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A profibrotic gene expression program induced by Egr-1 in skin fibroblasts

ABSTRACT: Systemic sclerosis (SSc) is characterized by vascular damage, autoimmunity and fibrosis and is associated with highly variable clinical presentation and disease course. Aberrant transforming growth factor-ß (TGF-ß) signaling via the early immediate transcription factor Egr-1 is implicated in the pathogenesis of SSc. To shed light on the role of Egr-1 in fibrosis, regulation of gene expression in human skin fibroblasts overexpressing Egr-1 was examined by genome-wide expression analysis. Over 600 genes were found to be regulated by Egr-1. The Egr-1-responsive gene signature is largely comprised of genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. Expression of the Egr-1 responsive genes was evaluated in a microarray dataset comprising skin biopsies from 17 patients with scleroderma and six healthy controls (GEO GSE9285; PMID 18648520). The “Egr-1 responsive gene signature” was enriched in the ‘diffuse-proliferation’ subset of skin biopsies in the patients with diffuse cutaneous SSc (dcSSc), but was not associated with other forms of scleroderma, or with healthy controls. Skin biopsies from patients with scleroderma can provide more insights into the relevant pathological processes in the subset of disease and could be developed into a diagnostic tool for identifying a subset of diffuse scleroderma patients who may be responsive to Egr-1 therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE27165 | GEO | 2011/10/26

SECONDARY ACCESSION(S): PRJNA137379

REPOSITORIES: GEO

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A profibrotic gene expression program induced by Egr-1 in skin fibroblasts

Project description:Systemic sclerosis (SSc) is characterized by vascular damage, autoimmunity and fibrosis and is associated with highly variable clinical presentation and disease course. Aberrant transforming growth factor-ß (TGF-ß) signaling via the early immediate transcription factor Egr-1 is implicated in the pathogenesis of SSc. To shed light on the role of Egr-1 in fibrosis, regulation of gene expression in human skin fibroblasts overexpressing Egr-1 was examined by genome-wide expression analysis. Over 600 genes were found to be regulated by Egr-1. The Egr-1-responsive gene signature is largely comprised of genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. Expression of the Egr-1 responsive genes was evaluated in a microarray dataset comprising skin biopsies from 17 patients with scleroderma and six healthy controls (GEO GSE9285; PMID 18648520). The “Egr-1 responsive gene signature” was enriched in the ‘diffuse-proliferation’ subset of skin biopsies in the patients with diffuse cutaneous SSc (dcSSc), but was not associated with other forms of scleroderma, or with healthy controls. Skin biopsies from patients with scleroderma can provide more insights into the relevant pathological processes in the subset of disease and could be developed into a diagnostic tool for identifying a subset of diffuse scleroderma patients who may be responsive to Egr-1 therapy. Cultures of primary fibroblasts from neonatal foreskin treated by Egr1 and Tgfb1 were measured at 24 and 48 hours. Control samples without any treatment were also measured at the same time points. Two biological replicates per condition/time point were measured using the Illumina HumanRef-8 V2 Expression BeadChip.

2011-10-25 | E-GEOD-27165 | biostudies-arrayexpress

Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

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Genome-wide reduction in chromatin accessibility and unique transcription factor footprints in endothelial cells and fibroblasts in scleroderma skin

Project description:We assessed genome-wide chromatin accessibility and transcription factor footprinting in endothelial cells and fibroblasts isolated from skin biopsies from healthy subjects and diffuse cutaneous scleroderma patients.

