title: A highly expressed miR-101 isomiR is a functional silencing small RNA.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression usually producing translational repression and gene silencing. High-throughput sequencing technologies have revealed heterogeneity at length and sequence level for the majority of mature miRNAs (IsomiRs). Most isomiRs can be explained by variability in either Dicer1 or Drosha cleavage during miRNA biogenesis at 5' or 3' of the miRNA (trimming variants). Although isomiRs have been described in different tissues and organisms, their functional validation as modulators of gene expression remains elusive. Here we have characterized the expression and function of a highly abundant miR-101 5'-trimming variant (5'-isomiR-101).
  
  
  RESULTS
  The analysis of small RNA sequencing data in several human tissues and cell lines indicates that 5'-isomiR-101 is ubiquitously detected and a highly abundant, especially in the brain. 5'-isomiR-101 was found in Ago-2 immunocomplexes and complementary approaches showed that 5'-isomiR-101 interacted with different members of the silencing (RISC) complex. In addition, 5'-isomiR-101 decreased the expression of five validated miR-101 targets, suggesting that it is a functional variant. Both the binding to RISC members and the degree of silencing were less efficient for 5'-isomiR-101 compared with miR-101. For some targets, both miR-101 and 5'-isomiR-101 significantly decreased protein expression with no changes in the respective mRNA levels. Although a high number of overlapping predicted targets suggest similar targeted biological pathways, a correlation analysis of the expression profiles of miR-101 variants and predicted mRNA targets in human brains at different ages, suggest specific functions for miR-101- and 5'-isomiR-101.
  
  
  CONCLUSIONS
  These results suggest that isomiRs are functional variants and further indicate that for a given miRNA, the different isomiRs may contribute to the overall effect as quantitative and qualitative fine-tuners of gene expression.
authors: Molecular and Cellular Neurobiotechnology Group, Institut de Bioenginyeria de Catalunya, Parc Científic de Barcelona, Barcelona, Spain.
authors: Franc
authors: F
authors: Llorens
authors: Mónica
authors: M
authors: Bañez-Coronel
authors: Lorena
authors: L
authors: Pantano
authors: Jose Antonio
authors: JA
authors: del Río
authors: Isidre
authors: I
authors: Ferrer
authors: Xavier
authors: X
authors: Estivill
authors: Eulàlia
authors: E
authors: Martí
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics; D060565:Argonaute Proteins / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics; D059368:RNA Isoforms / Q000235:genetics* / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D060565:Argonaute Proteins; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D059368:RNA Isoforms; D051546:Cyclooxygenase 2; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases