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Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

ABSTRACT: Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

PROVIDER: PRJNA535485 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8956010_1.fastq.gz	Fastqsanger.gz
	SRR8956010_2.fastq.gz	Fastqsanger.gz
	SRR8956020_1.fastq.gz	Fastqsanger.gz
	SRR8956020_2.fastq.gz	Fastqsanger.gz
	SRR8956030_1.fastq.gz	Fastqsanger.gz

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Project description:Systemic sclerosis is a connective tissue disease affecting skin and internal organs, characterized by a triad of inflammation, vasculopathy and progressive fibrosis, due to deposition of mainly type I collagen. Out of the intricate mechanisms involved in the pathogenesis of the disease, evidence indicates that TGFbeta signaling plays a central role in mediating the effects of several pro-fibrotic effectors. In addition, TGFbeta is induced by hypoxia in cultured fibroblasts, an observation suggesting a role for this cytokine in linking vasculopathy and fibrosis in the disease. Not surprisingly, TGFbeta and Wnt signaling are among the most prevalent pathways found in global gene expression studies performed on systemic sclerosis skin biopsies. In this perspective, modulation of TGFbeta activity remains a top therapeutic target in systemic sclerosis drug development. We recently performed whole-body magnetic resonance imaging (MRI) studies in systemic sclerosis patients, and evidenced deep connective tissue infiltrates surrounding tendons in patients with active disease, and tendon friction rubs. Tenosynovitis and arthritis were also found by MRI in one third of the patients. We performed tenosynovial biopsies in patients with clinically active tenosynovitis, in order to evaluate whether such samples would provide additional information on disease mechanisms. Here, we report that these samples are characterized by the over-expression of genes involved in fibrosis, TGFbeta/Wnt signaling, chemokines and cytokines, but also by the concurrent over-expression of several ubiquitin-specific peptidases (USPs). Among the USPs overexpressed in systemic sclerosis tenosynovial biopsies, USP15 is known to specifically deubiquitinate SMAD3, and the TGFbeta Receptor 1. These results triggered us to perform additional experiments in order to test whether USP15 overexpression plays a role in the pathogenesis of systemic sclerosis via decreased ubiquitin-mediated degradation of proteins involved in TGFbeta signaling.

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Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

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