Gene expression analysis using RNA-Seq of dithranol-treated psoriasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE249936 | GEO | 2024/03/06
REPOSITORIES: GEO
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Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
2021-08-22 | GSE175473 | GEO
Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
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Project description:Applying ChIP-seq with anti-acetylation of lysine 27 on Histone 3 (H3K27Ac), we report high-throughput profiling of H3K27Ac in human skin biopsies taken from psoriasis patients, both from the lesion and from adjacent non-lesion skin, and from skin biopsies from healthy match volunteers, in term of age, gender, and the biopsies place in the body. From each group we had 4 samples. There is a clearly different H3K27 acetylation patterns in psoriatic skin compared to uninvolved or healthy volunteer skin. in many of the most over express genes in psoriasis lesion, there is enrichment of H3K27Ac. However, loss of acetylation on H3K27 is not part of the biochemical mechanism by which gene expression is decreased in psoriatic skin. Finally, we show Many of the over express genes in psoriasis lesion, that also were enriched with H3K27Ac harbor a putative GRHL transcription factor binding site.
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Project description:Applying ChIP-seq with anti-acetylation of lysine 27 on Histone 3 (H3K27Ac), we report high-throughput profiling of H3K27Ac in human skin biopsies taken from psoriasis patients, both from the lesion and from adjacent non-lesion skin, and from skin biopsies from healthy match volunteers, in term of age, gender, and the biopsies place in the body. From each group we had 4 samples. On three samples of each group we performed mRNA array. There is a clearly different H3K27 acetylation patterns in psoriatic skin compared to uninvolved or healthy volunteer skin. in many of the most over express genes in psoriasis lesion, there is enrichment of H3K27Ac. However, loss of acetylation on H3K27 is not part of the biochemical mechanism by which gene expression is decreased in psoriatic skin. Finally, we show Many of the over express genes in psoriasis lesion, that also were enriched with H3K27Ac harbor a putative GRHL transcription factor binding site.
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Project description: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 fourteen pairs of skin samples collected from psoriatic patients with consequent pathway analysis and identification of the main transcriptional regulators of psoriasis-associated pathways. In order to identify the most important regulators of the disease, we combined the results obtained with MetaCore Interactome enrichment tool and cisExpress algorithm and compared them to regulatory psoriasis response elements found in literature. Comparative approach 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.), hyper-proliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C), and with lipid metabolism (TFAP2, RARA, VDR). We also identified 66 transcription factors not previously associated with psoriasis. Using MetaCore pathway maps we illustrated and described the molecular basis of psoriatic skin lesions.
2017-09-14 | GSE78023 | GEO
Project description:Background and Aims: Chronic plaque psoriasis results from genetic and environmental factors that activate inflammatory pathways involving both innate and adaptive immunity. Although the histological features are well known, protein-level changes—especially with spatial resolution—are less understood. This study aimed to investigate layer-specific proteomic changes in psoriatic skin. Methods: Skin biopsies from psoriasis patients (N=8) and healthy controls (N=8) were separated into four layers (stratum corneum, inner epidermis, dermis, subcutis) using laser-capture microdissection. Proteins were extracted and analyzed by mass spectrometry. Results: We identified 7,236 proteins, with 1,649 differentially expressed in lesional vs. non-lesional inner epidermis. Upregulated proteins were linked to innate immunity, cholesterol synthesis and tissue structure. The stratum corneum in lesions showed more complex protein profiles than in controls. The dermis displayed increased proteins related to IL-17 signaling and neutrophil recruitment. No significant changes were found in the subcutis. Conclusion: This dataset highlights the inner epidermis as a key site of proteomic alterations in psoriasis, driven by proteins related to immune activity, tissue structure and cholesterol synthesis. The layer-specific approach offers detailed spatial insights into disease-associated protein changes.
2025-06-10 | PXD063539 | Pride
Project description:Recent studies have shown that LRRC8A, the essential subunit of the volume-regulated anion channel LRRC8, which is responsible for mediating cell volume regulation during hypotonic stress, is predominantly localized in the basal layer of the epidermis. This prompted us to investigate whether LRRC8A plays a role in maintaining epidermal homeostasis by regulating key processes initiated in this layer, such as cell proliferation and/or differentiation. LRRC8A was found to be strongly upregulated in transiently amplifying cells at the onset of differentiation. While LRRC8A mRNA remains high when keratinocytes mature further, the LRRC8A protein is drastically downregulated. Interference with LRRC8A expression at this step inhibits transition of keratinocyte stem cells into transiently amplifying cells and impairs terminal differentiation. As psoriasis is a common chronic inflammatory skin disease characterized by disturbed epidermal differentiation and aberrant function of transiently amplifying cells, we investigated the involvement of LRRC8A in this disease. Indeed, LRRC8A was strongly decreased in lesional psoriatic skin, which could also be mimicked in vitro using Th1/Th17 cytokine mixes. Thus, our data suggest that LRRC8 could serve as a therapeutic target for the topical treatment strategies of psoriatic lesions by restoring the capacity of keratinocytes to initiate differentiation.
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Project description:Epidermal hyperplasia, a characteristic feature of psoriatic skin lesions, is epigenetically driven by Enhancer of Zeste homolog 2 (EZH2). EZH2 and EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) are both abnormally upregulated in psoriatic lesions. To identify microRNAs that could potentially target these epigenetic regulators we profiled miRNAs from psoriatic lesional skin in comparison with healthy skin. Analysis of the differentially expressed miRNAs revealed miR-101, as one of the most significant miRNA, consistently downregulated in psoriatic lesions compared to the healthy skin. A clear inverse correlation in the expression of miR-101 versus EZH2 was apparent in normal skin versus psoriatic lesional skin indicating that EZH2 is a potential target of miR-101, which was further confirmed by luciferase assay. Investigating the upstream effectors of the miR-101- EZH2 pathway in psoriasis, we identified the pro-inflammatory cytokine IL-17 as regulator of miR-101 expression. Here we propose a model, depicting a pathway triggered by IL-17 – mediated modulation of miR-101 expression, which in turn elicit sustained expression of EZH2, leading to enhanced keratinocyte proliferation and epidermal hyperplasia in psoriasis. Taken together, this indicates that miR-101 is a potential therapeutic target to alleviate the downstream effects of IL-17 mediated epidermal hyperplasia in psoriasis.
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