Filaggrin status modulates gene transcription, DNA damage and epidermal barrier repair during clinical response to methotrexate in atopic eczema
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ABSTRACT:
PROVIDER: PRJNA1192991 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31566136_1.fastq.gz | Fastqsanger.gz | |||
| SRR31566136_2.fastq.gz | Fastqsanger.gz | |||
| SRR31566137_1.fastq.gz | Fastqsanger.gz | |||
| SRR31566137_2.fastq.gz | Fastqsanger.gz |
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Project description:Background: Methotrexate (MTX) is an effective treatment for atopic eczema (AE); however, the mechanism of action remains incompletely understood. MTX is known to induce keratinocyte differentiation, which can occur following DNA damage triggered by external stimuli. Objectives: We sought to investigate the mechanism of action of MTX in AE using a combination of in vitro models and study of AE skin during the early phases of therapy with MTX. Specifically, we investigated the relationship between MTX-induced DNA damage, keratinocyte differentiation, barrier function, filaggrin status and disease activity. Methods: Lesional and non-lesional skin from two AE cohorts and in vitro human 3-D epidermal organoids (living epidermal equivalents – [LEEs]) were used to assess response to MTX. Markers of late keratinocyte differentiation and response to purine/pyrimidine nucleosides were assessed. Keratinocyte DNA damage following MTX was evaluated through measurement of DNA damage markers and transcriptomic analysis. Results: MTX restored barrier function and induced filaggrin and loricrin expression in AE skin and LEE, through a mechanism inhibited by thymidine. MTX-induced DNA damage and DNA damage response signalling pathways in LEE and AE skin which were upstream of keratinocyte differentiation. There was an interaction between gene expression, disease severity (EASI) and FLG status (heterozygotes versus wildtype, e.g. LGALS7, SPINK7). Conclusions: MTX induces key epidermal barrier proteins through thymidine-dependent DNA damage in the absence of inflammatory cells. Findings were associated with improved disease outcomes in AE skin.
2025-06-01 | GSE283265 | GEO
Project description:The aim of this study was to find disease-associated genes in atopic eczema. Keywords: Skin biopsy, DNA microarray, atopic eczema
2006-10-13 | GSE6012 | GEO
Project description:The aim of this study was to find disease-associated genes in atopic eczema. Experiment Overall Design: Skin biopsies were analyzed from ten patients with active atopic eczema and ten healthy controls.
2008-06-14 | E-GEOD-6012 | biostudies-arrayexpress
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:The microRNA expression profile of heathly, psoriasis and atopic eczema skin smaples was compared.
2007-08-16 | E-MEXP-1123 | biostudies-arrayexpress
Project description:Background: Atopic eczema (AE) is a common chronic inflammatory skin disorder. In order to dissect the genetic background several linkage and genetic association studies have been performed. Yet very little is known about specific genes involved in this complex skin disease, and the underlying molecular mechanisms are not fully understood. Results: We used human DNA microarrays to identify a molecular picture of the programmed responses of the human genome to AE. The transcriptional program was analyzed in skin biopsy samples from lesional and patch-tested skin from AE patients sensitized to Malassezia sympodialis (M. sympodialis), and corresponding biopsies from healthy individuals. The most notable feature of the global gene-expression pattern observed in AE skin was a reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. The overall transcriptional response in M. sympodialis patch-tested AE skin was similar to the gene-expression signature identified in lesional AE skin. In the constellation of genes differentially expressed in AE skin compared to healthy control skin, we have identified several potential susceptibility genes that may play a critical role in the pathological condition of AE. Many of these genes, including genes with a role in immune responses, lipid homeostasis, and epidermal differentiation, are localized on chromosomal regions previously linked to AE. Conclusion: Through genome-wide expression profiling, we were able to discover a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes in skin from AE patients. We found a significant enrichment of differentially expressed genes in AE with cytobands associated to the disease, and furthermore new chromosomal regions were found that could potentially guide future region-specific linkage mapping in AE. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: Skin biopsies from normal ('normal') and lesional and patch-tested ('leisonal') skin from Atopic eczema patients sensitized to Malassezia sympodialis Organism Part: location of skin biopsy Keywords: disease state analysis Computed
2010-06-24 | E-GEOD-12511 | biostudies-arrayexpress
