caa a22 4500 606176462 CHVBK 20210128100747.0 cr unu---uuuuu 210128e20150701xx s 000 0 eng 10.1007/s00018-015-1875-5 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1875-5 Interferon-alpha competing endogenous RNA network antagonizes microRNA-1270 [Elektronische Daten] [Tominori Kimura, Shiwen Jiang, Noriyuki Yoshida, Ryou Sakamoto, Mikio Nishizawa] A new form of circuitry for gene regulation has been identified in which RNAs can crosstalk by competing for shared microRNAs (miRNAs). Such competing endogenous RNAs (ceRNAs) form a network via shared miRNA response elements (MREs) to antagonize miRNA function. We previously reported natural antisense RNA (AS) as an important modulator of interferon-α1 (IFN-α1) mRNA levels by promoting IFN-α1 mRNA stability. We show that IFN-α1 AS forms a ceRNA network with specific IFN-α AS (IFN-α7/-α8/-α10/-α14) and mRNA (IFN-α8/-α10/-α14/-α17) subtypes from the IFN-α gene (IFNA) family to antagonize miRNA-1270 (miR-1270), thereby modulating IFN-α1 mRNA levels. Bioinformatic analysis demonstrated that IFN-α1 AS harbors multiple miR-1270 MREs (MRE-1270s), whose presence was substantiated by miR-1270 overexpression and transfection of antimiR-1270. The antimiR-1270, complementary to the miR-1270 seed region, revealed that IFN-α1 AS likely shares the MRE-1270 with IFN-α1 mRNA and specific IFN-α AS and mRNA subtypes. Subsequent bioinformatic analysis for MRE-1270s showed that IFN-α1 AS and other RNA subtypes shared the 6-mer MRE-1270 site. Further MRE-mapping demonstrated that the total number of MRE-1270s in IFN-α1 AS accounted for approximately 30% of the miR-1270 population. AntimiR-1270 transfection also caused specific de-repression of five cellular mRNAs, including that of CAPRIN1. These results suggest that IFN-α1 AS, together with specific IFN-α AS and mRNA subtypes, as well as the five cellular mRNAs, participate as competing molecules in the ceRNA network against miR-1270. This coordinated regulatory architecture suggests a vital function for the innate immune system in maintaining precise physiological type I IFN levels via post-transcriptional regulatory mechanisms. The Author(s), 2015 Non-coding RNA nationallicence Regulatory RNA network nationallicence Competing endogenous RNA nationallicence Natural antisense RNA nationallicence Mechanisms of action nationallicence miRNA : microRNA nationallicence miR-1270 : miRNA-1270 nationallicence ceRNA : Competing endogenous RNA nationallicence MRE : miRNA response element nationallicence AS : Antisense RNA nationallicence IFN-α1 : Interferon-α1 nationallicence IFNA : Interferon-α gene nationallicence MRE-1270 : miR-1270 response element nationallicence ncRNA : Non-coding RNA nationallicence NAT : Natural antisense transcript nationallicence BSL : Bulged-stem loop nationallicence 3′-untranslated region : 3′-UTR nationallicence lncRNA : Long non-coding RNA nationallicence ARE : AU-rich element nationallicence HuR : Human antigen R nationallicence HIF1A : Hypoxia-induced factor 1α nationallicence SeV : Sendai virus nationallicence R : Revertant nationallicence DS : Downstream fragment of IFNA1 3′ UTR nationallicence DSR : Antisense fragment downstream of IFNA1 3′ UTR nationallicence PCR : Polymerase chain reaction nationallicence LNA : Locked nucleic acid nationallicence RT-qPCR : Reverse-transcription quantitative polymerase chain reaction nationallicence Ct : Cycle threshold nationallicence CSS : Conserved secondary structure nationallicence SL : Stem loop nationallicence TLR : Toll-like receptor nationallicence Luc : Luciferase nationallicence CAPRIN1 : Cell cycle-associated protein 1, transcript variant 1 nationallicence CTSE : Cathepsin E (CTSE) transcript variant 1 nationallicence GLI2 : GLI family zinc finger 2 nationallicence KRT40 : Keratin 40 nationallicence LYZ : Lysozyme nationallicence MARCH5 : Membrane-associated ring finger (C3HC4) 5 nationallicence OTUD3 : OTU deubiquitinase 3 nationallicence RASAL2 : RAS protein activator-like 2, transcript variant 2 nationallicence TC2N : Tandem C2 domains, nuclear, transcript variant 1 nationallicence PI3K : Phosphatidylinositol-3 kinase nationallicence Mnk : Mitogen-activated protein kinase-integrating kinase 1 nationallicence Kimura Tominori Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut Jiang Shiwen Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut Yoshida Noriyuki Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut Sakamoto Ryou Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut Nishizawa Mikio Department of Biomedical Sciences, Laboratory of Medical Chemistry, College of Life Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut Cellular and Molecular Life Sciences Springer Basel 72/14(2015-07-01), 2749-2761 1420-682X 72:14<2749 2015 72 18 https://doi.org/10.1007/s00018-015-1875-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1875-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kimura Tominori Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut NATIONALLICENCE 700 1- Jiang Shiwen Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut NATIONALLICENCE 700 1- Yoshida Noriyuki Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut NATIONALLICENCE 700 1- Sakamoto Ryou Department of Pharmacy, Laboratory of Microbiology and Cell Biology, College of Pharmaceutical Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut NATIONALLICENCE 700 1- Nishizawa Mikio Department of Biomedical Sciences, Laboratory of Medical Chemistry, College of Life Sciences, Ritsumeikan University, 525-8577, Kusatsu, Shiga, Japan aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/14(2015-07-01), 2749-2761 1420-682X 72:14<2749 2015 72 18