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Leveraging cell-type specific regulatory networks to interpret genetic variations in abdominal aortic aneurysm

ABSTRACT: Leveraging cell-type specific regulatory networks to interpret genetic variations in abdominal aortic aneurysm

PROVIDER: PRJNA739707 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14872074_1.fastq.gz	Fastqsanger.gz
	SRR14872074_2.fastq.gz	Fastqsanger.gz
	SRR14872075_1.fastq.gz	Fastqsanger.gz
	SRR14872075_2.fastq.gz	Fastqsanger.gz
	SRR14872076_1.fastq.gz	Fastqsanger.gz

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Leveraging cell-type specific regulatory networks to interpret genetic variations in abdominal aortic aneurysm

Project description:Abdominal aortic aneurysm (AAA) is a common degenerative cardiovascular disease without clear understanding of its pathobiology. To detect AAA associated variants that may affect gene regulation, we generated H3K27ac HiChIP data for aortic smooth muscle cells (AoSMC) and aortic endothelia cells (HAEC), the two cell types most relevant to the AAA disease. We further implemented cell type-specific REs defined from HiChIP experiments, and observed the consistency between the chromatin accessibility of REs and the expression levels of their target genes. Moreover, the cell type-specific REs contributed to detect the AAA most relevant cell type, AoSMC, and locate the important AAA-related TFs, ERG and KLF family.

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Project description:The aim of this study was to assess the relative gene expression in human AAA and AOD. Genome-wide expression analysis of abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) specimens obtained from 20 patients with small AAA (mean maximum aortic diameter=54.3±2.3 mm), 29 patients with large AAA (mean maximum aortic diameter=68.4±14.3 mm), and 9 AOD patients (mean maximum aortic diameter=19.6±2.6 mm). Relative aortic gene expression was compared with that of 10 control aortic specimen of organ donors.

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Project description:An abdominal aortic aneurysm (AAA) is a pathological widening of the aortic wall characterized by loss of AoSMCs, extracellular matrix degradation and local inflammation. This condition is often asymptomatic until rupture occurs, leading to high morbidity and mortality rates. We conducted single-cell RNA sequencing (scRNA-seq) from AAA patients´s specimens to profile gene expression at single cell level and to gain insight on cell types relevant to disease dynamics.

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RNA-sequencing of abdominal aortic aneurysm (AAA) and control abdominal aorta tissues

Project description:RNA-sequencing of abdominal aortic aneurysm (AAA) and control abdominal aorta tissues

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Leveraging cell-type-specific regulatory networks to interpret genetic variants in abdominal aortic aneurysm.

Project description:Abdominal aortic aneurysm (AAA) is a common degenerative cardiovascular disease whose pathobiology is not clearly understood. The cellular heterogeneity and cell-type-specific gene regulation of vascular cells in human AAA have not been well-characterized. Here, we performed analysis of whole-genome sequencing data in AAA patients versus controls with the aim of detecting disease-associated variants that may affect gene regulation in human aortic smooth muscle cells (AoSMC) and human aortic endothelial cells (HAEC), two cell types of high relevance to AAA disease. To support this analysis, we generated H3K27ac HiChIP data for these cell types and inferred cell-type-specific gene regulatory networks. We observed that AAA-associated variants were most enriched in regulatory regions in AoSMC, compared with HAEC and CD4+ cells. The cell-type-specific regulation defined by this HiChIP data supported the importance of ERG and the KLF family of transcription factors in AAA disease. The analysis of regulatory elements that contain noncoding variants and also are differentially open between AAA patients and controls revealed the significance of the interleukin-6-mediated signaling pathway. This finding was further validated by including information from the deleteriousness effect of nonsynonymous single-nucleotide variants in AAA patients and additional control data from the Medical Genome Reference Bank dataset. These results shed important insights into AAA pathogenesis and provide a model for cell-type-specific analysis of disease-associated variants.

| S-EPMC8740683 | biostudies-literature

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