Project description:Background: Atopic eczema (AE) is a common chronic inflammatory skin disorder. In order to dissect the genetic background several linkage and genetic association studies have been performed. Yet very little is known about specific genes involved in this complex skin disease, and the underlying molecular mechanisms are not fully understood. Results: We used human DNA microarrays to identify a molecular picture of the programmed responses of the human genome to AE. The transcriptional program was analyzed in skin biopsy samples from lesional and patch-tested skin from AE patients sensitized to Malassezia sympodialis (M. sympodialis), and corresponding biopsies from healthy individuals. The most notable feature of the global gene-expression pattern observed in AE skin was a reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. The overall transcriptional response in M. sympodialis patch-tested AE skin was similar to the gene-expression signature identified in lesional AE skin. In the constellation of genes differentially expressed in AE skin compared to healthy control skin, we have identified several potential susceptibility genes that may play a critical role in the pathological condition of AE. Many of these genes, including genes with a role in immune responses, lipid homeostasis, and epidermal differentiation, are localized on chromosomal regions previously linked to AE. Conclusion: Through genome-wide expression profiling, we were able to discover a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes in skin from AE patients. We found a significant enrichment of differentially expressed genes in AE with cytobands associated to the disease, and furthermore new chromosomal regions were found that could potentially guide future region-specific linkage mapping in AE. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: Skin biopsies from normal ('normal') and lesional and patch-tested ('leisonal') skin from Atopic eczema patients sensitized to Malassezia sympodialis Organism Part: location of skin biopsy Keywords: disease state analysis
2008-12-17 | GSE12511 | GEO
Project description:A subgroup of atopic dermatitis (AD) patients suffers from recurrent, disseminated herpes simplex virus (HSV) skin infections, eczema herpeticum (EH). To determine transcriptional mechanisms of the skin and immune system pathobiology that underlies ADEH disease development, we performed RNA-sequencing analysis of non-lesional skin (epidermis, dermis) from AD patients with (ADEH+, n=15) and without (ADEH-, n=13) history of EH, and healthy controls (HC, n=15). We also performed RNA-sequencing on participants’ plasmacytoid dendritic cells (pDCs) infected in vitro with HSV-1. ADEH+ patients exhibited dysregulated gene expression, limited in dermis (differentially expressed genes [DEGs]=14) and more widespread in epidermis (DEGs=129). ADEH+-upregulated epidermal DEGs were enriched in type 2 cytokine (T2) (IL4R, CCL22, CRLF2, IL7R), interferon (CXCL10, ICAM1, IFI44, IRF7), and IL-36γ (IL36G) inflammatory gene pathways. All ADEH+ participants exhibited T2 and interferon endotypes and 87% were IL36G-high. In contrast, these endotypes were more variably expressed among ADEH- participants. ADEH+ skin also dysregulated epidermal differentiation complex (EDC) gene expression within LCE, S100, and SPRR families, which are involved in skin barrier function and antimicrobial activities. pDC transcriptional responses to HSV-1 infection were unaltered by ADEH status. Pathobiology underlying ADEH+ risk is associated with a unique, multi-faceted epidermal inflammation that accompanies dysregulation of EDC genes. These findings will help direct future studies that define how these inflammatory patterns may drive risk of eczema herpeticum in AD.
2024-03-26 | GSE262071 | GEO
Project description:Loss-of-function mutations in the filaggrin gene are heavily associated with the incidence and severity of atopic dermatitis. Moreover, filaggrin insufficiency in epidermal keratinocytes can lead to persistent allergic inflammation and an associated immune response suggesting a role for this protein in regulation of immunity. Here, we investigate how filaggrin insufficiency affects the gene expression pattern in a filaggrin-insufficient (shFLG) keratinocyte cell line HaCaT in response to stimulation with various inflammatory mediators and allergens.
2022-05-20 | GSE203409 | GEO
Project description:We studied genes that are related to atopic diseases [i.e., atopic eczema (AE)]. Immunological factors and principal genes involved in the biosynthesis of polyunsaturated fatty acids were included. We analyzed whether expression of genes encoding key enzymes of LC-PUFA synthesis (FADS1, FADS2 and ELOVL5) is associated with circulating LC-PUFA levels and risk of AE in 4-year-old children. AE (n=20) and non-AE (n=104) children participating in the Sabadell cohort within the INfancia y Medio Ambiente (INMA) Project were included in the present study. RT-PCR with TaqMan Low-Density Array cards was used to measure the expression of these genes. RT-PCR gene expression profile. The samples are described in the sumary. Each sample was measured in duplicate in the same TLDA card and we present the average of each sample.
2013-06-29 | E-GEOD-48310 | biostudies-arrayexpress