Journal Article

A highly expressed miR-101 isomiR is a functional silencing small RNA

del Río, Jose Antonio, Ferrer, Isidre, Martí, Eulàlia, Bañez-Coronel, Mónica, Llorens, Franc, Pantano, Lorena, Estivill, Xavier

2013

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Amyloid beta-Protein Precursor - deficiency / Amyloid beta-Protein Precursor - genetics / Animal Genetics and Genomics / Argonaute Proteins - metabolism / Binding sites / Biomedical and Life Sciences / Biomedical research / Brain / Cell Line / Correlation analysis / Cyclooxygenase 2 - deficiency / Cyclooxygenase 2 - genetics / DEAD-box RNA Helicases - metabolism / Disease / Dual Specificity Phosphatase 1 - deficiency / Dual Specificity Phosphatase 1 - genetics / Enhancer of Zeste Homolog 2 Protein / Expressió gènica / Gene expression / Gene Expression Regulation - genetics / Gene Silencing / Genomics / Health aspects / Heterogeneity / Humans / Life Sciences / Microarrays / Microbial Genetics and Genomics / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Myeloid Cell Leukemia Sequence 1 Protein / Physiological aspects / Plant Genetics and Genomics / Polycomb Repressive Complex 2 - deficiency / Polycomb Repressive Complex 2 - genetics / Proteomics / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-bcl-2 - deficiency / Proto-Oncogene Proteins c-bcl-2 - genetics / Regulation / Research Article / RNA / RNA Isoforms - genetics / RNA Isoforms - metabolism / RNA sequencing / Software / Statistical methods / Studies / Transcriptomics