Alteration of the whole skin gene expression as a result of Flg deficiency
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE164623 | GEO | 2021/05/01
REPOSITORIES: GEO
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Project description:Defects of filaggrin (FLG) compromise epidermal barrier function and represent an important known genetic risk factor for atopic dermatitis (AD), but also for systemic atopy, including allergic sensitization and asthma. A loss of epidermal barrier integrity can provide a significant stress for the keratinocytes in the skin, either due to the increased moisture evaporation from the skin or increased penetration of the antigens and microflora into the lower epidermal layers. To understand the effect of this loss of barrier integrity on keratinocyte function our aim is to analyze the alterations in the transcriptional profile of keratinocytes from Flg-deficient mice.
2021-01-01 | GSE158028 | GEO
Project description:Atopic eczema is an itchy inflammatory disorder characterised by skin barrier dysfunction. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a major risk factor, but the mechanisms by which filaggrin haploinsufficiency leads to atopic inflammation remain incompletely understood. Skin as an organ which can be modelled using primary cells in vitro provides the opportunity for selected genetic effects to be investigated in detail.
2019-08-14 | PXD014875 | Pride
Project description:Comparison of gene expression in atopic dermatitis (AD) and ichthyosis vulgaris (IV) patients skin compared to healthy control skin depending on filaggrin(FLG) genotype
2011-10-01 | E-MTAB-768 | biostudies-arrayexpress
Project description:Filaggrin (FLG) is a key structural protein expressed in epidermal keratinocytes. Mutations in the filaggrin gene (FLG) are strongly linked to atopic dermatitis (AD) and allergic inflammation occurring later in life at distant body locations in AD patients. Keratinocytes secrete exosomes, small, lipid-rich membrane vesicles to communicate with distant cells, including within the immune system. The FLG gene was silenced in the HaCaT keratinocyte cell line by shRNA delivered using a lentiviral vector. HaCaT cells transduced with scrambled shRNA were used as a control.
2022-08-12 | PXD026859 | Pride
Project description:ADAM17 and EGFR are essential key players for epidermal integrity. Keratinocyte-specific deletion of ADAM17 in mice results in pronounced alterations in terminal differentiation of keratinocytes leading to severe epidermal barrier defects with enhanced transepidermal water loss. Thereby, mice deficient for ADAM17 in keratinocytes phenocopy mice with a keratinocyte-specific deletion of EGFR, highlighting the role of ADAM17 as a “ligand sheddase”, as it sheds membrane bound EGFR ligands from the cell surface and finally modulates EGFR signaling. In this study we aim for the first proteomic / degradomic approach to characterize the disruption of the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation. Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17 and EGFR deficiency. These include massive proteome alterations of structural and regulatory components important for barrier formation, like transglutaminases, involucrin, S100 protein family members and S100 fused-type proteins, such as filaggrin, filaggrin-2 and hornerin. Cleavage site analysis using TAILS reveals, among other ADAM17 dependent cleavage sites, increased proteolytic processing of S100 fused-type proteins, including filaggrin-2. Alterations in proteolytic processing are supported by altered protein abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion, among them kallikreins, cathepsins and their inhibitors. In addition, N-terminal proteomics indicated usage of alternative translation start sites. This study highlights the essential role of proteolytic processing for maintenance of a functional epidermal barrier. Furthermore it suggests that most defects in formation of the postnatal epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR.
2016-04-20 | PXD002597 | Pride
Project description:Introduction Disruption of the epithelial barrier can induce eosinophilic esophagitis (EoE), a TH2-mediated food- and aeroallergen associated chronic inflammatory disease 1, 2. The expression of IL-20 subfamily cytokines, IL-19, IL-20 and IL-24, is increased in TH2-mediated diseases, yet their function in EoE is unknown. Methods Combining RNA-sequencing (RNA-seq) and proteome analysis, we have examined the effects of the IL-20 subfamily on esophageal epithelial cells using patient-derived organoids and an experimental EoE mouse model. Results When stimulated with IL-20 subfamily cytokines patient-derived esophageal organoids showed decreased expression of Filaggrin (FLG) and Filaggrin 2 (FLG2) responsible for epithelial cornification. In agreement, EoE patients with active inflammation showed elevated IL-20 subfamily cytokines and decreased FLG and FLG2 expression. Topical corticosteroid treatment in EoE patients restored filaggrin expression, while reducing IL-20 subfamily cytokines. Abolishment of IL-20 subfamily signalling in Il20R2-/- animals attenuated experimental EoE in an OVA-induced mouse model. In the esophageal keratinocyte cell line, KYSE-180, we identified IL-20 subfamily-induced STAT3 and MAPK (ERK1/2) pathway activation. However, Stat3fl/flKrt5cre mice with an epithelium specific deletion of Stat3 developed exacerbated experimental EoE with a pronounced decrease of Flg2. In line, combined stimulation of patient-derived esophageal organoids with IL-20 subfamily cytokines and pharmacological inhibition of STAT3 resulted in aggravated decrease of FLG and FLG2. In addition, pharmacological STAT3 inhibition resulted in reduced transepithelial electrical resistance (TEER) and increased macromolecular flux in patient-derived air liquid interface (ALI) cultures. Whereas, inhibition of the MAPK (ERK1/2) pathway hampered IL-20 subfamily induced TEER reduction and paracellular flux increment. Finally, MAPK (ERK1/2) inhibitor treatment reduced infiltrating CD45+ immune cells in the esophagus and alleviated experimental EoE in mice. Conclusion We discovered a novel regulatory function of the IL-20 subfamily for epithelial barrier integrity. Aberrant IL-20 subfamily signaling disturbs the epithelial barrier function, while abrogation of IL-20 subfamily and ERK1/2 signaling restores epithelial integrity and attenuates experimental EoE. Therefore, we propose that targeting the IL-20 subfamily pathway could present a novel therapeutic strategy for EoE treatment.
