Integrated computational approach to the analysis of RNA-seq data reveals new transcriptional regulators of psoriasis

Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the ( CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3− ) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions. Psoriasis: Searching for genetic triggers Highly sensitive genetic sequencing has uncovered genes and regulatory elements that may play key roles in the development of psoriasis. Little is known about the exact reasons of the manifestation of skin disease psoriasis, although it appears to be triggered by abnormal immune cell signalling. It can also cause systemic inflammation resulting in serious heart conditions and strokes. Sergey Bruskin together with scientists across Russia and the US, carried out RNA sequencing on samples from the skin lesions and healthy skin of 14 Caucasian patients. Using comparative bioinformatic approach The team identified 38 novel transcriptional regulators previously unassociated with psoriasis, and dissected 42 proteins to be the main governors of the disease. One of the novel transcription regulators, the protein known as FOXA1, appears to inhibit the maturation of regulatory