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Project description:This SuperSeries is composed of the following subset Series: GSE3886: Scleroderma Morphea Normal Fibroblasts GSE3887: Scleroderma Architecture Cell Lines Abstract: We used DNA microarrays representing >12,000 human genes to characterize gene expression patterns in skin biopsies from individuals with a diagnosis of systemic sclerosis with diffuse scleroderma. We found consistent differences in the patterns of gene expression between skin biopsies from individuals with scleroderma and those from normal, unaffected individuals. The biopsies from affected individuals showed nearly indistinguishable patterns of gene expression in clinically affected and clinically unaffected tissue, even though these were clearly distinguishable from the patterns found in similar tissue from unaffected individuals. Genes characteristically expressed in endothelial cells, B lymphocytes, and fibroblasts showed differential expression between scleroderma and normal biopsies. Analysis of lymphocyte populations in scleroderma skin biopsies by immunohistochemistry suggest the B lymphocyte signature observed on our arrays is from CD20+ B cells. These results provide evidence that scleroderma has systemic manifestations that affect multiple cell types and suggests genes that could be used as potential markers for the disease Refer to individual Series

2006-03-07 | E-GEOD-4385 | biostudies-arrayexpress

Gene Expression Profiling of Scleroderma Skin

Project description:We have analyzed the genome-wide patterns of gene expression with DNA microarrays in skin biopsies from 34 subjects: 17 patients with SSc with diffuse scleroderma (dSSc), 7 patients with SSc with limited scleroderma (lSSc), 3 patients with morphea and 6 healthy controls. In total, 61 skin biopsies were analyzed. The addition of 14 technical replicates resulted in a total of 75 microarray hybridizations. The Intrinsic_scleroderma_genes.txt supplementary file lists the 995 genes with the most consistent expression between each forearm-back pair and technical replicates, but with the highest variance across all samples analyzed. An intrinsic gene identifier algorithm was used to select a set of intrinsic scleroderma genes. A total of 34 experimental groups were defined, each representing the 34 different subjects in our study. Replicate hybridizations for a given patient were assigned to the same experimental group. Each gene was analyzed and assigned a score that is inversely related to how intrinsic the gene's expression is across the samples analyzed. The analysis was repeated on randomized data in order to estimate a False Discovery Rate (FDR). An intrinsic score of 0.3 selected 995 genes with an FDR of 4% (39 ± 7 genes) while retaining reproducible clustering of technical replicates. Keywords: global gene expression profiling using Agilent Whole Human genome oligo arrays

2008-07-15 | GSE9285 | GEO

LGR5 expressing skin fibroblasts define a major hub perturbed in Systemic Sclerosis

Project description:Systemic sclerosis (SSc) is an incurable autoimmune disease with high morbidity and mortality rates, with no effective treatment. Here, we conducted a population scale single-cell genomic analysis of skin and blood samples of 56 healthy controls, and 97 SSc patients at different stages of disease. We found immune compartment activation in only a subset of diffuse SSc patients, but global dysregulation of the stromal compartment, including a novel subset of LGR5+ scleroderma associated fibroblasts (ScAF). ScAF cells are mainly localized in the deep reticular dermis of healthy subjects and are dramatically perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of the epigenetic and transcriptional landscapes of stromal cells in healthy subjects and SSc patients, revealed ScAF-specific markers, pathways, and transcription factors important in disease development. Systematic analysis combining the clinical metadata and molecular features of the patients, associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our study provides a high-resolution atlas of the entire spectrum of sclerodermatous skin, proposing a paradigm shift in the understanding of SSc disease and facilitating the development of new biomarkers and therapeutic strategies for SSc.

2022-04-04 | GSE195452 | GEO

Transcription profiling of human fibroblast isolated from either back or forearm punch biopsies from normal control patients, patients with a diagnosis of Systemic Sclerosis with Diffuse Scleroderma and patients with a diagnosis of morphea

Project description:Fibroblast were isolated from either back or forearm punch biopsies taken by Dr. Kari Connolly(UCSF) from either normal control patients, patients with a diagnosis of Systemic Sclerosis with Diffuse Scleroderma and patients with a diagnosis of morphea. Scleroderma fibroblast were grown to confluence, media was changed and the RNA prepared from the cells 48 hrs later (to avoid serum responsive genes).

