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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 gender dependencies.[2][3]

There are four main variation types:

  • 5' trimming—the 5' dicing site is upstream or downstream from the reference miRNA sequence
  • 3' trimming—the 3' dicing site is upstream or downstream from the reference miRNA sequence
  • 3' nucleotide addition—nucleotides added to the 3' end of the reference miRNA
  • nucleotide substitution—nucleotides changes from the miRNA precursor. It is thought that may be similar process than post-transcriptional modifications.


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,[4][2][5] or even lead to opposite changes in mRNA expression.[2]


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 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, isomiRs have been detected deregulated in D. melanogaster development and differential expressed during Hippoglossus hippoglossus L. early development, suggesting a biologically relevant function.[15][19]

  • Trimming variants: these are possible due to slight variations by Drosha and/or Dicer
  • Nucleotide addition: Wyman et al.[20] have described the process of nucleotide transferases adding individual nucleotides to miRNA sequences
  • Nucleotide substitution: there is a huge range of possible changes in such an event, some of them can be explained by current Adenosine_deaminase like A to G or C to U, in a similar way to what happens in post-transcriptional RNA editing events involving mRNA.


  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. ^ a b c 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.
  3. ^ 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
  4. ^ 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.
  5. ^ Mercey, Olivier; Popa, Alexandra; Cavard, Amélie; Paquet, Agnès; Chevalier, Benoît; Pons, Nicolas; Magnone, Virginie; Zangari, Joséphine; Brest, Patrick (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. ^ a b 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. ^ a b 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". Cell. 128 (6): 1089–1103. doi:10.1016/j.cell.2007.01.043. PMID 17346786.
  15. ^ a b 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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