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

ABSTRACT: 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 (NF?B, 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.

SUBMITTER: Zolotarenko A

PROVIDER: S-EPMC5133374 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Zolotarenko Alena A Chekalin Evgeny E Mesentsev Alexandre A Kiseleva Ludmila L Gribanova Elena E Mehta Rohini R Baranova Ancha A Tatarinova Tatiana V TV Piruzian Eleonora S ES Bruskin Sergey S

Experimental & molecular medicine 20161104 11

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 algo ...[more]

PMID: 27811935

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Project description:Rationale: V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule. Vsir-/- mice have exacerbated psoriasis-like skin inflammation. The immune cell subsets involved in inflammation in Vsir-/- psoriatic mice are largely unknown. We have used scRNA-seq as an unbiased profiling strategy to study the heterogeneity of immune cells at a single cell level in the skin of Vsir-/- psoriatic mice. Methods: In the present study, the right ear and shaved back skin of wild type and Vsir-/- mice were treated with IMQ for 5 consecutive days to induce psoriasis-like dermatitis. Then, the single-cell RNA sequencing analysis of mouse back skin lesions was performed using 10 × Genomics technique. Results: We identified 12 major cell subtypes among 23,258 cells. The major populations of the skin cells included macrophages, dendritic cells and fibroblasts. Macrophages constituted the main immune cell population in the WT (61.29%) and Vsir-/- groups (77.7%). It should be noted that DCs and fibroblasts were expanded in the Vsir-/- psoriatic mice. Furthermore, the gene expression signatures were assessed. We observed that Hspb1 and Cebpb were significantly upregulated in the Vsir-/- psoriatic mice. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these subsets and uncovered putative functions of each cell type. Date analysis resulted in the discovery of a number of novel psoriasis-associated genes in Vsir-/- mice. Conclusion: We present a comprehensive single-cell landscape of the skin immune cells in Vsir-/- psoriatic mice. These unprecedented data uncovered the transcriptional landscape and phenotypic heterogeneity of skin macrophages in psoriasis and identified their gene expression signature suggesting specialized functions in Vsir-/- mice. Our findings will open novel opportunities to investigate the role of VISTA in driving psoriasis.

Dataset Information

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

Publications

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

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