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

RNA Modification Technologies

To determine the transcriptome-wide landscape of RNA modifications, recently many studies have developed high-throughput modification sequencing methods to identify diverse post-transcriptional modifications of RNA molecules.[1][2][3] Application of these methods (MeRIP-seq,[5] m6A-seq,[6] methylation-iCLIP,[7] m6A-CLIP,[8] Pseudo-seq,[9] Ψ-seq,[10] CeU-seq,[11] Aza-IP,[12] RiboMeth-seq[13]) has identified various modifications (e.g. pseudouridine, m6A, m5C, 2′-O-Me) within coding genes and non-coding genes (e.g. 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,[14] alternative polyA choice [8] and stem cell pluripotency.[15] 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.[16] 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) [17] and dyskeratosis congenital.[18]

RNA Modification DataBases

Name Description type Link References
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. database website [4]
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. database website [19]
RNAMDB RNAMDB has served as a focal point for information pertaining to naturally occurring RNA modifications database website [20]
.

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. PMID 24898039. doi:10.1146/annurev-genom-090413-025405.
  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. PMC 3537840 Freely accessible. PMID 23138310. doi:10.1038/nbt.2398.
  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. PMC 4393108 Freely accessible. PMID 24713629. doi:10.1038/nrm3785.
  4. 1 2 3 4 5 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. PMC 4702777 Freely accessible. PMID 26464443. doi:10.1093/nar/gkv1036.
  5. ↑ 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. PMC 3383396 Freely accessible. PMID 22608085. doi:10.1016/j.cell.2012.05.003.
  6. ↑ 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. PMID 22575960. doi:10.1038/nature11112.
  7. ↑ 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;.
  8. 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. PMC 4604345 Freely accessible. PMID 26404942. doi:10.1101/gad.269415.115.
  9. ↑ 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. PMC 4224642 Freely accessible. PMID 25192136. doi:10.1038/nature13802.
  10. ↑ 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. PMC 4180118 Freely accessible. PMID 25219674. doi:10.1016/j.cell.2014.08.028.
  11. ↑ 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. PMID 26075521. doi:10.1038/nchembio.1836.
  12. ↑ Khoddami, V; Cairns, BR (April 2013). "Identification of direct targets and modified bases of RNA cytosine methyltransferases.". Nature Biotechnology. 31 (5): 458–64. PMC 3791587 Freely accessible. PMID 23604283. doi:10.1038/nbt.2566.
  13. ↑ 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. PMID 25417815. doi:10.1002/anie.201408362.
  14. ↑ 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. PMC 3877715 Freely accessible. PMID 24284625. doi:10.1038/nature12730.
  15. ↑ 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. PMID 25569111. doi:10.1126/science.1261417.
  16. ↑ Karijolich, J; Yu, YT (14 June 2011). "Converting nonsense codons into sense codons by targeted pseudouridylation.". Nature. 474 (7351): 395–8. PMC 3381908 Freely accessible. PMID 21677757. doi:10.1038/nature10165.
  17. ↑ 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. PMC 1182096 Freely accessible. PMID 15108122. doi:10.1086/421530.
  18. ↑ 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. PMID 9590285. doi:10.1038/ng0598-32.
  19. ↑ 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. PMC 3531130 Freely accessible. PMID 23118484. doi:10.1093/nar/gks1007.
  20. ↑ 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. PMC 3013656 Freely accessible. PMID 21071406. doi:10.1093/nar/gkq1028.
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