RESEARCH ARTICLE Interferon-alpha competing endogenous RNA network antagonizes microRNA-1270

Abstract A new form of circuitry for gene regulation has been identified in which RNAs can crosstalk by competing for shared microRNAs (miRNAs). Such competing en-dogenous 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-a1 (IFN-a1) mRNA levels by promoting IFN-a1 mRNA stability. We show that IFN-a1 AS forms a ceRNA network with specific IFN-a AS (IFN-a7/-a8/-a10/-a14) and mRNA (IFN-a8/-a10/-a14/-a17) subtypes from the IFN-a gene (IFNA) family to antagonize miRNA-1270 (miR-1270), thereby modulating IFN-a1 mRNA levels. Bioinformatic analysis demonstrated that IFN-a1 AS harbors multiple miR-1270 MREs (MRE-1270s), whose presence was sub-stantiated by miR-1270 overexpression and transfection of antimiR-1270. The antimiR-1270, complementary to the miR-1270 seed region, revealed that IFN-a1 AS likely shares the MRE-1270 with IFN-a1 mRNA and specific IFN-a AS and mRNA subtypes. Subsequent bioinformatic analysis for MRE-1270s showed that IFN-a1 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-a1 AS accounted for approximately 30 % of the miR-1270 population. AntimiR-1270 trans-fection also caused specific de-repression of five cellular mRNAs, including that of CAPRIN1. These results suggest that IFN-a1 AS, together with specific IFN-a 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