Advertisement

RNA epigenetics

  • Nian Liu
    Affiliations
    Department of Chemistry, University of Chicago, Chicago, Ill
    Search for articles by this author
  • Tao Pan
    Correspondence
    Reprint requests: Tao Pan, Department of Biochemistry and Molecular Biology, University of Chicago, 929 East 57th Street, GCIS, W134, Chicago, IL 60637
    Affiliations
    Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Ill

    Institute of Biophysical Dynamics, University of Chicago, Chicago, Ill
    Search for articles by this author
Published:April 09, 2014DOI:https://doi.org/10.1016/j.trsl.2014.04.003
      Mammalian messenger RNA (mRNA) and long noncoding RNA (lncRNA) contain tens of thousands of posttranscriptional chemical modifications. Among these, the N6-methyl-adenosine (m6A) modification is the most abundant and can be removed by specific mammalian enzymes. m6A modification is recognized by families of RNA binding proteins that affect many aspects of mRNA function. mRNA/lncRNA modification represents another layer of epigenetic regulation of gene expression, analogous to DNA methylation and histone modification.

      Abbreviations:

      lncRNA (long noncoding RNA), m1A (N1-methyl-A), m1G (N1-methyl-G), m5C (5-methyl cytosine), m6A (N6-methyl adenosine), METTL14 (Methyltransferaselike 14), mRNA (Messenger RNA), Nm (2′-O-methyl nucleotides), Ψ (pseudouridine), RT (reverse transcriptase), tRNA (transfer RNA)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Piekna-Przybylska D.
        • Decatur W.A.
        • Fournier M.J.
        The 3D rRNA modification maps database: with interactive tools for ribosome analysis.
        Nucl Acids Res. 2008; 36: D178-D183
        • El Yacoubi B.
        • Bailly M.
        • de Crecy-Lagard V.
        Biosynthesis and function of posttranscriptional modifications of transfer RNAs.
        Annu Rev Genet. 2012; 46: 69-95
        • Grosjean H.
        • de Crecy-Lagard V.
        • Marck C.
        Deciphering synonymous codons in the three domains of life: co-evolution with specific tRNA modification enzymes.
        FEBS Lett. 2009; 584: 252-264
        • Song X.
        • Nazar R.N.
        Modification of rRNA as a “quality control mechanism” in ribosome biogenesis.
        FEBS Lett. 2002; 523: 182-186
        • Agris P.F.
        Decoding the genome: a modified view.
        Nucl Acids Res. 2004; 32: 223-238
        • Desrosiers R.
        • Friderici K.
        • Rottman F.
        Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells.
        Proc Natl Acad Sci U S A. 1974; 71: 3971-3975
        • Adams J.M.
        • Cory S.
        Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA.
        Nature. 1975; 255: 28-33
        • Wei C.M.
        • Gershowitz A.
        • Moss B.
        5′-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA.
        Biochemistry. 1976; 15: 397-401
        • Perry R.P.
        • Kelley D.E.
        • Friderici K.
        • Rottman F.
        The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5′terminus.
        Cell. 1975; 4: 387-394
        • Wei C.
        • Gershowitz A.
        • Moss B.
        N6, O2′-dimethyladenosine a novel methylated ribonucleoside next to the 5′terminal of animal cell and virus mRNAs.
        Nature. 1975; 257: 251-253
        • Narayan P.
        • Rottman F.M.
        An in vitro system for accurate methylation of internal adenosine residues in messenger RNA.
        Science. 1988; 242: 1159-1162
        • Horowitz S.
        • Horowitz A.
        • Nilsen T.W.
        • Munns T.W.
        • Rottman F.M.
        Mapping of N6-methyladenosine residues in bovine prolactin mRNA.
        Proc Natl Acad Sci U S A. 1984; 81: 5667-5671
        • Harper J.E.
        • Miceli S.M.
        • Roberts R.J.
        • Manley J.L.
        Sequence specificity of the human mRNA N6-adenosine methylase in vitro.
        Nucl Acids Res. 1990; 18: 5735-5741
        • Dubin D.T.
        • Taylor R.H.
        The methylation state of poly A-containing messenger RNA from cultured hamster cells.
        Nucl Acids Res. 1975; 2: 1653-1668
        • Schaefer M.
        • Pollex T.
        • Hanna K.
        • Lyko F.
        RNA cytosine methylation analysis by bisulfite sequencing.
        Nucl Acids Res. 2009; 37: e12
        • Squires J.E.
