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Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis

ABSTRACT: Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis

PROVIDER: PRJNA777445 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16761072.fastq.gz	Fastqsanger.gz
	SRR16761073.fastq.gz	Fastqsanger.gz
	SRR16761074.fastq.gz	Fastqsanger.gz
	SRR16761075.fastq.gz	Fastqsanger.gz
	SRR16761076.fastq.gz	Fastqsanger.gz

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Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis

Project description:We identified the transcription factor ETS-related gene (ERG) as a putative orchestrator of lung capillary homeostasis and repair following injury, and whose function was dysregulated in aging. Single-cell RNA-seq of ERG deficient mouse lungs revealed transcriptional abnormalities and fibrogenic features, resembling those associated with aging and IPF, including reduced number of lung progenitor ECs, known as general capillary (gCap) ECs.

2021-12-31 | GSE187333 | GEO

Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis.

Project description:Vascular dysfunction is a hallmark of chronic diseases in elderly. The contribution of the vasculature to lung repair and fibrosis is not fully understood. Here, we performed an epigenetic and transcriptional analysis of lung endothelial cells (ECs) from young and aged mice during the resolution or progression of bleomycin-induced lung fibrosis. We identified the transcription factor ETS-related gene (ERG) as putative orchestrator of lung capillary homeostasis and repair, and whose function is dysregulated in aging. ERG dysregulation is associated with reduced chromatin accessibility and maladaptive transcriptional responses to injury. Loss of endothelial ERG enhances paracrine fibroblast activation in vitro, and impairs lung fibrosis resolution in young mice in vivo. scRNA-seq of ERG deficient mouse lungs reveales transcriptional and fibrogenic abnormalities resembling those associated with aging and human lung fibrosis, including reduced number of general capillary (gCap) ECs. Our findings demonstrate that lung endothelial chromatin remodeling deteriorates with aging leading to abnormal transcription, vascular dysrepair, and persistent fibrosis following injury.

| S-EPMC9314350 | biostudies-literature

ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning

Project description:Precise vascular patterning is critical for normal growth and development. The ERG transcription factor drives Delta like ligand 4 (DLL4)/Notch signalling and is thought to act as pivotal regulators of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC specific Focal Adhesion Kinase (FAK)-knockout (KO) and point-mutant FAK-knockin mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins identified that endothelial nuclear-FAK interacts with the de-ubiquitinase USP9x and the ubiquitin ligase TRIM25 enzymes. Further in silico analysis corroborates that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x.

2022-07-05 | PXD033447 | Pride

ChIP-seq of ERG-bound regulatory elements in human and bovine vascular endothelial cells

Project description:In this study we set out to discover conserved orthologous ERG-bound gene regulatory elements in primary vascular endothelial cells isolated from human and cow

2017-06-15 | E-MTAB-5148 | biostudies-arrayexpress

Loss of ERG in human lung endothelial cells leads to release of pro-inflammatory and pro-fibrotic factors.

Project description:: Although vascular dysfunction is a hallmark of chronic aging-associated diseases, including idiopathic pulmonary fibrosis, the role of the pulmonary vasculature to lung repair versus lung fibrosis is not fully understood. We identified the endothelial transcription factor ETS-related gene (ERG) as an orchestrator of vascular homeostasis and repair following lung injury. To evaluate whether loss of endothelial ERG influences the activation of neighboring naïve lung fibroblasts, we collected the conditioned media (CM) generated by control- and ERG-silenced human lung endothelial cells (ECs) and we applied them to normal human lung fibroblasts. We found that CM from ERG-silenced human lung ECs strongly promoted human lung fibroblast activation and enhanced the effect of the fibrogenic mediator TGF. In support of these results, analysis of CM using nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS) revealed increased secretion of numerous pro-inflammatory and pro-fibrogenic mediators by ERG-silenced human lung ECs in comparison to control-silenced human lung ECs.

2022-06-24 | PXD033847 | Pride

Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Project description:Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

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Project description:Atherosclerosis is a persistent inflammatory state accompanied by lipid overload. Vascular fibrosis is one of the primary causes of atherosclerosis development. Although ligustilide (Lig) was shown to exert obvious antiatherogenic effects in previous studies, its precise mechanism has not been comprehensively discussed. In this paper, pharmacologic studies were performed to explore the pharmacodynamic effects of Lig on protecting aorta vascular wall structures and modulating serum inflammatory factors in ApoE-/- mice. Chemical proteomics based on a Lig-derived photoaffinity labelling (Lig-PAL) probe were applied to identify potential therapeutic targets. Mothers against decapentaplegic homologue 3 (SMAD3), which is closely related to the development of vascular fibrosis and atherosclerosis, was identified as a potential target of Lig. Lig suppressed the phosphorylation and nuclear translocation of SMAD3 by blocking the interaction between SMAD3 and transforming growth factor-β (TGF-β) receptor 1, thereby inhibiting the collagen synthesis process, preventing vascular fibrosis and improving atherosclerosis. The quantitative proteomics results from Lig-treated atherosclerotic ApoE-/- mice also indicated that Lig inhibits the expression of collagens I and III, interferes with collagen fibril organization processes and protects the aorta from vascular fibrosis. Hence, developing a novel SMAD3 inhibitor may present another therapeutic option for preventing atherosclerosis.

2020-01-21 | PXD017125 | Pride

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

Project description:Effect of ERG knockdown, with and without VEGF stimulation, on vascular endothelial cell (HUVEC) gene expression

2017-06-15 | E-MTAB-5207 | biostudies-arrayexpress

SOX7 and ETS factors regulate an endothelial transcriptional program during vascular development (DamID)

Project description:Vascular development involves complex changes in gene expression necessary to dictate the behaviour of differentiating endothelial cells within the emerging vascular network. However, the transcriptional programs regulating vascular development are poorly understood. Here we use a DamID approach to profile for the first time the global DNA binding pattern of SOX7, FLI1 and ERG in endothelial precursor cells. We uncover that SOX7, FLI1 and ERG bind together at endothelial specific regulatory regions to drive a transcriptional program important for vascular development.

2017-11-25 | GSE63645 | GEO

ChIP-seq of ERG-bound regulatory elements in human and bovine vascular endothelial cells

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