TAL1 activation in T-ALL: A novel oncogenic 3' Neo-enhancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA827034 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18768934.fastq.gz | Fastqsanger.gz | |||
| SRR18768935.fastq.gz | Fastqsanger.gz | |||
| SRR18768936.fastq.gz | Fastqsanger.gz | |||
| SRR18768937.fastq.gz | Fastqsanger.gz | |||
| SRR18768938.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-05-10 | GSE200860 | GEO
Project description:Aberrant activation of the TAL1 oncogene is associated with up to 60% of T-ALL patients and is involved in CTCF mediated genome organization within the TAL1 locus, suggesting the importance of the CTCF boundary in the molecular pathogenesis of T-ALL. Here, we show that deletion of CTCF binding site (CBS) or alternation of CTCF boundary orientation alters expression of the TAL1 oncogene in a cell context dependent manner. Deletion of the CTCF binding site located at -31 Kb upstream of TAL1 (-31CBS) reduces chromatin accessibility in the +51 enhancer and the TAL1 promoter I, and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter 1b that inhibits expression of TAL1 in erythroid cells, but not in T-ALL cells. However, in the TAL1 expressed T-ALL primary patient samples or cell line, the T-ALL prone TAL1 promoter IV specifically interacts with the +19 stem cell enhancer that is located 19 kb downstream of the TAL1 promoter and required for TAL1 transcription in the hematopoietic stem cell (HSC) stage. Inversion of -31CBS orientation, but not deletion of -31CBS, alters chromatin accessibility, enhancer/promoter histone modifications, CTCF-mediated topological associated domain (TAD), and enhancer/promoter interaction in the TAL1 locus leading to inhibition of TAL1 oncogene expression and TAL1-driven T cell leukemogenesis. Thus, our data reveal that the TAL1 +19 stem cell enhancer acts not only as stem cell enhancer, but also as a leukemia specific enhancer to activate the TAL1 oncogene in T-ALL. Manipulation of CTCF defined chromatin boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.
2020-04-06 | GSE135320 | GEO
Project description:TAL1 activation in T-Cell Acute Lymphoblastic Leukemia: A novel oncogenic 3’ Neo-enhancer
| PRJEB56774 | ENA
Project description:The TAL1 oncogene driving T-cell lymphoblastic leukemia (T-ALL) is frequently activated through a mutated cis-regulatory element, whereby small indels create a binding site for the transcription factor MYB. Unravelling how noncoding mutations create oncogenic enhancers is key to understanding cancer biology and can provide important insights into fundamental mechanisms of gene regulation. Utilising a CRISPR-Cas9 screening approach, we identified GATA3 as the key transcriptional regulator of enhancer-mediated TAL1 overexpression. CRISPR-Cas9 engineering of the mutant enhancer revealed a tandem GATA3 site that is required for binding of GATA3, acquisition of an open chromatin state and recruitment of MYB. Reciprocally, MYB binding to its motif is required for GATA3 recruitment, consistent with a transcription factor cooperativity model. Importantly, we show that GATA3 stabilises a TAL1-MYB interaction and that complex formation requires GATA3 binding to DNA. Our work sheds light on the mechanisms of enhancer-mediated oncogene activation, where key TFs cooperate to achieve maximal transcriptional output and thereby support leukemogenesis.
2025-04-01 | GSE290905 | GEO
Project description:In many cancers, critical oncogenes are driven from large regulatory elements, called super-enhancers, which recruit much of the cellM-bM-^@M-^Ys transcriptional apparatus and are defined by extensive H3K27 acetylation. We found that in T-cell acute lymphoblastic leukemia (T-ALL), somatic heterozygous mutations introduce MYB binding motifs in a precise noncoding site, which nucleate a super-enhancer upstream of the TAL1 oncogene. Further analysis of genome-wide binding identified MYB and its histone acetylase binding partner CBP as core components of the TAL1 complex and of the TAL1-mediated feed-forward auto-regulatory loop that drives T-ALL. Furthermore, MYB and CBP occupy endogenous MYB binding sites in the majority of super-enhancer sites found in T-ALL cells. Thus, our study reveals a new mechanism for the generation of super-enhancers in malignant cells involving the introduction of somatic indel mutations within non-coding sequences, which introduce aberrant binding sites for the MYB master transcription factor. ChIP-Seq for transcription factors and co-factors in T cell acute lymphoblastic leukemia cell lines
2014-11-13 | E-GEOD-59657 | biostudies-arrayexpress
Project description:Tissue-specific gene expression requires coordinated control of gene-proximal and distal cis-regulatory elements (CREs), yet functional analysis of putative gene-distal CREs such as enhancers remains challenging. Here we describe enhanced CRISPR/dCas9-based epigenetic editing systems, enCRISPRa and enCRISPRi, for multiplexed analysis of enhancer function in situ and in vivo. Using dual effector proteins capable of re-writing enhancer-associated chromatin modifications, we show that enCRISPRa and enCRISPRi modulate gene transcription by remodeling local epigenetic landscapes at sgRNA-targeted enhancers and associated genes. Comparing with existing methods, our systems display more robust and specific perturbations of gene transcription with minimal off-targets. Allele-specific targeting of enCRISPRa to oncogenic TAL1 super-enhancer modulates TAL1 expression and cancer progression in xenotransplants. Furthermore, multiplexed perturbations of lineage-specific enhancers in an enCRISPRi knock-in mouse establish in vivo evidence for lineage-restricted requirement of developmentally regulated enhancers during hematopoietic lineage specification. Hence, enhanced CRSIPR epigenetic editing provides opportunities for interrogating enhancer function in development and disease.
