RNA sequencing of a large number of psoriatic patients identifies 131 novel miRNAs and 11 miRNAs associated with disease severity

Background: MicroRNAs are small regulatory molecules that are dysregulated in psoriasis. Despite previous efforts, much is unknown about the regulatory mechanisms of psoriasis genetics and their contributions to disease development and activity. Objectives: To globally characterize the miRNAome of psoriatic skin in a large sample of psoriatic cases and controls for increased understanding of psoriasis pathophysiology. Methods: Skin biopsies from psoriatic cases (n=75) and non-psoriatic controls (n=57) were RNA sequenced. Count data was meta-analyzed with a previously published dataset (cases, n=24, controls, n=20), increasing the number of psoriatic cases four-fold from previously published studies. Differential expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell specific analyses were performed. Results: We identified 439 significantly differentially expressed miRNAs (DEMs), of which 131 were novel and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in all psoriatic skin. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including "thyroid hormone signaling" "insulin resistance" and various infectious diseases. Cell specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells. Conclusions: We have provided the most comprehensive overview of the miRNome in psoriatic skin to date and identified a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.