Core transcriptional regulatory circuit controlled by the TAL1 complex in human T-cell acute lymphoblastic leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Richard Young
PROVIDER: E-GEOD-29181 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The oncogenic transcription factor TAL1/SCL is aberrantly overexpressed in over 40% of cases of T-cell acute lymphoblastic leukemia (T-ALL), emphasizing the importance of the TAL1-regulated transcriptional program in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, GATA3, ETS1 and RUNX1 in T-ALL cells. We find that TAL1 forms an interconnected auto-regulatory loop with its partners, which contributes to the sustained upregulation of its direct target genes. Importantly, we also find the MYB oncogenic transcription factor is directly activated by the TAL1 complex and positively regulates many of the same target genes, thus forming a feed-forward positive regulatory loop that further promotes the TAL1-regulated oncogenic program. Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total TAL1 (Santa Cruz SC-12984), TCF12/HEB (Santa Cruz SC-357),TCF3/E2A (Santa Cruz SC-349X), LMO1 (Santa Cruz SC-10494), LMO2 (R&D Systems AF2726), GATA3 (Santa Cruz SC-22206) and RUNX1 (Santa Cruz SC-8563). This represents the ChIP-seq portion of this dataset. Human Jurkat cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total TAL1 (Santa Cruz SC-12984), TCF12/HEB (Santa Cruz SC-357),TCF3/E2A (Santa Cruz SC-349X), LMO1 (Santa Cruz SC-10494), GATA3 (Santa Cruz SC-22206) and RUNX1 (Santa Cruz SC-8563). This represents the ChIP-seq portion of this dataset.
2012-03-14 | E-GEOD-33850 | biostudies-arrayexpress
Project description:The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of T-cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1, LMO2, GATA3 and RUNX1 in T-ALL cells. We show that TAL1 forms an interconnected auto-regulatory loop with its partners, and that the TAL1 complex directly activates the MYB oncogene, forming a feed-forward positive regulatory loop that further promotes the TAL1-regulated oncogenic program. one of the cirtical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and HEB/E2A, and is essential for the survival of T-ALL cells. Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total TAL1 (Santa Cruz SC-12984), TCF12/HEB (Santa Cruz SC-357),TCF3/E2A (Santa Cruz SC-349X), LMO1 (Santa Cruz SC-10494), LMO2 (R&D AF2726),GATA3 (Santa Cruz SC-22206) and RUNX1 (Santa Cruz SC-8563). This represents the ChIP-seq portion of this dataset.
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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:The oncogenic transcription factor TAL1/SCL is aberrantly overexpressed in over 40% of cases of T-cell acute lymphoblastic leukemia (T-ALL), emphasizing the importance of the TAL1-regulated transcriptional program in the molecular pathogenesis of T-ALL. Here we identify regions occupied by TAL1 and its regulatory partners HEB, E2A, and GATA3 in a T-ALL cell line (RPMI-8402). Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total TAL1 (Santa Cruz SC-12984), TCF12/HEB (Santa Cruz SC-357),TCF3/E2A (Santa Cruz SC-349X), and GATA3 (Santa Cruz SC-22206).
2012-07-09 | E-GEOD-39179 | biostudies-arrayexpress
Project description:While many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly co-expressed genes, some of which are restricted to a single lineage, but most are expressed at variable levels across multiple lineages. We found densely interconnected cis-regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states, suggesting a more complex regulatory system than previously assumed. We functionally validated a subset of candidate factors using RNA interference and ChIP-Seq. Our dataset, analytic tools, and findings, available on a web-based portal, provide a unique resource to study the regulatory architecture of hematopoiesis. Human CD133-positive Umbilical Cord Blood (UCB) cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total TAL1 (Santa Cruz SC-12984), PU.1/SPI1 (Santa Cruz SC-352X), IKAROS (Santa Cruz SC-9859X) and MEIS1 (Abcam ab19867). This submission represents the ChIP-seq component of the study.
2011-01-26 | E-GEOD-26014 | biostudies-arrayexpress
Project description:Three transcriptional states can be defined by histone modifications and RNA polymerase II enriched at promoters and across the body of genes. To gain insight into the active, poised and silent genes in human T-ALL cells, two antibodies against RNAP2, and antibodies against H3K4me3, H3K79me2, and H3K27me3 were used for chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq). Genomic DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. ChIP was performed using an antibody against RNAP2, H3K4me3, H3K79me2, and H3K27me3 using whole cell extract (WCE) as a background control. ChIP was performed using a two antibody against hypophosphorylated forms of RNAP2 in two biological replicates. All other ChIPs were done in biological replicates with a single lane of sequencing.
2010-07-24 | E-GEOD-23080 | biostudies-arrayexpress
Project description:Transcription of oncogenes is regulated by co-factors, some of which are now targetable with small molecules. This series contains ChIP-Seq targeting transcriptional co-factors and RNA polymerase from cells treated with small molecules targeting co-factors. ChIP-Seq of RNA polymerase and co-factors in Jurkat T-ALL cells
2016-06-27 | E-GEOD-83777 | biostudies-arrayexpress
Project description:Here we identify the genome-wide occupancy of PHF6 in T-ALL cells. Human T-ALL cells were cross-linked with formaldehyde for 20 min. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. A sample of whole cell extract (WCE) was sequenced and used as the background to determine enrichment. ChIP was performed using an antibody against total PHF6 (Bethyl A301-451A). This represents the ChIP-seq portion of this dataset.
2014-04-01 | E-GEOD-45864 | biostudies-arrayexpress
Project description:A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected autoregulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell type-specific transcriptional regulation in healthy and diseased cells. ChIP-Seq for RUNX1 and GATA3 in Jurkat T cell acute lymphoblastic leukemia cells.
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