RNA modification

RNA modification occurs in all living organisms, and is one of the most evolutionarily conserved properties of RNAs.[1][2][3] It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.[1][2][3][4]

More than 160 types of RNA modifications have been described so far,[5] recent studies have revealed they are abundant in tRNAs and in regulatory non-coding RNAs (e.g., lncRNAs, miRNAs, snRNAs, snoRNAs) as well as in mRNAs and rRNAs.[4]

RNA Modification Technologies

To identify diverse post-transcriptional modifications of RNA molecules and determine the transcriptome-wide landscape of RNA modifications by means of next generation RNA sequencing, recently many studies have developed conventional[6] or specialised sequencing methods.[1][2][3] Examples of specialised methods are MeRIP-seq,[7] m6A-seq,[8] methylation-iCLIP,[9] m6A-CLIP,[10] Pseudo-seq,[11] Ψ-seq,[12] CeU-seq,[13] Aza-IP[14] and RiboMeth-seq[15]). Application of these methods have identified various modifications (e.g. pseudouridine, m6A, m5C, 2′-O-Me) within coding genes and non-coding genes (e.g. tRNA, lncRNAs, microRNAs) at single nucleotide or very high resolution.[4] A novel database, RMBase (http://mirlab.sysu.edu.cn/rmbase/),[4] has provide various web interfaces to show all RNA modification sites identified from above-mentioned sequencing technologies.

RNA Modification Functions

Recently, functional experiments have revealed many novel functional roles of RNA modifications. For example, m6A has been predicted to affect protein translation and localization,[1][2][3] mRNA stability,[16] alternative polyA choice [10] and stem cell pluripotency.[17] Pseudouridylation of nonsense codons suppresses translation termination both in vitro and in vivo, suggesting that RNA modification may provide a new way to expand the genetic code.[18] Importantly, many modification enzymes are dysregulated and genetically mutated in many disease types.[1] For example, genetic mutations in pseudouridine synthases cause mitochondrial myopathy, sideroblastic anemia (MLASA) [19] and dyskeratosis congenital.[20]

RNA Modification DataBases

Name DescriptiontypeLinkReferences
RMBase RMBase is designed for decoding the landscape of RNA modifications identified from high-throughput sequencing data (Pseudo-seq, Ψ-seq, CeU-seq, Aza-IP, MeRIP-seq, m6A-seq, m6A-CLIP, RiboMeth-seq). It demonstrated thousands of RNA modifications located within mRNAs, regulatory ncRNAs (e.g. lncRNAs, miRNAs), miRNA target sites and disease-related SNPs.databasewebsite[21][22]
MODOMICS MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, RNA-modifying enzymes and location of modified residues in RNA sequences.databasewebsite[23]
RNAMDB RNAMDB has served as a focal point for information pertaining to naturally occurring RNA modificationsdatabasewebsite[24]
.

