Integrated mRNA-microRNA profiling of human NK cell differentiation identifies MiR-583 as a negative regulator of IL2Rγ expression

PLoS One. 2014 Oct 14;9(10):e108913. doi: 10.1371/journal.pone.0108913. eCollection 2014.

Abstract

Natural killer (NK) cells are innate immune effector cells that protect against cancer and some viral infections. Until recently, most studies have investigated the molecular signatures of human or mouse NK cells to identify genes that are specifically expressed during NK cell development. However, the mechanism regulating NK cell development remains unclear. Here, we report a regulatory network of potential interactions during in vitro differentiation of human NK cells, identified using genome-wide mRNA and miRNA databases through hierarchical clustering analysis, gene ontology analysis and a miRNA target prediction program. The microRNA (miR)-583, which demonstrated the largest ratio change in mature NK cells, was highly correlated with IL2 receptor gamma (IL2Rγ) expression. The overexpression of miR-583 had an inhibitory effect on NK cell differentiation. In a reporter assay, the suppressive effect of miR-583 was ablated by mutating the putative miR-583 binding site of the IL2Rγ 3' UTR. Therefore, we show that miR-583 acts as a negative regulator of NK cell differentiation by silencing IL2Rγ. Additionally, we provide a comprehensive database of genome-wide mRNA and miRNA expression during human NK cell differentiation, offering a better understanding of basic human NK cell biology for the application of human NK cells in immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Base Sequence
  • Binding Sites
  • Cell Differentiation*
  • Cells, Cultured
  • Cluster Analysis
  • Databases, Genetic
  • Down-Regulation*
  • Fetal Blood / cytology
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Humans
  • Interleukin Receptor Common gamma Subunit / antagonists & inhibitors
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / metabolism*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA Interference
  • RNA, Messenger / metabolism*
  • Sequence Alignment

Substances

  • 3' Untranslated Regions
  • Interleukin Receptor Common gamma Subunit
  • MicroRNAs
  • RNA, Messenger

Grants and funding

This work was supported in part by grants from the GRL project (FGM1401223), the Ministry of Science, ICT & Future Planning, KRIBB Research Initiative Program, the Korean Health Technology R&D Project (A121934), and Basic Science Research Program through the National Research Foundation of Korea (RBM0261312). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.