IsomiR

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Variations from the reference sequence found in isomiRs Isomirs.jpg
Variations from the reference sequence found in isomiRs

isomiRs (from iso- + miR) are miRNA sequences that have variations with respect to the reference sequence. The term was coined by Morin et al in 2008. [1] It has been found that isomiR expression profiles can also exhibit race, population, and sex dependencies. [2]

Contents

There are four main variation types:

Discovery

miRBase is considered to be the gold-standard miRNA database—it stores miRNA sequences detected by thousand of experiments. In this database each miRNA is associated with a miRNA precursor and with one or two mature miRNA (-5p and -3p). In the past it had always been said that the same miRNA precursor generates the same miRNA sequences. However, the advent of deep sequencing has now allowed researchers to detect a huge variability in miRNA biogenesis, meaning that from the same miRNA precursor many different sequences can be generated potentially have different targets, [3] [4] [5] or even lead to opposite changes in mRNA expression. [4]

Biogenesis

The advent of sequencing has permitted scientists to elucidate a huge landscape of new miRNAs, to increase our knowledge of the biogenesis involved and to discover putative post-transcriptional editing processes in miRNAs ignored until now. These processes mostly generate variations of the current miRNAs that are annotated in miRBase in the 3' and 5' terminus and in minor frequencies, nucleotide substitution along the miRNA length. [6] [7] [8] [9] The variations are mainly generated by a shift of Drosha and Dicer in the cleavage site, but also by nucleotide additions at the 3'-end, [10] resulting in new sequences different from the annotated miRNA. These were named "isomiRs" by Morin et al., 2008. IsomiRs have been well established along different species in metazoa [11] [12] [13] [14] [15] and deeply described for the first time in human stem cells and human brain samples. [8] [9] Moreover, it has been proven that isomiRs are not caused by RNA degradation during sample preparation for next generation sequencing. [16] Some studies have tried to explain the miRNA diversity by structural bases of precursors but without clear results. [17] The functionality of adenylation or uridynilation at the 3'end (3'addition isomiRs) has been related to alterations in the miRNA-3'-UTR stability. [18] Furthermore, differential expression of isomiRs has been detected during development in D. melanogaster and Hippoglossus hippoglossus L., suggesting a biological function. [15] [19]

Related Research Articles

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An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. In RNA splicing, introns are removed and exons are covalently joined to one another as part of generating the mature RNA. Just as the entire set of genes for a species constitutes the genome, the entire set of exons constitutes the exome.

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<span class="mw-page-title-main">Post-transcriptional modification</span> RNA processing within a biological cell

