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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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			Action	DRS
	SRR13602600.fastq.gz	Fastqsanger.gz
	SRR13602601.fastq.gz	Fastqsanger.gz
	SRR13602502.fastq.gz	Fastqsanger.gz
	SRR13602602.fastq.gz	Fastqsanger.gz
	SRR13602503.fastq.gz	Fastqsanger.gz

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

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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.

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Scalable pooled CRISPR screens with single cell chromatin accessibility profiling.

Project description:A scalable, cost-effective method that combines CRISPR perturbations with a single-cell indexing assay for transposase-accessible chromatin (CRISPR-sciATAC). This method links genome-wide chromatin accessibility to genetic perturbations through simultaneous capture of ATAC-seq fragments and CRISPR guide RNAs from single cells using a 96-well plate combinatorial indexing approach.

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Project description:Multiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting, repressive chromatin formation using CRISPR interference (CRISPRi) avoids genotoxicity and is more effective for perturbing non-coding regulatory elements in pooled assays. However, current CRISPRi pooled screening approaches are limited to targeting 1-3 genomic sites per cell. We engineer an Acidaminococcus Cas12a (AsCas12a) variant, multiplexed transcriptional interference AsCas12a (multiAsCas12a), that incorporates R1226A, a mutation that stabilizes the ribonucleoprotein:DNA complex via DNA nicking. The multiAsCas12a-KRAB fusion improves CRISPRi activity over DNase-dead AsCas12a-KRAB fusions, often rescuing the activities of lentivirally delivered CRISPR RNAs (crRNA) that are inactive when used with the latter. multiAsCas12a-KRAB supports CRISPRi using 6-plex crRNA arrays in high-throughput pooled screens. Using multiAsCas12a-KRAB, we discover enhancer elements and dissect the combinatorial function of cis-regulatory elements in human cells. These results instantiate a group testing framework for efficiently surveying numerous combinations of chromatin perturbations for biological discovery and engineering.

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Project description:Engineered CRISPR-Cas12a for higher-order combinatorial chromatin perturbations (amplicon)

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