Whole lung transcriptomics of a house dust mite model of mild/moderate asthma

Purpose: Identify whole lung gene expression patterns in a house dust mite model of mild/moderate asthma Methods: Lung gene expression profiles of 10 week old BALB/c female mice were generated by ribosome-depleted, 150 nt, paired-end, stranded RNA-seq with Illumina HiSeq v4. Sequence reads that passed quality filters after trimming were analyzed with Sailfish-cir to identify linear RNAs and circular RNAs. Differential expression of linear RNAs was assessed with Deseq2 . QRT–PCR validation was performed using TaqMan and SYBR Green methods. Results: 100 million sequence reads per sample were mapped to the mouse genome (build mm10) using Sailfish-cir to identify linear and circular RNA transcripts. Pathway analysis of differentially expressed genes identified upregulation of gene sets for human asthma, mouse lung allergic inflammation, Muc5ac regulated genes and smooth muscle genes after allergic sensitization. Gene level exppression in each asthma-related pathway was reduced by the miR-145 antagonist. The miR-145 antagonist and several nontargeting oligos also upregulated interferon signaling pathways suggesting a general antiinflammatory effect of LNA/DNA oligos in the lung. Conclusions: Lung-directed delivery of LNA/DNA oligonucleotides with cationic lipid nanoparticles is an efffective means to prevent inflammatory gene expression in a house dust mite model of mild/moderate asthma. Overall design: Linear and circular RNA transcript expression was compared in whole lung tissue from unsensitized, house dust mite sensitzed, antimiR-145 treated treated mice

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Ramelli SC, Comer BS, McLendon JM, Sandy LL, Ferretti AP, Barrington R, Sparks J, Matar M, Fewell J, Gerthoffer WT