2005-10-19 | E-SMDB-2225 | biostudies-arrayexpress

Transcription profiling of human microvascular endothelial cells in systemic sclerosis

Project description:Patients with the diffuse avascular form of Systemic Sclerosis (SSc) and healthy controls (N) were used as sources of microvascular endothelial cells (MVEC). MVEC were obtained from biopsies of involved skin of the hands in 6 SSc patients and from 6 healthy patients undergoing surgery for traumatic events at the hands. The controls were matched by age and sex to the SSc cases. All patients fulfilled the American College of Rheumatology criteria for SSc, as well as the criteria for the diffuse form of the disease.

2005-08-30 | E-MEXP-417 | biostudies-arrayexpress

Real-time quantitative PCR analysis of 88 microRNAs involved in human cell differentiation and development in normal fibroblasts stimulated with exogenous TGF-β1 and systemic sclerosis (SSc) dermal fibroblasts

Project description:Normal fibroblasts and SSc fibroblasts between the third and six subpassages were used for experiments. Normal and scleroderma fibroblasts were serum-starved for 24 hours and incubated in the presence or absence of TGF-β1 (2ng/ml) for 6 hours. Total RNA was extracted from culture cells with ISOGEN (Nippon Gene, Tokyo, Japan). MicroRNA isolation from total RNA was performed using RT2 qPCR-Grade miRNA Isolation Kit (SA Bioscience). For RT2 Profiler PCR Array (SABioscience), microRNAs were reverse-transcribed into first strand cDNA using RT2 miRNA First Strand Kit (SABiosciences). A mixture of equal amounts of cDNAs from 5 normal fibroblasts or 5 SSc fibroblasts was prepared. The cDNA was mixed with RT2 SYBR Green/ROX qPCR Master Mix and the mixture was added into a 96-well RT2 miRNA PCR Array (SABiosciences) that included primer pairs for 88 human microRNAs. Human dermal fibroblasts were obtained by skin biopsy from the affected areas (dorsal forearm) of 5 patients with diffuse cutaneous SSc and <2 years of skin thickening. Control fibroblasts were obtained by skin biopsies from 5 healthy donors. Control donors were each matched with a SSc patient for age, sex, and biopsy site.

2012-04-01 | E-GEOD-34827 | biostudies-arrayexpress

Gene Expression Profiling of Scleroderma Skin

Project description:We have analyzed the genome-wide patterns of gene expression with DNA microarrays in skin biopsies from 34 subjects: 17 patients with SSc with diffuse scleroderma (dSSc), 7 patients with SSc with limited scleroderma (lSSc), 3 patients with morphea and 6 healthy controls. In total, 61 skin biopsies were analyzed. The addition of 14 technical replicates resulted in a total of 75 microarray hybridizations. The Intrinsic_scleroderma_genes.txt supplementary file lists the 995 genes with the most consistent expression between each forearm-back pair and technical replicates, but with the highest variance across all samples analyzed. An intrinsic gene identifier algorithm was used to select a set of intrinsic scleroderma genes. A total of 34 experimental groups were defined, each representing the 34 different subjects in our study. Replicate hybridizations for a given patient were assigned to the same experimental group. Each gene was analyzed and assigned a score that is inversely related to how intrinsic the gene's expression is across the samples analyzed. The analysis was repeated on randomized data in order to estimate a False Discovery Rate (FDR). An intrinsic score of 0.3 selected 995 genes with an FDR of 4% (39 Â± 7 genes) while retaining reproducible clustering of technical replicates. Keywords: global gene expression profiling using Agilent Whole Human genome oligo arrays common reference design; we used Universal Human Reference RNA (Stratagene) as our reference for every array; For every hybridization sample RNA was always labeled with Cy3, and reference RNA was always labeled with Cy5; Microarray hybridizations were performed for 61 RNA samples from 34 subjects resulting 61 hybridizations. Fourteen replicate hybridizations were added, resulting in a total of 75 microarray hybridizations.

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