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CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions [pooled CRISPR screen]

ABSTRACT: CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions [pooled CRISPR screen]

PROVIDER: PRJNA698581 | ENA |

REPOSITORIES: ENA

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CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions [pooled CRISPR screen]

Project description:Genome-wide association studies have identified 161 genetic variants associated with coronary artery disease (CAD), but the causal genes and biological pathways remain unknown at most loci. This knowledge is critical to optimize precision medicine strategies and develop new drugs for CAD. Here, we performed multiple pooled CRISPR screens to test the impact of CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect by flow cytometry on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signaling). At a false discovery rate ≤10%, we identified 42 significant variants located within 26 CAD loci. Although a few of these loci include genes previously characterized in endothelial cells (e.g. MIA3/AIDA, FURIN, ARHGEF26, ADAMTS7), most are implicated in endothelial dysfunction for the first time. Detailed cellular and molecular characterization of the RNA helicase DHX38, as well as CRISPR-mediated over-expression experiments at the FURIN/FES, CCDC92/ZNF664 and CNNM2 loci, revealed a strong effect on vascular endothelial cell senescence. Our findings implicate many CAD-associated loci in the regulation of atherosclerosis-related endothelial functions and offer new insights into how modulating these functions could help prevent or treat CAD.

2021-02-11 | GSE165923 | GEO

CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions

Project description:CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions

| PRJNA698579 | ENA

CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions [RNA-seq]

Project description:CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions [RNA-seq]

| PRJNA698583 | ENA

CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions [RNA-seq]

2021-02-11 | GSE165924 | GEO

CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-10 | GSE165925 | GEO

Pooled CRISPR screens in human intestinal organoids [CRISPR screens]

Project description:Pooled CRISPR screens in human intestinal organoids [CRISPR screens]

| PRJNA608420 | ENA

9p21 DNA variants associated with coronary artery disease impair interferon-? signalling response.

Project description: Not available

| S-EPMC3079517 | biostudies-literature

Pooled CRISPR screens in human macrophages

Project description:To identify the possible genes influencing macrophage pro-inflammatory activation, we designed CRISPR screens using a human metabolic sgRNA library containing metabolism-related transcription factors, small molecule transporters, and metabolic enzymes in a Cas9-expressing lentiviral vector.

2023-08-03 | GSE216353 | GEO

Pooled CRISPR screens in human intestinal organoids [CRISPR screens]

Project description:We performed CRISPR screens on both a sub-library and a genome-wide scale in human intestinal organoids to discover cancer driver genes. We investigated the Wnt and the TGFB pathway and used both WT, APC-mutant and APC-TP53-mutant organoids.

2020-02-26 | GSE145184 | GEO

Identification of Functional Regulatory Elements in the Human Genome Using Pooled CRISPR Screens

Project description:Genome-scale pooled CRISPR screens are powerful tools for identifying genetic dependencies across varied cellular processes. The vast majority of CRISPR screens reported to date have focused exclusively on the perturbation of protein-coding gene function. However, protein-coding genes comprise <2% of the sequence space in the human genome leaving a substantial portion of the genome uninterrogated. Noncoding regions of the genome harbor important regulatory elements (e.g. promoters, enhancers, suppressors) that influence cellular processes but high-throughput methods for evaluating their essentiality have yet to be established. Here, we describe a CRISPR-based screening approach that facilitates the functional profiling of thousands of noncoding regulatory elements in parallel. We selected the tumor suppressor p53 as a model system and designed a pooled CRISPR library targeting thousands of p53 binding sites throughout the genome. Following transduction into dCas9-KRAB-expressing cells we identified several regulatory elements that influence cell proliferation. Moreover, we uncovered multiple elements that are required for the p53-mediated DNA damage response. Surprisingly, many of these elements are located deep within intergenic regions of the genome that have no prior functional annotations. This work diversifies the applications for pooled CRISPR screens and provides a framework for future functional studies focused on noncoding regulatory elements.

2019-08-21 | GSE126320 | GEO

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