2023-05-10 | PXD031509 | Pride
Project description:The breakdown of epidermal barrier and consequent loss of skin hydration is a feature of skin aging and eczematous dermatitis. Few treatments, however, resolve these underlying processes to provide full symptomatic relief. In this study, we generated a novel compound, isosorbide di-(linoleate/oleate) (IDL), by esterifying isosorbide with sunflower fatty acids. Topical effects of IDL in skin were compared to those of ethyl linoleate/oleate (EL), which has previously been shown to improve skin barrier function. Both IDL and EL down-regulated inflammatory gene expression, but IDL more effectively up-regulated the expression of genes associated with keratinocyte differentiation (e.g., KRT1, GRHL2, SPRR4). Consistent with this, IDL increased abundance of epidermal barrier proteins (filaggrin and involucrin) and prevented cytokine-mediated stratum corneum degradation. IDL also down-regulated expression of “unhealthy skin signature” genes linked to loss of epidermal homeostasis and uniquely repressed an interferon-inducible co-expression module activated in multiple skin diseases including psoriasis. In a double-blind placebo-controlled trial enrolling females with dry skin, 2% IDL lotion applied over 2 weeks significantly improved skin hydration and decreased transepidermal water loss (NCT04253704). These results demonstrate mechanisms by which IDL improves skin hydration and epidermal barrier function, supporting IDL as an effective intervention for treatment of xerotic pruritic skin.
2020-11-16 | GSE157932 | GEO
Project description:Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are still poorly understood. We have previously demostrated that a dominante mutation in ZNF750 leads to a clinical phenotype that reminiscent of psoriasis and seborrehic dermatitis. We defined ZNF750 as a nuclear effector that is atrongly activated in and essiential for keratinocyte terminal differentiation. ZNF750 knockdown in HaCaT keratinocytes markedly reduced the expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, ZNF750 over-expression in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differnetiation, and with its downstream targets can serve in future elucidation of therapeutics for common disease of skin barrier Gene expression analysis: To determine the differentaition signature for HaCaT keratinocytes, with ZNF750 gene silencing, total RNA was isolated in biologic triplicates from cells induced to differentiate for twelve days and hybridized to Affymerix Human Gene 1.0 ST arrays.
2012-09-24 | E-GEOD-38039 | biostudies-arrayexpress
Project description:Atopic dermatitis (AD) is a heritable inflammatory disease, characterised by skin barrier dysfunction. Genome-wide association studies (GWAS) have identified molecular targets with relevance for drug development, but the strongest genetic association, FLG, has not yet been successfully targeted in atopic disease. An AD-associated locus on chromosome 11q13.5 lies between two genes - EMSY and LRRC32 - but the functional mechanisms leading to AD are unclear. We applied a combination of genomic and molecular analytical techniques followed up in patient biopsies, to investigate pathomechanisms at this GWAS locus. Chromosome conformation capture data in keratinocytes shows interaction of the intergenic region in threedimensional space with EMSY. siRNA-mediated knockdown of EMSY in skin organoid culture leads to enhanced development of barrier function, measured by water evaporation and dye penetration. Global proteomic analysis of skin organoids with EMSY knockdown shows increased expression of structural and functional proteins, confirmed by histological and ultrastructural features. Lipid analysis shows an increase in ceramides known to be reduced in AD. Conversely, over-expression of EMSY in primary human keratinocytes leads to a reduction in biomarkers of barrier formation. Finally, skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, consistent with increased functional effect of this DNAbinding protein. Together our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach for AD.
2019-06-24 | PXD014088 | Pride
Project description:Skin constitutes the outer permeability barrier that protects the body from dehydration and a myriad of external assaults. Epidermal keratinocytes act as the first line of innate immune defense, and barrier defects underlie common inflammatory skin diseases. However, the molecular mechanisms that maintain barrier integrity when skin is under challenge to regulate the interplay between epidermal and immune cells are not fully understood. Here we report upregulated expression of transcriptional repressorencoding Ovol1 in epidermal cells of inflamed skin, and its functional importance in maintaining barrier integrity of physically or chemically challenged skin. Following stimulation with imiquimod, Ovol1-deficient mice exhibit significantly aggravated epidermal hyperplasia and psoriasis-like skin inflammation featuring persistent neutrophil accumulation. Using bulk and single-cell RNA-sequencing, we characterize molecular changes in epidermal, fibroblasts, and immune cells that reflect altered epidermal proliferation and differentiation and/or significantly enhanced inflammatory responses as consequences of Ovol1 deletion. We identify both proliferation/differentiation-regulating and neutrophil-attracting chemokine genes as candidate direct targets of Ovol1. Finally, we provide evidence for altered IL-1a signaling in the microenvironment of Ovol1- deficient inflamed skin that functionally contributes to neutrophil accumulation and epidermal hyperplasia. Collectively, our study demonstrates a protective role for an epidermally expressed, disease-linked transcription factor in coordinating robust barrier maintenance with suppression of skin inflammation.
2021-10-27 | GSE158112 | GEO