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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence [Perturb-seq]

ABSTRACT: Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence [Perturb-seq]

PROVIDER: PRJNA841559 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19359259_1.fastq.gz	Fastqsanger.gz
	SRR19359259_2.fastq.gz	Fastqsanger.gz
	SRR19359260_1.fastq.gz	Fastqsanger.gz
	SRR19359260_2.fastq.gz	Fastqsanger.gz
	SRR19359261_1.fastq.gz	Fastqsanger.gz

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence [Perturb-seq]

Project description:T cell exhaustion limits anti-tumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic antigen stimulation assay, we performed genome-wide CRISPR/Cas9 screens to systematically discover genetic regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of several epigenetic regulators, including members of the INO80 and BAF chromatin remodeling complexes, improved T cell persistence in tumors. In vivo paired CRISPR perturbation and single-cell RNA sequencing revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of terminal exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a-depletion limited the global acquisition of chromatin accessibility associated with T cell exhaustion and led to improved anti-tumor immunity after adoptive cell therapy. In summary, we provide a comprehensive atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of the epigenetic state of T cell exhaustion can improve T cell responses in cancer immunotherapy.

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence [ATAC-seq]

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence

Project description:Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence [ATAC-seq]

Project description:Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence [ATAC-seq]

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Compressed Perturb-seq: highly efficient screens for regulatory circuits using random composite perturbations

Project description:Pooled CRISPR screens with single-cell RNA-seq readout (Perturb-seq) have emerged as a key technique in functional genomics, but are limited in scale by cost and combinatorial complexity. Here, we reimagine Perturb-seq’s design through the lens of algorithms applied to random, low-dimensional observations. We present compressed Perturb-seq, in which we measure multiple perturbations per cell or multiple cells per droplet, and decompress these measurements by leveraging the sparse structure of regulatory circuits. Applying compressed Perturb-seq to 598 genes in the immune response to bacterial lipopolysaccharide, we achieve the same accuracy as conventional Perturb-seq at 4 to 20-fold reduced cost, with greater power to learn genetic interactions. We identify known and novel regulators of immune responses and uncover evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing GWAS or trans-eQTL studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence.

Project description:T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to systematically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of the INO80 and BAF chromatin remodeling complexes improved T cell persistence in tumors. In vivo Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chromatin accessibility and led to improved antitumor immunity. In summary, we provide an atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of epigenetic state can improve T cell responses in cancer immunotherapy.

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Compressed Perturb-seq: highly efficient screens for regulatory circuits using random composite perturbations

Project description:Compressed Perturb-seq: highly efficient screens for regulatory circuits using random composite perturbations

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence

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

2022-05-26 | GSE203593 | GEO

MULTIMODAL STIMULATION SCREENS REVEAL UNIQUE AND SHARED GENES LIMITING T-CELL FITNESS

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Project description:Perturb-seq: Dissecting molecular circuits with scalable single cell RNA profiling of pooled genetic screens

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