        • Patel H.R.
        • Nousch M.
        • et al.
        Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA.
        Nucl Acids Res. 2012; 40: 5023-5033
        • Bokar J.A.
        The biosynthesis and functional roles of methylated nucleosides in eukaryotic mRNA.
        in: Grosjean H. Fine-tuning of RNA functions by modification and editing. Springer-Verlag, Berlin2005: 141-178
        • Kariko K.
        • Buckstein M.
        • Ni H.
        • Weissman D.
        Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA.
        Immunity. 2005; 23: 165-175
        • Jia G.
        • Fu Y.
        • Zhao X.
        • et al.
        N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.
        Nat Chem Biol. 2011; 7: 885-887
        • Trewick S.C.
        • Henshaw T.F.
        • Hausinger R.P.
        • Lindahl T.
        • Sedgwick B.
        Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.
        Nature. 2002; 419: 174-178
        • Delaney J.C.
        • Essigmann J.M.
        Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli.
        Proc Natl Acad Sci U S A. 2004; 101: 14051-14056
        • Frayling T.M.
        • Timpson N.J.
        • Weedon M.N.
        • et al.
        A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
        Science. 2007; 316: 889-894
        • Gerken T.
        • Girard C.A.
        • Tung Y.C.
        • et al.
        The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.
        Science. 2007; 318: 1469-1472
        • Church C.
        • Lee S.
        • Bagg E.A.
        • et al.
        A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene.
        PLoS Genet. 2009; 5: e1000599
        • He C.
        Grand challenge commentary: RNA epigenetics?.
        Nat Chem Biol. 2010; 6: 863-865
        • Yi C.
        • Pan T.
        Cellular dynamics of RNA modification.
        Acc Chem Res. 2011; 44: 1380-1388
        • Dominissini D.
        • Moshitch-Moshkovitz S.
        • Schwartz S.
        • et al.
        Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.
        Nature. 2012; 485: 201-206
        • Meyer K.D.
        • Saletore Y.
        • Zumbo P.
        • Elemento O.
        • Mason C.E.
        • Jaffrey S.R.
        Comprehensive analysis of mRNA methylation reveals enrichment in 3′UTRs and near stop codons.
        Cell. 2012; 149: 1635-1646
        • Schwartz S.
        • Agarwala S.D.
        • Mumbach M.R.
        • et al.
        High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis.
        Cell. 2013; 155: 1409-1421
        • Vilfan I.D.
        • Tsai Y.C.
        • Clark T.A.
        • et al.
        Analysis of RNA base modification and structural rearrangement by single-molecule real-time detection of reverse transcription.
        J Nanobiotechnol. 2013; 11: 8
        • Harcourt E.M.
        • Ehrenschwender T.
        • Batista P.J.
        • Chang H.Y.
        • Kool E.T.
        Identification of a selective polymerase enables detection of n(6)-methyladenosine in RNA.
        J Am Chem Soc. 2013; 135: 19079-19082
        • Liu N.
        • Parisien M.
        • Dai Q.
        • Zheng G.
        • He C.
        • Pan T.
        Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA.
        RNA. 2013; 19: 1848-1856
        • Bokar J.A.
        • Shambaugh M.E.
        • Polayes D.
        • Matera A.G.
        • Rottman F.M.
        Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.
        RNA. 1997; 3: 1233-1247
        • Zhong S.
        • Li H.
        • Bodi Z.
        • et al.
        MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor.
        Plant Cell. 2008; 20: 1278-1288
        • Clancy M.J.
        • Shambaugh M.E.
        • Timpte C.S.
        • Bokar J.A.
        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.
        Nucl Acids Res. 2002; 30: 4509-4518
        • Hongay C.F.
        • Orr-Weaver T.L.
        Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis.
        Proc Natl Acad Sci U S A. 2011; 108: 14855-14860
        • Liu J.
        • Yue Y.
        • Han D.
        • et al.
        A METTL3-METTL14 complex mediates mammalian nuclear RNA N-adenosine methylation.
        Nat Chem Biol. 2014; 10: 93-95
        • Wang Y.
        • Li Y.
        • Toth J.I.
        • Petroski M.D.
        • Zhang Z.
        • Zhao J.C.
        N-methyladenosine modification destabilizes developmental regulators in embryonic stem cells.
        Nat Cell Biol. 2014; 16: 191-198
        • Ping X.L.
        • Sun B.F.
        • Wang L.
        • et al.
        Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.
