Integrative systems biology framework discovers common gene regulatory signatures in multiple mechanistically distinct inflammatory skin diseases.

Abstract

Abstract More than 20% of the population across the world is affected by non-communicable inflammatory skin diseases including psoriasis, atopic dermatitis, hidradenitis suppurativa, rosacea, etc. Many of these chronic diseases are painful and debilitating with limited effective therapeutic interventions. However, recent advances in psoriasis treatment have improved the effectiveness and provide better management of the disease. This study aims to identify common regulatory pathways and master regulators that regulate molecular pathogenesis. We designed an integrative systems biology framework to identify the significant regulators across several inflammatory skin diseases. With conventional transcriptome analysis, we identified 55 shared genes, which are enriched in several immune-associated pathways in eight inflammatory skin diseases. Next, we exploited the gene co-expression-, and protein-protein interaction-based networks to identify shared genes and protein components in different diseases with relevant functional implications. Additionally, the network analytics unravels 55 high-value proteins as significant regulators in molecular pathogenesis. We believe that these significant regulators should be explored with critical experimental approaches to identify the putative drug targets for more effective treatments. As an example, we identified IKZF1 as a shared significant master regulator in three inflammatory skin diseases, which can serve as a putative drug target with known disease-derived molecules for developing efficacious combinatorial treatments for hidradenitis suppurativa, atopic dermatitis, and rosacea. The proposed framework is very modular, which can indicate a significant path of molecular mechanism-based drug development from complex transcriptomics data and other multi-omics data.