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CRISPR screen in regulatory T cells reveals ubiquitination modulators of Foxp3 stability

ABSTRACT: CRISPR screen in regulatory T cells reveals ubiquitination modulators of Foxp3 stability

PROVIDER: PRJNA588260 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10417042.fastq.gz	Fastqsanger.gz
	SRR10417043_1.fastq.gz	Fastqsanger.gz
	SRR10417043_2.fastq.gz	Fastqsanger.gz
	SRR10417044.fastq.gz	Fastqsanger.gz
	SRR10417045_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

CRISPR screen in regulatory T cells reveals ubiquitination modulators of Foxp3 stability

Project description:Regulatory T cells (Tregs) are required to control immune responses and maintain homeostasis, but are a significant barrier to anti-tumor immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of pro-inflammatory properties2, can promote autoimmunity and/or facilitate more effective tumor immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. Despite improved functional genetic tools that now allow for systematic interrogation, dissection of the gene regulatory programs that modulate Foxp3 expression has not yet been reported. In this study, we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Tregs and applied this technology to perform a targeted loss-of-function screen of 490 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We discovered several novel modulators including , Ataxin 7 like 3 (Atxn7l3) and members of the deubiquitination module of the SAGA chromatin modifying complex, Usp22 and Atxn7l3, were discovered to be positive regulators that stabilized Foxp3 expression; whereas the screen suggested Rnf20, an E3 ubiquitin ligase, is a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein and created defects in their suppressive function that led to spontaneous autoimmunity, but protected against tumor growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Tregs could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Tregs. These results reveal novel modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

2020-04-29 | GSE140102 | GEO

Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.

2019-09-02 | PXD011164 | Pride

A genome-wide CRISPR/Cas phenotypic screen for modulators of DUX4 cytotoxicity reveals screen complications

Project description:In pursuit of unraveling the underlying mechanism of FSHD we performed a genome-wide CRISPR/Cas9 phenotypic rescue screen in an inducible DUX4 transgenic cell line (DIE) to identify modulators of DUX4-induced apoptosis.

2020-07-29 | GSE155034 | GEO

FOXP3 exon 2 controls Treg stability and autoimmunity

Project description:FOXP3 exon 2 controls Treg stability and autoimmunity

| PRJNA820377 | ENA

FOXP3 exon 2 controls Treg stability and autoimmunity [RNA-seq]

Project description:Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing – a longer isoform (FOXP3 FL) containing all the coding exons and the other shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans yet their differences in controlling regulatory T cell phenotype and functionality remains unclear. Here we show that patients expressing only the shorter isoform failed to maintain self-tolerance and developed IPEX syndrome. Mice with Foxp3 exon 2 deletion developed excessive TFH and GC B cell responses and systemic autoimmune disease with anti-dsDNA and anti-nuclear autoantibody production and immune-complex glomerulonephritis. Regulatory T cells expressing FOXP3 ΔE2 were unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, FOXP3 ΔE2 isoform allows increased expression of selected cytokines but decreased expression of a set of Foxp3 positive regulators without altered binding to these gene loci. We demonstrate that exon 2 of FOXP3 is required to maintain Treg stability and immune homeostasis.

2022-06-27 | GSE199477 | GEO

FOXP3 exon 2 controls Treg stability and autoimmunity [ChIP-seq]

2022-06-27 | GSE199277 | GEO

A genome-wide CRISPR/Cas phenotypic screen for modulators of DUX4 cytotoxicity reveals screen complications

Project description:A genome-wide CRISPR/Cas phenotypic screen for modulators of DUX4 cytotoxicity reveals screen complications

| PRJNA648311 | ENA

FOXP3 exon 2 controls Treg stability and autoimmunity [RNA-seq]

Project description:FOXP3 exon 2 controls Treg stability and autoimmunity [RNA-seq]

| PRJNA820177 | ENA

FOXP3 exon 2 controls Treg stability and autoimmunity [ChIP-seq]

Project description:FOXP3 exon 2 controls Treg stability and autoimmunity [ChIP-seq]

| PRJNA819105 | ENA

Conserved non-coding sequence 2 (CNS2) of the Foxp3 genomic locus is essential for the function and stability of regulatory T cells during their activation

Project description:Regulatory T (Treg) cells play an indispensable role in immune homeostasis. The development and function of Tregs are dependent on transcriptional factor Foxp3, but how constant expression of Foxp3 is maintained in Tregs is not clear. Here we show that ablation of the conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus in mice led to spontaneous lymphoproliferative disease and exacerbation of experimental autoimmune encephalomyelitis (EAE). CNS2 is required for activated Treg cells to maintain elevated Foxp3 expression, which is critical for their suppressor function and lineage stability. Mechanistically, upon TCR stimulation, NFAT binds to both CNS2 and Foxp3 promoter and mediates the interaction between CNS2 and Foxp3 promoter. Our findings demonstrated an essential role for CNS2 in maintaining the stability and function of activated Treg cells and identified NFAT as a key mediator of its function. Gene expression was profiled in T regulatory cells (Treg) in WT and CNS2 knockout mice. CNS2 knockout mice lack a conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus. Treg cells were further sorted into Foxp3-high and Foxp3-low populations based on the expression level of Foxp3. mRNA was profiled using RNA-Seq (unstranded, polyA+, SE100) in replicate for each condition

2014-09-04 | E-GEOD-57272 | biostudies-arrayexpress

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