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

Abstract

ABSTRACTAimMore 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. Similar effective treatments are also needed for other chronic skin disorders regulated molecular pathogenesis. This study aims to identify common regulatory pathways and master regulators that regulate molecular pathogenesis.MethodsWe designed an integrative systems biology framework to identify the significant regulators across several inflammatory skin diseases. We exploited the gene co-expression-, and protein-protein interaction-based networks to identify shared genes and pro components in different diseases with relevant functional implications. Further, we utilized network analytics to unravel the high-priority proteins, that play a crucial role in disease pathogenesis.ResultsWith conventional transcriptome analysis we identified 55 shared genes, which are enriched in several immune-associated pathways in eight inflammatory skin diseases. Our correlation-based co-expression networks identified the core co-expression networks and the integrative multi-omics interactomes providing core interactions across four of the eight diseases. Next, by implementing network analytics, we unraveled 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.ConclusionThe conventional transcriptome results identify huge complexity among inflammatory skin diseases, which demands a systems biology perspective for comprehensive understanding. 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.