IQGAP3 Is an Important Mediator of Skin Inflammatory Diseases.

IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) is member of the IQGAP family of scaffold proteins, which are essential for assembling multiprotein complexes that coordinate various intracellular signaling pathways. Previous research has shown that IQGAP3 is overexpressed in psoriatic skin lesions. Given its involvement in processes like cell proliferation and chemokine signaling, we sought to explore its molecular role in driving the psoriatic phenotype of keratinocytes. By conducting transcriptome profiling of HaCaT keratinocytes, we identified numerous psoriasis-associated pathways that were affected when IQGAP3 was knocked down. These included alterations in NFkB signaling, EGFR signaling, activation of p38/MAPK and ERK1/ERK2, lipid metabolism, cytokine production, and the response to inflammatory cytokine stimulation. Real-time analysis further revealed changes in cell growth dynamics, including proliferation and wound healing. The balance between cell proliferation and apoptosis was altered, as were skin barrier functions and the production of IL-6 and IFNγ. Despite these significant findings, the diversity of the alterations observed in the knockdown cells led us to conclude that IQGAP3 may not be the best target for the therapeutic inhibition to normalize the phenotype of keratinocytes in psoriasis.

FRA1 mediates the activation of keratinocytes: Implications for the development of psoriatic plaques.

In this study we investigated the role of FRA1, a transcription factor from the AP-1 family, in the regulation of keratinocyte characteristics important for the development of psoriatic plaques. FRA1 is characterized by elevated expression in the skin of psoriasis patients, thus leading us to predict it to be one of the major regulators of keratinocyte phenotype during the development of psoriatic lesions. Pathway analysis of RNAseq data allowed us to identify FRA1-mediated signaling cascades leading to the manifestation of the most prominent skin characteristics of the disease: the development of inflammation, epithelial-mesenchymal transition, activation of metalloproteases, and keratinocyte proliferation and migration. We have confirmed that FRA1-overexpressing keratinocytes produce elevated amounts of proinflammatory cytokines and active matrix metalloproteases, leading to the induction of the autoinflammatory loop and paracrine activation in neighbor cells. Therefore, the elevated expression of FRA1 and its altered transcriptional regulation in the skin of patients with psoriasis is an important driving factor in the development of psoriatic plaques.

Identification of Transcriptional Regulators of Psoriasis from RNA-Seq Experiments.

Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the molecular mechanisms of regulation of the disease we performed RNA sequencing (RNA-Seq) analysis of 14 pairs of skin samples collected from psoriatic patients. Subsequent pathway analysis and an extraction of transcriptional regulators governing psoriasis-associated pathways was executed using a combination of MetaCore Interactome enrichment tool and cisExpress algorithm, and followed by comparison to a set of previously described psoriasis response elements. A comparative approach has allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFkB, IRF9, JUN, FOS, SRF), activity of T-cells in the psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1, etc.), hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C), and lipid metabolism (TFAP2, RARA, VDR). After merging the ChIP-seq and RNA-seq data, we conclude that the atypical expression of FOXA1 transcriptional factor is an important player in psoriasis, as it inhibits maturation of naive T cells into this Treg subpopulation (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3-), therefore contributing to the development of psoriatic skin lesions.

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.