Adan, A. | bioRxiv Science

bioRxiv2020

Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that have been found in more than 200 diverse organisms. Although it is still not fully established if RNA viruses could generate miRNAs that would target their own genes or alter the host gene expression, there are examples of miRNAs functioning as an antiviral defense mechanism. In the case of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there are several mechanisms that would make miRNAs impact the virus, like interfering with replication, translation and even modulating the host expression. In this study, we performed a machine learning based miRNA prediction analysis for the SARS-CoV-2 genome to identify miRNA-like hairpins and searched for potential miRNA - based interactions between the viral miRNAs and human genes and human miRNAs and viral genes. Our PANTHER gene function analysis results indicate that viral derived miRNA candidates could target various human genes involved in crucial cellular processes including transcription. For instance, a transcriptional regulator, STAT1 and transcription machinery might be targeted by virus-derived miRNAs. In addition, many known human miRNAs appear to be able to target viral genes. Considering the fact that miRNA-based therapies have been successful before, comprehending mode of actions of miRNAs and their possible roles during SARS-CoV-2 infections could create new opportunities for the development and improvement of new therapeutics.

bioinformatics↗

bioRxiv2018

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis.

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed \"MHC-I-opathy\" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n=360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: OR[95% CI]=2.07[1.58-2.71], p=1.24 x 10(-7)) and rs2287987 (OR[95% CI]: =2.01 [1.51-2.67], p=1.41 x 10(-6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 x 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

genetics↗