References

  1. 1 2 3 4 5 Li, S; Mason, CE (2013). "The pivotal regulatory landscape of RNA modifications". Annual Review of Genomics and Human Genetics. 15: 127–50. doi:10.1146/annurev-genom-090413-025405. PMID 24898039.
  2. 1 2 3 4 Song, CX; Yi, C; He, C (October 2012). "Mapping recently identified nucleotide variants in the genome and transcriptome". Nature Biotechnology. 30 (11): 1107–16. doi:10.1038/nbt.2398. PMC 3537840. PMID 23138310.
  3. 1 2 3 4 Meyer, KD; Jaffrey, SR (April 2014). "The dynamic epitranscriptome: N6-methyladenosine and gene expression control". Nature Reviews Molecular Cell Biology. 15 (5): 313–26. doi:10.1038/nrm3785. PMC 4393108. PMID 24713629.
  4. 1 2 3 4 Sun, WJ; Li, JH; Liu, S; Wu, J; Zhou, H; Qu, LH; Yang, JH (11 October 2015). "RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data". Nucleic Acids Research. 44: gkv1036. doi:10.1093/nar/gkv1036. PMC 4702777. PMID 26464443.
  5. ↑ Boccaletto, Pietro; Machnicka, Magdalena A; Purta, Elzbieta; Piątkowski, Paweł; Bagiński, Błażej; Wirecki, Tomasz K; de Crécy-Lagard, Valérie; Ross, Robert; Limbach, Patrick A (2017-11-02). "MODOMICS: a database of RNA modification pathways. 2017 update". Nucleic Acids Research. 46 (D1): D303–D307. doi:10.1093/nar/gkx1030. ISSN 0305-1048.
  6. ↑ "Accurate Mapping of tRNA Reads"; Anne Hoffmann et al.; Bioinformatics, btx756, https://doi.org/10.1093/bioinformatics/btx756
  7. ↑ Meyer, KD; Saletore, Y; Zumbo, P; Elemento, O; Mason, CE; Jaffrey, SR (21 June 2012). "Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons". Cell. 149 (7): 1635–46. doi:10.1016/j.cell.2012.05.003. PMC 3383396. PMID 22608085.
  8. ↑ Dominissini, D; Moshitch-Moshkovitz, S; Schwartz, S; Salmon-Divon, M; Ungar, L; Osenberg, S; Cesarkas, K; Jacob-Hirsch, J; Amariglio, N; Kupiec, M; Sorek, R; Rechavi, G (28 April 2012). "Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq". Nature. 485 (7397): 201–6. doi:10.1038/nature11112. PMID 22575960.
  9. ↑ Hussain, S.; Sajini, A. A.; Blanco, S.; Dietmann, S.; Lombard, P.; Sugimot, Y.; et al. (2013). "NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs". Cell Rep. 4: 255–261. doi:10.1016/j.celrep.2013.06.029;.
  10. 1 2 Ke, S; Alemu, EA; Mertens, C; Gantman, EC; Fak, JJ; Mele, A; Haripal, B; Zucker-Scharff, I; Moore, MJ; Park, CY; Vågbø, CB; Kusnierczyk, A; Klungland, A; Darnell, JE; Darnell, RB (24 September 2015). "A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation". Genes & Development. 29 (19): 2037–53. doi:10.1101/gad.269415.115. PMC 4604345. PMID 26404942.
  11. ↑ Carlile, TM; Rojas-Duran, MF; Zinshteyn, B; Shin, H; Bartoli, KM; Gilbert, WV (5 November 2014). "Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells". Nature. 515 (7525): 143–6. doi:10.1038/nature13802. PMC 4224642. PMID 25192136.
  12. ↑ Schwartz, S; Bernstein, DA; Mumbach, MR; Jovanovic, M; Herbst, RH; León-Ricardo, BX; Engreitz, JM; Guttman, M; Satija, R; Lander, ES; Fink, G; Regev, A (24 September 2014). "Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA". Cell. 159 (1): 148–62. doi:10.1016/j.cell.2014.08.028. PMC 4180118. PMID 25219674.
  13. ↑ Li, X; Zhu, P; Ma, S; Song, J; Bai, J; Sun, F; Yi, C (July 2015). "Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome". Nature Chemical Biology. 11 (8): 592–7. doi:10.1038/nchembio.1836. PMID 26075521.
  14. ↑ Khoddami, V; Cairns, BR (April 2013). "Identification of direct targets and modified bases of RNA cytosine methyltransferases". Nature Biotechnology. 31 (5): 458–64. doi:10.1038/nbt.2566. PMC 3791587. PMID 23604283.
  15. ↑ Birkedal, U; Christensen-Dalsgaard, M; Krogh, N; Sabarinathan, R; Gorodkin, J; Nielsen, H (6 January 2015). "Profiling of ribose methylations in RNA by high-throughput sequencing". Angewandte Chemie International Edition in English. 54 (2): 451–5. doi:10.1002/anie.201408362. PMID 25417815.
  16. ↑ Wang, X; Lu, Z; Gomez, A; Hon, GC; Yue, Y; Han, D; Fu, Y; Parisien, M; Dai, Q; Jia, G; Ren, B; Pan, T; He, C (1 January 2014). "N6-methyladenosine-dependent regulation of messenger RNA stability". Nature. 505 (7481): 117–20. doi:10.1038/nature12730. PMC 3877715. PMID 24284625.
  17. ↑ Geula, S; Moshitch-Moshkovitz, S; Dominissini, D; Mansour, AA; Kol, N; Salmon-Divon, M; Hershkovitz, V; Peer, E; Mor, N; Manor, YS; Ben-Haim, MS; Eyal, E; Yunger, S; Pinto, Y; Jaitin, DA; Viukov, S; Rais, Y; Krupalnik, V; Chomsky, E; Zerbib, M; Maza, I; Rechavi, Y; Massarwa, R; Hanna, S; Amit, I; Levanon, EY; Amariglio, N; Stern-Ginossar, N; Novershtern, N; Rechavi, G; Hanna, JH (26 February 2015). "Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation". Science. 347 (6225): 1002–6. doi:10.1126/science.1261417. PMID 25569111.
  18. ↑ Karijolich, J; Yu, YT (14 June 2011). "Converting nonsense codons into sense codons by targeted pseudouridylation". Nature. 474 (7351): 395–8. doi:10.1038/nature10165. PMC 3381908. PMID 21677757.
  19. ↑ Bykhovskaya, Y; Casas, K; Mengesha, E; Inbal, A; Fischel-Ghodsian, N (May 2004). "Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)". American Journal of Human Genetics. 74 (6): 1303–8. doi:10.1086/421530. PMC 1182096. PMID 15108122.
  20. ↑ Heiss, NS; Knight, SW; Vulliamy, TJ; Klauck, SM; Wiemann, S; Mason, PJ; Poustka, A; Dokal, I (April 1998). "X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions". Nature Genetics. 19 (1): 32–8. doi:10.1038/ng0598-32. PMID 9590285.
  21. ↑ Xuan, JJ; Sun, WJ; Lin, PH; Zhou, KR; Liu, S; Zheng, LL; Qu, LH; Yang, JH (4 January 2018). "RMBase v2.0: deciphering the map of RNA modifications from epitranscriptome sequencing data". Nucleic Acids Research. 46 (D1): D327–D334. doi:10.1093/nar/gkx934. PMID 29040692.
  22. ↑ Sun, WJ; Li, JH; Liu, S; Wu, J; Zhou, H; Qu, LH; Yang, JH (4 January 2016). "RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data". Nucleic Acids Research. 44 (D1): D259–65. doi:10.1093/nar/gkv1036. PMID 26464443.
  23. ↑ Machnicka, MA; Milanowska, K; Osman Oglou, O; Purta, E; Kurkowska, M; Olchowik, A; Januszewski, W; Kalinowski, S; Dunin-Horkawicz, S; Rother, KM; Helm, M; Bujnicki, JM; Grosjean, H (December 2012). "MODOMICS: a database of RNA modification pathways--2013 update". Nucleic Acids Research. 41 (Database issue): D262–7. doi:10.1093/nar/gks1007. PMC 3531130. PMID 23118484.
  24. ↑ Cantara, WA; Crain, PF; Rozenski, J; McCloskey, JA; Harris, KA; Zhang, X; Vendeix, FA; Fabris, D; Agris, PF (December 2010). "The RNA Modification Database, RNAMDB: 2011 update". Nucleic Acids Research. 39 (Database issue): D195–201. doi:10.1093/nar/gkq1028. PMC 3013656. PMID 21071406.
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