2020-01-30 | GSE132212 | GEO
Project description:T-cell acute lymphoblastic leukemia’s (T-ALL) are malignant proliferations of thymocytes occurring through a large diversity of genomic and epigenetic alteration. TAL1 is amongst the most frequently deregulated oncogenes. Known TAL1 dysregulation mechanisms consist of t(1;14) translocations and SIL-TAL deletions. Yet, over half of TAL1+ cases lack TAL1 lesions, pointing to unrecognized (epi)genetic deregulation mechanisms. In such “unresolved cases”, TAL1 expression can be mono-allelic, compatible with a direct alteration in cis within or around the TAL1 gene, or bi-allelic, likely reflecting indirect deregulation in trans. Using ChIP-seq, we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3 repressive mark is focally diminished in TAL1+ T-ALLs. Sequencing revealed that >20% of mono-allelic TAL1+ patients without previously known alterations display micro-insertions or RAG1/2-mediated episomal reintegration in a single site 5’ to TAL1. Using “allelic-ChIP” and CrispR assays, we demonstrate that such insertions induce selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies reveal a new adverse mechanism of mono-allelic oncogenic activation through site-specific epigenetic de-silencing. ChIP-seq experiments were designed to asses the dynamic enrichment of H3K27me3 and H3K27ac marks on the genome and understand the mechanisms underlying the TAL1 expression cys-regulation.
2014-07-10 | E-GEOD-59257 | biostudies-arrayexpress
Project description:Here, we showed that a long non-coding RNA (lncRNA), ncRNA-a3 that is transcribed from TAL1 erythroid +51kb enhancer, is required for TAL1 activation during EPO-induced lineage commitment and formation of erythroblasts. ncRNA-a3 regulates long-range chromatin interactions between +51 enhancer, promoter and other regulatory elements in the TAL1 locus to maintain the erythroid interaction hub. By binding and recruiting p300/BRG1 to the TAL1 locus ncRNA-a3 facilitates chromatin accessibility in the TAL1 locus and activates TAL1 transcription program, including subsequent epigenetic and transcriptional activation of erythroid specific TAL1 target genes.
2025-05-07 | GSE272339 | GEO
Project description:Here, we showed that a long non-coding RNA (lncRNA), ncRNA-a3 that is transcribed from TAL1 erythroid +51kb enhancer, is required for TAL1 activation during EPO-induced lineage commitment and formation of erythroblasts. ncRNA-a3 regulates long-range chromatin interactions between +51 enhancer, promoter and other regulatory elements in the TAL1 locus to maintain the erythroid interaction hub. By binding and recruiting p300/BRG1 to the TAL1 locus ncRNA-a3 facilitates chromatin accessibility in the TAL1 locus and activates TAL1 transcription program, including subsequent epigenetic and transcriptional activation of erythroid specific TAL1 target genes.
2025-05-07 | GSE272338 | GEO
Project description:Here, we showed that a long non-coding RNA (lncRNA), ncRNA-a3 that is transcribed from TAL1 erythroid +51kb enhancer, is required for TAL1 activation during EPO-induced lineage commitment and formation of erythroblasts. ncRNA-a3 regulates long-range chromatin interactions between +51 enhancer, promoter and other regulatory elements in the TAL1 locus to maintain the erythroid interaction hub. By binding and recruiting p300/BRG1 to the TAL1 locus ncRNA-a3 facilitates chromatin accessibility in the TAL1 locus and activates TAL1 transcription program, including subsequent epigenetic and transcriptional activation of erythroid specific TAL1 target genes.
2025-05-07 | GSE272341 | GEO