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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

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

High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

Project description:Computational modeling indicated that a pathological level of high shear stress (HSS, 100 dyn/cm2) is generated in distal pulmonary arteries (PA) (100-500 um) in a congenital heart defect with increased PA blood flow causing PA hypertension (PAH), and in idiopathic PAH with occlusive vascular remodeling. The response of human PA endothelial cells (EC) to HSS compared to physiologic laminar shear stress (LSS, 15 dyn/cm2), was therefore assessed. Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS was observed. HSS did not alter induction of the transcription Krüppel-like factors (KLF) 2/4, but H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was the interaction between ERG and KLF2/4 and ERG expression. In PAEC under LSS, reducing ERG by siRNA caused EndMT related to decreased bone morphogenetic protein receptor 2 (BMPR2), cadherin 5 (CDH5) and platelet and endothelial cell adhesion molecule 1 (PECAM1), and increased Snail/Slug (SNAI1/2) and smooth muscle alpha α-2 actin (ACTA2). In PAEC under HSS, transfection of ERG prevented EndMT. We induced HSS in mice by an aorto-caval shunt that causes a progressive increase in PAH over eight weeks and used an adeno-associated viral vector (AAV2-ESGHGYF) to replenish ERG selectively in PAEC. Elevated PA pressure and resistance, EndMT and vascular remodeling assessed by muscularization of peripheral arteries were markedly reduced by ERG delivery in the aorto-caval shunt mice. Thus, agents that restore ERG in the pulmonary vasculature will be of therapeutic benefit in overcoming the adverse effect of HSS on progressive PAH.

2025-01-06 | GSE250550 | GEO

Vascular remodeling following pulmonary hypertension

Project description:Hypoxia can induce vasoconstriction followed by vascular remodeling including hypertrophy and hyperplasia of pulmonary vascular smooth muscle and proliferation of endothelial cells. The goal of this project is to elucidate the genes involved in vascular remodeling following pulmonary hypertension. Total RNA was isolated from lungs of normoxic and hypoxic treated animals. Keywords: other

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

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Th2 cytokine IL-4 is critical in initiating pulmonary vascular inflammation under hypoxic conditions and induces pulmonary vascular endothelial cell activation.

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