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Manipulating the transcriptome and chromatin accessibility in T cells through CRISPR-induced alternative splicing of IKZF1 (RNAseq)

ABSTRACT: Manipulating the transcriptome and chromatin accessibility in T cells through CRISPR-induced alternative splicing of IKZF1 (RNAseq)

PROVIDER: PRJNA1062296 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27462433_1.fastq.gz	Fastqsanger.gz
	SRR27462433_2.fastq.gz	Fastqsanger.gz
	SRR27462434_1.fastq.gz	Fastqsanger.gz
	SRR27462434_2.fastq.gz	Fastqsanger.gz
	SRR27462435_1.fastq.gz	Fastqsanger.gz

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Manipulating the transcriptome and chromatin accessibility in T cells through CRISPR-induced alternative splicing of IKZF1 (ATACseq)

Project description:Genome-wide association studies have identified statistically significant associations between genetic variants in or near the IKZF1 gene and several autoimmune disorders. IKZF1, encoding the transcription factor Ikaros, produces at least 10 distinct transcripts via alternative splicing. To explore the role of alternative splicing of IKZF1 in mature T cells, we generated a panel of Jurkat T-cell clones with various truncating mutations in IKZF1 exon 4, exon 6 or both. Differences among clones in gene expression, chromatin accessibility, and protein abundance were assessed by RNA-seq, ATAC-seq and immunoblotting. Clones with single targeting events in either exon 4 or 6 clustered separately from double-targeted clones on multiple parameters, but overall, clone responses were highly heterogeneous. Perturbation of IKZF1 splicing resulted in significant differences in expression and chromatin accessibility of other autoimmunity-associated genes and elicited compensatory expression changes in other IKZF family members. Our results suggest that even modest perturbations of IKZF1 splicing can have significant effects on gene expression and function in mature T cells.

2024-06-01 | GSE255337 | GEO

Manipulating the transcriptome and chromatin accessibility in T cells through CRISPR-induced alternative splicing of IKZF1 (RNAseq)

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Manipulating the transcriptome and chromatin accessibility in T cells through CRISPR-induced alternative splicing of IKZF1 (ATACseq)

Project description:Manipulating the transcriptome and chromatin accessibility in T cells through CRISPR-induced alternative splicing of IKZF1 (ATACseq)

| PRJNA1074710 | ENA

Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia

Project description:Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations were associated with acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Rexinoid receptor agonists reversed this phenotype, in part by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing a new therapeutic option in IKZF1-mutated ALL. Significance: The outcome of therapy for high-risk acute lymphoblastic leukemia remains suboptimal despite contemporary chemotherapy and the advent of targeted therapeutic approaches. Recent genomic studies have identified deletions or mutations of IKZF1 as a hallmark of high-risk ALL, but an understanding of how IKZF1 alteration contribute to leukemia development are lacking. Here we show that IKZF1 alterations drive lymphoid lineage, a stem cell-like phenotype, abnormal bone marrow adhesion, and poor responsiveness to tyrosine kinase inhibitor (TKI) therapy. Using a high-content screen, we show that retinoids reverse this phenotype in part by inducing expression of wild type IKZF1, and increase responsiveness to TKIs. These findings provide new insight into the pathogenesis of high-risk ALL and potential new therapeutic approaches. Pre-B mRNA profiles of p185 MIG and IK6 cells, DMSO or drug treated, in 3 or 4 replicates, using Illumina HiSeq 2500.

2015-09-04 | E-GEOD-68391 | biostudies-arrayexpress

Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

Project description:Analysis of the effect of Prednisolone in mouse splenocytes with and without Ikzf1 at gene expression level. The hypothesis tested in the present study was that loss of Ikzf1 affects the induction and repression of the Glucocorticoid receptor target genes. Results provide important information of the differentially expressed genes regulated by Ikzf1 upon Prednisolone treatment, explaining the resistance towards Glucocorticoid-induced apoptosis in splenocytes harboring Ikzf1 loss. Total RNA was obtained from WT and Ikzf1+/- splenocytes subjected to 16 hours Prednsiolone treatment compared to untreated cells.

2015-02-04 | E-GEOD-65554 | biostudies-arrayexpress

Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia

2015-09-04 | GSE68391 | GEO

IKZF1 in BCR-ABL1 driven pre-B cells

Project description:In order to investigate the function of IKZF1 in ALL, we isolated bone marrow cells from C57Bl6 mice and transformed them with BCR-ABL1. In a second transduction the BCR-ABL1 driven pre-B cells were transformed either with IKZF1-GFP or empty vector control (GFP) and subjected to gene expression analysis.

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Integration of high-throughput reporter assays identify a critical enhancer of the Ikzf1 gene

Project description:The Ikzf1 locus encodes the lymphoid specific transcription factors Ikaros, which play an essential role in both T and B cell differentiation, while deregulation or mutation of IKZF1/Ikzf1 is involved in leukemia. Tissue-specific and cell identity genes are usually associated with clusters of enhancers, also called super-enhancers, which are believed to ensure proper regulation of gene expression throughout cell development and differentiation. Several potential regulatory regions have been identified in close proximity of Ikzf1, however, the full extent of the regulatory landscape of the Ikzf1 locus is not yet established. In this study, we combined epigenomics and transcription factor binding along with high-throughput enhancer assay and 4C-seq to prioritize an enhancer element located 120 kb upstream of the Ikzf1 gene. We found that the deletion of the E120 enhancer resulted in a significant reduction of Ikzf1 mRNA. However, the epigenetic landscape and 3D topology of the locus were only slightly affected, highlighting the complexity of the regulatory landscape regulating the Ikzf1 locus

2021-03-31 | GSE147234 | GEO

Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

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IKZF1 gene deletions in BCP-ALL promote resistance to cytarabine treatment

Project description:To obtain further insight into the pathways or specific genes that drive resistance to AraC upon loss of IKZF1, we performed RNAsequencing on samples from wildtype and IKZF1 knockout Sem cells treated with and without AraC

2023-08-31 | GSE234637 | GEO

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