proper control of the transcriptome is key for diverse aspects of gene expression, cellular functions and development, and its disruption can result in disease. A rapidly accumulating wealth of studies are identifying and functionally characterizing diverse types of RNA base modifications in protein-coding and non-coding RNAs, which have energized the emerging field of 'epitranscriptomics'. In this Viewpoint article, five experts discuss our latest understanding of RNA modifications, including recommendations for best practices and visions for the future.

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

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

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

[4]  John H Livingston,et al.  Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature , 2012, Nature Genetics.

[5]  T. Preiss,et al.  The emerging epitranscriptomics of long noncoding RNAs. , 2016, Biochimica et biophysica acta.

[6]  Eduard Batlle,et al.  Role of tRNA modifications in human diseases. , 2014, Trends in molecular medicine.

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

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

[9]  Martin Kircher,et al.  High‐throughput DNA sequencing – concepts and limitations , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[10]  Gideon Rechavi,et al.  Adenosine-to-inosine RNA editing meets cancer. , 2011, Carcinogenesis.

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

[12]  Benjamin L. Oakes,et al.  Programmable RNA recognition and cleavage by CRISPR/Cas9 , 2014, Nature.

[13]  Takeo Suzuki,et al.  Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. , 2011, Annual review of genetics.

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

[15]  F. Tuorto,et al.  RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis , 2012, Nature Structural &Molecular Biology.

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

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

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

[19]  Chengqi Yi,et al.  Transcriptome-wide dynamics of RNA pseudouridylation , 2015, Nature Reviews Molecular Cell Biology.

[20]  H. Ueda,et al.  Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. , 2010, Nature chemical biology.

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

[22]  Andreas Hildebrandt,et al.  The reverse transcription signature of N-1-methyladenosine in RNA-Seq is sequence dependent , 2015, Nucleic acids research.

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

[24]  E. Kool,et al.  Epigenetics: A new methyl mark on messengers , 2016, Nature.

[25]  B. Moss,et al.  N6, O2′-dimethyladenosine a novel methylated ribonucleoside next to the 5′ terminal of animal cell and virus mRNAs , 1975, Nature.

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

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

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

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

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

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

[32]  Chuan He,et al.  RNA epigenetics--chemical messages for posttranscriptional gene regulation. , 2016, Current opinion in chemical biology.

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

[34]  Isabelle Behm-Ansmant,et al.  Use of Specific Chemical Reagents for Detection of Modified Nucleotides in RNA , 2011, Journal of nucleic acids.

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

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

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

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

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

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

[41]  Joseph K. Pickrell,et al.  Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome” , 2012, Science.

[42]  Julian König,et al.  Analysis of CLIP and iCLIP methods for nucleotide-resolution studies of protein-RNA interactions , 2012, Genome Biology.

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