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Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126325 | GEO | 2020/03/12

REPOSITORIES: GEO

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Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension.

Project description:Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymal-transition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-β, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.

| S-EPMC7125148 | biostudies-literature

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIP-seq]

Project description:Pulmonary Arterial Hypertension (PAH) is a cardiovascular disease characterized by progressively increasing blood pressure as a result of obliteration and loss of pulmonary arteries. We have extracted pulmonary arterial endothelial cells from lungs of a cohort of PAH patients (n=10) and controls (n=9), cultured the cells for 3-5 passages, and performed chromatin (H3K27ac, H3K4me1, and H3K4me3 ChIP-Seq), expression (RNA-Seq) and chromatin interaction profiling (ChIA-PET). We observed a large-scale remodelling of the active chromatin landscape at enhancers while promoters and gene expression remained unchanged.

2020-03-12 | GSE126322 | GEO

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [RNA-seq]

2020-03-12 | GSE126262 | GEO

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIA-PET]

2020-03-12 | GSE139234 | GEO

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

Project description:Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

| PRJNA521550 | ENA

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [RNA-seq]

Project description:Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [RNA-seq]

| PRJNA521416 | ENA

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIP-seq]

Project description:Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIP-seq]

| PRJNA521549 | ENA

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIA-PET]

Project description:Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIA-PET]

| PRJNA578859 | ENA

Endothelial periostin regulates vascular remodeling by promoting endothelial dysfunction in pulmonary arterial hypertension.

Project description:Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with extracellular matrix (ECM) deposition, vascular cell hyperproliferation, and neointima formation in the small pulmonary artery. Endothelial dysfunction is considered a key feature in the initiation of vascular remodeling. Although vasodilators have been used for the treatment of PAH, it remains a life-threatening disease. Therefore, it is necessary to identify novel therapeutic targets for PAH treatment. Periostin (POSTN) is a secretory ECM protein involved in physiological and pathological processes, such as tissue remodeling, cell adhesion, migration, and proliferation. Although POSTN has been proposed as a potential target for PAH treatment, its role in endothelial cells has not been fully elucidated. Here, we demonstrated that POSTN upregulation correlates with PAH by analyzing a public microarray conducted on the lung tissues of patients with PAH and biological experimental results from in vivo and in vitro models. Moreover, POSTN overexpression leads to ECM deposition and endothelial abnormalities such as migration. We found that PAH-associated endothelial dysfunction is mediated at least in part by the interaction between POSTN and integrin-linked protein kinase (ILK), followed by activation of nuclear factor-κB signaling. Silencing POSTN or ILK decreases PAH-related stimuli-induced ECM accumulation and attenuates endothelial abnormalities. In conclusion, our study suggests that POSTN serves as a critical regulator of PAH by regulating vascular remodeling, and targeting its role as a potential therapeutic strategy for PAH.

| S-EPMC10769143 | biostudies-literature

Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.

Project description:Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodeled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension. CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of pulmonary arterial hypertension.CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, whereas CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension attenuated the abnormal angiogenic behavior that characterizes these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-?B, followed by stabilization of hypoxia-inducible factor-1? and increased downstream production of vascular endothelial growth factor and endothelin-1.Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.

| S-EPMC4033409 | biostudies-literature

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