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

ABSTRACT: We assessed transcriptomic changes in fibroblasts isolated from skin biopsies from diffuse cutaneous scleroderma patients before and after BET inhibitor JQ1 treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE186961 | GEO | 2022/03/01

REPOSITORIES: GEO

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

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

| PRJNA776895 | ENA

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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Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma.

Project description:Binding of the bromodomain and extraterminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. We sought to determine the antifibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan-BET inhibitor, JQ1; BRD2 inhibitor, BIC1; or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed antifibrotic effects in an animal model of SSc and in patient-derived diffuse cutaneous SSc (dcSSc) fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium (Ca2+) signaling. The antifibrotic effect of BRD4 inhibition was mediated at least in part by downregulation of Ca2+/calmodulin-dependent protein kinase II α and reduction of intracellular Ca2+ concentrations. On the basis of these results, we propose targeting Ca2+ pathways or BRD4 as potentially novel therapeutic approaches for progressive tissue fibrosis.

| S-EPMC9090238 | biostudies-literature

Transcription profiling of human skin bioposis from patients with diffuse scleroderma and limited scleroderma

Project description:RNA expression profiling was carried out for systemic sclerosis (scleroderma) on skin biopsies obtained from both diffuse scleroderma (dcSSc) and limited scleroderma (lcSSc) subjects patients and compared to normal subjects. The patient group comprised of 4 dcSSc and 2 lcSSc subjects, all of whom were Caucasian and belonged to the age range of 42-73 (Mean age = 61.6). Patient sample set consisted of 3 females and 3 males. Race matched female volunteers from the same geographical area were recruited as controls (n = 4) and belonged to the age range of 41-62 (Mean age = 52).

2015-03-25 | E-MEXP-1214 | biostudies-arrayexpress

Scleroderma Morphea Normal Fibroblasts

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). A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. User Defined

2005-12-20 | E-GEOD-3886 | biostudies-arrayexpress

Scleroderma Morphea Normal Fibroblasts

2005-12-21 | GSE3886 | GEO

Systemic and cell type-specific gene expression patterns in scleroderma skin

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

Expression data from non-small cell lung cancer cell line DV90 after Bromodomain and extra terminal domain (BET) inhibitor JQ1 treatment

Project description:Bromodomain and extra terminal domain (BET) inhibition reduces occupancy of BET-family proteins at promoter and enhancer sites resulting in changes in the transcription of specific genes. We used microarray profiling to investigate the transcriptional changes induced by BET inhibitor JQ1 treatment in DV90 cells to identify the underlying changes of gene regulation that lead to JQ1 sensitivity. DV90 cells (JQ1 sensitive non-small cell lung cancer cell line) were treated with 135 nM (IC50) or 785 nM (IC90) of JQ1 for 4h and 24h. DMSO treated controls served as reference and at least four replicates per condition were collected. RNA was extracted and hybridized to Affymetrix HuGene-2.1ST microarrays to identify treatment induced transcriptional changes.

2016-03-31 | E-GEOD-75960 | biostudies-arrayexpress

Determining the impact of the Bromodomain and extra-terminal inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer

Project description:To determine the impact of the Bromodomain and extra-terminal (BET) inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer we performed GATA2 ChIP-seq in the presence and absence of JQ1 and assessed differential binding upon JQ1 treatment for 24 hours. We first determined the GATA2 cistrome using our GATA2 ChIP-seq data. Overlapping this with previously published ChIP-seq data for the BET family of proteins (Asangani et al., 2014), we identified a substantial proportion of GATA2 genomic binding sites which are co-occupied by a BET protein. We then quantified differential binding of GATA2 upon JQ1 treatment genome-wide.

2019-01-17 | GSE125236 | GEO

Systemic and cell type-specific gene expression patterns in scleroderma skin

Project description: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 This SuperSeries is composed of the SubSeries listed below.

2006-03-08 | GSE4385 | GEO

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