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References

  1. ↑ Morin, R. D.; O'Connor, M. D.; Griffith, M.; Kuchenbauer, F.; Delaney, A.; Prabhu, A. -L.; Zhao, Y.; McDonald, H.; Zeng, T.; Hirst, M.; Eaves, C. J.; Marra, M. A. (2008). "Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells". Genome Research. 18 (4): 610–621. doi:10.1101/gr.7179508. PMC   2279248 . PMID   18285502.
  2. ↑ Loher P, Londin ER, Rigoutsos I (2014), "IsomiR Expression Profiles in Human Lymphoblastoid Cell Lines Exhibit Population and Gender Dependencies.", Oncotarget, 5 (18): 8790–802, doi:10.18632/oncotarget.2405, PMC   4226722 , PMID   25229428
  3. ↑ Llorens, Franc; Bañez-Coronel, Mónica; Pantano, Lorena; del Río, Jose Antonio; Ferrer, Isidre; Estivill, Xavier; Martí, Eulàlia (2013-02-15). "A highly expressed miR-101 isomiR is a functional silencing small RNA". BMC Genomics. 14: 104. doi: 10.1186/1471-2164-14-104 . ISSN   1471-2164. PMC   3751341 . PMID   23414127.
  4. 1 2 Telonis, Aristeidis G.; Loher, Phillipe; Jing, Yi; Londin, Eric; Rigoutsos, Isidore (2015-10-30). "Beyond the one-locus-one-miRNA paradigm: microRNA isoforms enable deeper insights into breast cancer heterogeneity". Nucleic Acids Research. 43 (19): 9158–9175. doi:10.1093/nar/gkv922. ISSN   1362-4962. PMC   4627084 . PMID   26400174.
  5. ↑ Mercey, Olivier; Popa, Alexandra; Cavard, Amélie; Paquet, Agnès; Chevalier, Benoît; Pons, Nicolas; Magnone, Virginie; Zangari, Joséphine; Brest, Patrick; Zaragosi, Laure-Emmanuelle; Ponzio, Gilles; Lebrigand, Kevin; Barbry, Pascal; Marcet, Brice (2017-02-13). "Characterizing isomiR variants within the microRNA-34/449 family". FEBS Letters. 591 (5): 693–705. doi:10.1002/1873-3468.12595. ISSN   1873-3468. PMC   5363356 . PMID   28192603.
  6. ↑ Ebhardt, H. A.; Tsang, H. H.; Dai, D. C.; Liu, Y.; Bostan, B.; Fahlman, R. P. (2009). "Meta-analysis of small RNA-sequencing errors reveals ubiquitous post-transcriptional RNA modifications". Nucleic Acids Research. 37 (8): 2461–2470. doi:10.1093/nar/gkp093. PMC   2677864 . PMID   19255090.
  7. ↑ Iida, K.; Jin, H.; Zhu, J. K. (2009). "Bioinformatics analysis suggests base modifications of tRNAs and miRNAs in Arabidopsis thaliana". BMC Genomics. 10: 155. doi: 10.1186/1471-2164-10-155 . PMC   2674459 . PMID   19358740.
  8. 1 2 Pantano, L.; Estivill, X.; Marti, E. (2009). "SeqBuster, a bioinformatic tool for the processing and analysis of small RNAs datasets, reveals ubiquitous miRNA modifications in human embryonic cells". Nucleic Acids Research. 38 (5): e34. doi:10.1093/nar/gkp1127. PMC   2836562 . PMID   20008100.
  9. 1 2 Marti, E.; Pantano, L.; Bañez-Coronel, M.; Llorens, F.; Miñones-Moyano, E.; Porta, S.; Sumoy, L.; Ferrer, I.; Estivill, X. (2010). "A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing". Nucleic Acids Research. 38 (20): 7219–7235. doi:10.1093/nar/gkq575. PMC   2978354 . PMID   20591823.
  10. ↑ Lu, S.; Sun, Y. -H.; Chiang, V. L. (2009). "Adenylation of plant miRNAs". Nucleic Acids Research. 37 (6): 1878–1885. doi:10.1093/nar/gkp031. PMC   2665221 . PMID   19188256.
  11. ↑ Reid, J. G.; Nagaraja, A. K.; Lynn, F. C.; Drabek, R. B.; Muzny, D. M.; Shaw, C. A.; Weiss, M. K.; Naghavi, A. O.; Khan, M.; Zhu, H.; Tennakoon, J.; Gunaratne, G. H.; Corry, D. B.; Miller, J.; McManus, M. T.; German, M. S.; Gibbs, R. A.; Matzuk, M. M.; Gunaratne, P. H. (2008). "Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5′-seed/ cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes". Genome Research. 18 (10): 1571–1581. doi:10.1101/gr.078246.108. PMC   2556275 . PMID   18614752.
  12. ↑ Luciano, D. J.; Mirsky, H.; Vendetti, N. J.; Maas, S. (2004). "RNA editing of a miRNA precursor". RNA. 10 (8): 1174–1177. doi:10.1261/rna.7350304. PMC   1370607 . PMID   15272117.
  13. ↑ Guo, L.; Lu, Z. (2010). "Global expression analysis of miRNA gene cluster and family based on isomiRs from deep sequencing data". Computational Biology and Chemistry. 34 (3): 165–171. doi:10.1016/j.compbiolchem.2010.06.001. PMID   20619743.
  14. ↑ Brennecke, J.; Aravin, A. A.; Stark, A.; Dus, M.; Kellis, M.; Sachidanandam, R.; Hannon, G. J. (2007). "Discrete Small RNA-Generating Loci as Master Regulators of Transposon Activity in Drosophila" (PDF). Cell. 128 (6): 1089–1103. doi: 10.1016/j.cell.2007.01.043 . PMID   17346786. S2CID   2246942.
  15. 1 2 Bizuayehu, T. T.; Lanes, C. F. C.; Furmanek, T.; Karlsen, B. O.; Fernandes, J. M. O.; Johansen, S. D.; Babiak, I. (2012). "Differential expression patterns of conserved miRNAs and isomiRs during Atlantic halibut development". BMC Genomics. 13: 11. doi: 10.1186/1471-2164-13-11 . PMC   3398304 . PMID   22233483.
  16. ↑ Lee, L. W.; Zhang, S.; Etheridge, A.; Ma, L.; Martin, D.; Galas, D.; Wang, K. (2010). "Complexity of the microRNA repertoire revealed by next-generation sequencing". RNA. 16 (11): 2170–2180. doi:10.1261/rna.2225110. PMC   2957056 . PMID   20876832.
  17. ↑ Starega-Roslan, J.; Krol, J.; Koscianska, E.; Kozlowski, P.; Szlachcic, W. J.; Sobczak, K.; Krzyzosiak, W. J. (2010). "Structural basis of microRNA length variety". Nucleic Acids Research. 39 (1): 257–268. doi:10.1093/nar/gkq727. PMC   3017592 . PMID   20739353.
  18. ↑ Burroughs, A. M.; Ando, Y.; De Hoon, M. J. L.; Tomaru, Y.; Nishibu, T.; Ukekawa, R.; Funakoshi, T.; Kurokawa, T.; Suzuki, H.; Hayashizaki, Y.; Daub, C. O. (2010). "A comprehensive survey of 3′ animal miRNA modification events and a possible role for 3′ adenylation in modulating miRNA targeting effectiveness". Genome Research. 20 (10): 1398–1410. doi:10.1101/gr.106054.110. PMC   2945189 . PMID   20719920.
  19. ↑ Fernandez-Valverde, S. L.; Taft, R. J.; Mattick, J. S. (2010). "Dynamic isomiR regulation in Drosophila development". RNA. 16 (10): 1881–1888. doi:10.1261/rna.2379610. PMC   2941097 . PMID   20805289.
  20. ↑ Wyman, S. K.; Knouf, E. C.; Parkin, R. K.; Fritz, B. R.; Lin, D. W.; Dennis, L. M.; Krouse, M. A.; Webster, P. J.; Tewari, M. (2011). "Post-transcriptional generation of miRNA variants by multiple nucleotidyl transferases contributes to miRNA transcriptome complexity". Genome Research. 21 (9): 1450–1461. doi:10.1101/gr.118059.110. PMC   3166830 . PMID   21813625.
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