        Cell Res. 2014; 24: 177-189
        • Horiuchi K.
        • Umetani M.
        • Minami T.
        • et al.
        Wilms’ tumor 1-associating protein regulates G2/M transition through stabilization of cyclin A2 mRNA.
        Proc Natl Acad Sci U S A. 2006; 103: 17278-17283
        • Fu Y.
        • Jia G.
        • Pang X.
        • et al.
        FTO-mediated formation of N6-hydroxymethyladenosine and N4-formyladenosine in mammalian RNA.
        Nat Commun. 2013; 4: 1798
        • Zheng G.
        • Dahl J.A.
        • Niu Y.
        • et al.
        ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
        Mol Cell. 2012; 49: 18-29
        • Yang C.G.
        • Yi C.
        • Duguid E.M.
        • et al.
        Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA.
        Nature. 2008; 452: 961-965
        • van den Born E.
        • Vagbo C.B.
        • Songe-Moller L.
        • et al.
        ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA.
        Nat Commun. 2011; 2: 172
        • Ma W.J.
        • Cheng S.
        • Campbell C.
        • Wright A.
        • Furneaux H.
        Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein.
        J Biol Chem. 1996; 271: 8144-8151
        • Kedde M.
        • Agami R.
        Interplay between microRNAs and RNA-binding proteins determines developmental processes.
        Cell Cycle. 2008; 7: 899-903
        • Kundu P.
        • Fabian M.R.
        • Sonenberg N.
        • Bhattacharyya S.N.
        • Filipowicz W.
        HuR protein attenuates miRNA-mediated repression by promoting miRISC dissociation from the target RNA.
        Nucl Acids Res. 2012; 40: 5088-5100
        • Stoilov P.
        • Rafalska I.
        • Stamm S.
        YTH: a new domain in nuclear proteins.
        Trends Biochem Sci. 2002; 27: 495-497
        • Wang X.
        • Lu Z.
        • Gomez A.
        • et al.
        N6-methyladenosine-dependent regulation of messenger RNA stability.
        Nature. 2014; 505: 117-120
        • Pan T.
        N6-methyl-adenosine modification in messenger and long non-coding RNA.
        Trends Biochem Sci. 2013; 38: 204-209
        • Smemo S.
        • Tena J.J.
        • Kim K.H.
        • et al.
        Obesity-associated variants within FTO form long-range functional connections with IRX3.
        Nature. 2014; 507: 371-375
        • Ito S.
        • Shen L.
        • Dai Q.
        • et al.
        Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.
        Science. 2011; 333: 1300-1303
        • Anderson J.
        • Phan L.
        • Hinnebusch A.G.
        The Gcd10p/Gcd14p complex is the essential two-subunit tRNA(1-methyladenosine) methyltransferase of Saccharomyces cerevisiae.
        Proc Natl Acad Sci U S A. 2000; 97: 5173-5178
        • Saikia M.
        • Fu Y.
        • Pavon-Eternod M.
        • He C.A.
        • Pan T.
        Genome-wide analysis of N-1-methyl-adenosine modification in human tRNAs.
        RNA. 2010; 16: 1317-1327
        • Ougland R.
        • Zhang C.M.
        • Liiv A.
        • et al.
        AlkB restores the biological function of mRNA and tRNA inactivated by chemical methylation.
        Mol Cell. 2004; 16: 107-116
        • Bjork G.R.
        • Wikstrom P.M.
        • Bystrom A.S.
        Prevention of translational frameshifting by the modified nucleoside 1-methylguanosine.
        Science. 1989; 244: 986-989
        • Jackman J.E.
        • Montange R.K.
        • Malik H.S.
        • Phizicky E.M.
        Identification of the yeast gene encoding the tRNA m1G methyltransferase responsible for modification at position 9.
        RNA. 2003; 9: 574-585
        • Bujnicki J.M.
        • Feder M.
        • Radlinska M.
        • Blumenthal R.M.
        Structure prediction and phylogenetic analysis of a functionally diverse family of proteins homologous to the MT-A70 subunit of the human mRNA:m(6)A methyltransferase.
        J Mol Evol. 2002; 55: 431-444
        • Niu Y.
        • Zhao X.
        • Wu Y.S.
        • Li M.M.
        • Wang X.J.
        • Yang Y.G.
        N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function.
        Genomics Proteomics Bioinformatics. 2013; 11: 8-17
        • Ortega A.
        • Niksic M.
        • Bachi A.
        • et al.
