Alteration of CTCF associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis
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ABSTRACT:
PROVIDER: PRJNA558386 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9894930_1.fastq.gz | Fastqsanger.gz | |||
| SRR9894930_2.fastq.gz | Fastqsanger.gz | |||
| SRR9894940_1.fastq.gz | Fastqsanger.gz | |||
| SRR9894940_2.fastq.gz | Fastqsanger.gz | |||
| SRR9894950_1.fastq.gz | Fastqsanger.gz |
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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:Aberrant activation of the TAL1 is associated with up to 60% of T-ALL cases and is involved in CTCF-mediated genome organization within the TAL1 locus, suggesting that CTCF boundary plays a pathogenic role in T-ALL. Here, we show that -31-Kb CTCF binding site (-31CBS) serves as chromatin boundary that defines topologically associating domain (TAD) and enhancer/promoter interaction required for TAL1 activation. Deleted or inverted -31CBS impairs TAL1 expression in a context-dependent manner. Deletion of -31CBS reduces chromatin accessibility and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter-1 leading to inhibition of TAL1 expression in erythroid cells, but not T-ALL cells. However, in TAL1-expressing T-ALL cells, the leukemia-prone TAL1 promoter-IV specifically interacts with the +19 stem cell enhancer located 19 Kb downstream of TAL1 and this interaction is disrupted by the -31CBS inversion in T-ALL cells. Inversion of -31CBS in Jurkat cells alters chromatin accessibility, histone modifications and CTCF-mediated TAD leading to inhibition of TAL1 expression and TAL1-driven leukemogenesis. Thus, our data reveal that -31CBS acts as critical regulator to define +19-enhancer and the leukemic prone promoter IV interaction for TAL1 activation in T-ALL. Manipulation of CTCF boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.
| S-EPMC7102946 | biostudies-literature
Project description:A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain the gene expression pattern during hematopoiesis. In this network transcription factors regulate each other and are involved in regulatory loops with microRNAs.The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes for six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.
2021-09-09 | PXD018052 | Pride
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: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.
2014-07-10 | GSE59257 | GEO
Project description:TAL1/SCL is a hematopoietic-specific oncogene and its activity is regulated by associated transcriptional co-activators and corepressors. Dysregulation of TAL1 activity has been associated with T-cell leukemogenesis. However, it remains unclear how the interactions between TAL1 and corepressors versus co-activators are properly regulated. Here, we reported that protein kinase A (PKA)-mediated phosphorylation regulates TAL1 interaction with the lysine-specific demethylase (LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails. Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 interaction leading to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis. Knockdown of TAL1 or LSD1 led to a derepression of the TAL1 target genes in T-cell acute lymphoblast leukemia (T-ALL) Jurkat cells, which is accompanied by elevating promoter H3K4 methylation. Similarly, treatment of PKA activator forskolin resulted in derepression of target genes by reducing its interaction with LSD1 while PKA inhibitor H89 represses them by suppressing H3K4 methylation levels. Consistent with the dual roles of TAL1 in transcription, TAL1-associated LSD1 is decreased while recruitment of hSET1 is increased at the TAL1 targets during erythroid differentiation. This process is accompanied by a dramatic increase in H3K4 methylation. Thus, our data revealed a novel interplay between PKA phosphorylation and TAL1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis.
| S-EPMC3510314 | biostudies-literature
Project description:miRNA profiling of Jurkat T-ALL cells after knockdown with two control shRNAs and two shRNAs targeting TAL1 to identify miRNAs that are regulated by TAL1
2013-06-15 | GSE46957 | GEO
Project description:miRNA profiling of Jurkat T-ALL cells after knockdown with two control shRNAs and two shRNAs targeting TAL1 to identify miRNAs that are regulated by TAL1 miRNA profiling using Exiqon arrays 48hrs after transduction of Jurkat cells with two control shRNAs (pLKO1-GFP and pLKO1-LUCIFERASE) vs two shRNAs targeting TAL1 (pLKO1-shRNA1 and pLKO1-shRNA2). Biological duplicates per shRNA. One replicate per array.Total of 8 arrays.
2013-06-15 | E-GEOD-46957 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE20544: TAL1 knock down in Jurkat cells GSE20545: TAL1 knock down in human erythroid progenitors Refer to individual Series
2010-12-14 | E-GEOD-20546 | biostudies-arrayexpress
Project description:Analyses of the consequences of up- and down-regulating SCL/TAL1 in human enriched hematopoietic stem progenitor cells (HSPCs). We used microarrays to detail the global gene expression program of human cord blood HSPCs (CD34+CD38-lowCD34RA-CD90+) in which SCL/TAL1 expression is either up- or down-regulated.
2015-10-23 | GSE62634 | GEO