Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection

Sci Rep. 2016 Sep 2:6:32348. doi: 10.1038/srep32348.

Abstract

Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu's H < -20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements*
  • Cell Survival
  • Exonucleases / genetics
  • Exonucleases / metabolism
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • HeLa Cells
  • Heat-Shock Response / genetics*
  • Hot Temperature
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Nuclear Receptor Subfamily 2, Group C, Member 1 / genetics
  • Nuclear Receptor Subfamily 2, Group C, Member 1 / metabolism
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Selection, Genetic
  • Signal Transduction
  • Stress, Physiological / genetics*
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism
  • Transcriptome*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism

Substances

  • FKBP9 protein, human
  • GTSE1 protein, human
  • MIRN15 microRNA, human
  • MicroRNAs
  • Microtubule-Associated Proteins
  • NR2C1 protein, human
  • Nuclear Receptor Subfamily 2, Group C, Member 1
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Ubiquitin-Conjugating Enzymes
  • Exonucleases
  • Rad1 protein, human
  • Tacrolimus Binding Proteins
  • ubiquitin-conjugating enzyme UBC9