MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components.
We studied 613 genes which regulate immunity and, utilizing predictive algorithms, identified 285 genes as microRNA (miRNA or miR) targets. Of these, approximately 250 are newly predicted gene-miR interactions. The frequency of predicted miRNA binding sites in immune gene 3'UTRs indicated preferential targeting of immune genes compared to the genome. Major targets include transcription factors, cofactors and chromatin modifiers whereas upstream factors, such as ligands and receptors (cytokines, chemokines and TLRs), were, in general, non-targets. About 10% of the immune genes were 'hubs' with eight or more different miRNAs predicted to target their 3'UTRs. Hubs were focused on certain key immune genes, such as BCL6, SMAD7, BLIMP1, NFAT5, EP300 and others. NF-kappaB and p53 do not themselves have binding sites for miRNAs but rather these pathways are targeted by miRNAs at downstream sites. MHC class II genes lacked miRNA targets but binding sites were identified in the CIITA gene and were shown experimentally to repress IFN-gamma-induced MHC class II activation. Unexpectedly, factors involved in regulating message stability via AU-rich elements (ARE) were heavily targeted. Moreover, multiple components involved in the generation and effector functions of miRNAs (Dicer and Argonautes) were themselves miRNA targets suggesting that a subset of miRNAs may indirectly control their own production as well as other miRNAs.
Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Ananthi J
AJ
Asirvatham
Christopher J
CJ
Gregorie
Zihua
Z
Hu
William J
WJ
Magner
Thomas B
TB
Tomasi
D002454:Cell Differentiation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015894:Genome, Human; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D035683:MicroRNAs / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000235:genetics*; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*; D015203:Reproducibility of Results; D043244:Ribonuclease III / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D002843:Chromatin; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D035683:MicroRNAs; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D043244:Ribonuclease III