        Biochemical function of female-lethal (2)D/Wilms’ tumor suppressor-1-associated proteins in alternative pre-mRNA splicing.
        J Biol Chem. 2003; 278: 3040-3047
        • Utsch B.
        • Kaya A.
        • Ozburun A.
        • Lentze M.J.
        • Albers N.
        • Ludwig M.
        Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias.
        Scand J Urol Nephrol. 2003; 37: 498-501
        • Su J.
        • Li S.J.
        • Chen Z.H.
        • et al.
        Evaluation of podocyte lesion in patients with diabetic nephropathy: Wilms’ tumor-1 protein used as a podocyte marker.
        Diabetes Res Clin Pract. 2010; 87: 167-175
        • Jin D.I.
        • Lee S.W.
        • Han M.E.
        • et al.
        Expression and roles of Wilms’ tumor 1-associating protein in glioblastoma.
        Cancer Sci. 2012; 103: 2102-2109
        • Zeggini E.
        • Weedon M.N.
        • Lindgren C.M.
        • et al.
        Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
        Science. 2007; 316: 1336-1341
        • Kalnina I.
        • Zaharenko L.
        • Vaivade I.
        • et al.
        Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes.
        Gene. 2013; 527: 462-468
        • Akilzhanova A.
        • Nurkina Z.
        • Momynaliev K.
        • et al.
        Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer.
        Anticancer Res. 2013; 33: 4049-4059
        • Reddy S.M.
        • Sadim M.
        • Li J.
        • et al.
        Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer.
        Br J Cancer. 2013; 109: 872-881
        • Karra E.
        • O'Daly O.G.
        • Choudhury A.I.
        • et al.
        A link between FTO, ghrelin, and impaired brain food-cue responsivity.
        J Clin Invest. 2013; 123: 3539-3551
        • Lin Y.
        • Ueda J.
        • Yagyu K.
        • et al.
        Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case-control study in Japan.
        BMC Cancer. 2013; 13: 337
        • Wang L.
        • Yu Q.
        • Xiong Y.
        • et al.
        Variant rs1421085 in the FTO gene contribute childhood obesity in Chinese children aged 3–6 years.
        Obes Res Clin Pract. 2013; 7: e1-88
        • Thalhammer A.
        • Bencokova Z.
        • Poole R.
        • et al.
        Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1alpha (HIF-1alpha).
        PLoS One. 2011; 6: e16210
        • Cardelli M.
        • Marchegiani F.
        • Cavallone L.
        • et al.
        A polymorphism of the YTHDF2 gene (1p35) located in an Alu-rich genomic domain is associated with human longevity.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 547-556
        • Heiliger K.J.
        • Hess J.
        • Vitagliano D.
        • et al.
        Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice.
        Endocr Rel Cancer. 2012; 19: 409-421
        • Wang W.
        • Furneaux H.
        • Cheng H.
        • et al.
        HuR regulates p21 mRNA stabilization by UV light.
        Mol Cell Biol. 2000; 20: 760-769
        • Li H.
        • Park S.
        • Kilburn B.
        • et al.
        Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1: coactivator-associated arginine methyltransferase.
        J Biol Chem. 2002; 277: 44623-44630
        • Lee S.J.
        • Lee A.W.
        • Kang C.S.
        • et al.
        Clinicopathological implications of human papillomavirus (HPV) L1 capsid protein immunoreactivity in HPV16-positive cervical cytology.
        Int J Med Sci. 2014; 11: 80-86
        • Yang H.
        • Zheng Y.
        • Li T.W.
        • et al.
        Methionine adenosyltransferase 2B, HuR, and sirtuin 1 protein cross-talk impacts on the effect of resveratrol on apoptosis and growth in liver cancer cells.
        J Biol Chem. 2013; 288: 23161-23170
        • Zhu Z.
        • Wang B.
        • Bi J.
        • et al.
        Cytoplasmic HuR expression correlates with P-gp, HER-2 positivity, and poor outcome in breast cancer.
        Tumour Biol. 2013; 34: 2299-2308
        • Yang F.
        • Miao L.
        • Mei Y.
        • Wu M.
        Retinoic acid-induced HOXA5 expression is co-regulated by HuR and miR-130a.
        Cell Signal. 2013; 25: 1476-1485
        • Pang L.
        • Tian H.
        • Chang N.
        • et al.
        Loss of CARM1 is linked to reduced HuR function in replicative senescence.
        BMC Mol Biol. 2013; 14: 15
      1. http://www.malacards.org/.