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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 06, 2020 |
| Title |
Genome-wide maps of factors and gene expression in pre-B leukemic 697 line |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
E2A, a basic helix-loop-helix (bHLH) transcription factor, plays a crucial role in determining tissue-specific cell fate, including differentiation of B cell lineages. In 5% of childhood acute lymphoblastic leukemia (ALL), the t(1,19) chromosomal translocation specifically targets the E2A gene and produces an oncogenic E2A-PBX1 fusion protein. While previous studies have demonstrated oncogenic functions of E2A-PBX1 in cell and animal models, the E2A-PBX1-enforced cistrome, the E2A-PBX1 interactome, and related mechanisms underlying leukemogenesis remain unclear. Here, by unbiased genomic profiling approaches, we identify the direct target sites of E2A-PBX1 in t(1,19)-positive pre-B ALL cells and show that, compared to normal E2A, E2A-PBX1 preferentially binds to a subset of gene loci co-bound by RUNX1 and gene-activating machineries (p300, MED1, and H3K27 acetylation). Using biochemical analyses, we further document a direct interaction between E2A-PBX1 and RUNX1 and show that E2A-PBX1 binding to gene enhancers is dependent on RUNX1, but not the DNA-binding activity harbored within the PBX1 homeodomain of E2A-PBX1. Transcriptome analyses and cell transformation assays further establish a significant RUNX1 requirement for E2A-PBX1-mediated target gene activation and leukemogenesis. Notably, the RUNX1 locus itself is also directly activated by E2A-PBX1, indicating a multilayered interplay between E2A-PBX1 and RUNX1. Collectively, our study provides the first unbiased profiling of the E2A-PBX1 cistrome in pre-B ALL cells and reveals a previously unappreciated pathway in which E2A-PBX1 acts in concert with RUNX1 to enforce transcriptome alterations for the development of pre-B ALL.
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| Overall design |
Genome-wide binding/occupancy profiling of E2A-PBX1, E2A, p300, RUNX1, H3K27ac, and MED1 by ChIP-seq and gene expression profiling by RNA-seq in 697 cells treated without or with indicated shRNAs
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| Contributor(s) |
Chen W, Pi W, Roeder R |
| Citation(s) |
32276273 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA178765 |
Transcriptional regulatory mechanisms in B cell development and leukemogenesis |
THE ROCKEFELLER UNIVERSITY |
ROBERT G ROEDER |
| R01 CA163086 |
Function and targeting of a stable transcription factor complex in leukemia |
THE ROCKEFELLER UNIVERSITY |
ROBERT G ROEDER |
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| Submission date |
Sep 26, 2019 |
| Last update date |
Feb 10, 2021 |
| Contact name |
Wei-Yi Chen |
| E-mail(s) |
chenwy@nycu.edu.tw
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| Phone |
+886-2-2826-7328
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| Organization name |
National Yang Ming Chiao Tung University
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| Department |
Institute of Biochemistry and Molecular Biology
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| Street address |
No. 155, Sec 2, Linong St.
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| City |
Taipei |
| ZIP/Postal code |
112 |
| Country |
Taiwan |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (19)
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| Relations |
| BioProject |
PRJNA574266 |
| SRA |
SRP223377 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE138031_697_RNA_Expression_rpkm.txt.gz |
3.2 Mb |
(ftp)(http) |
TXT |
| GSE138031_RAW.tar |
5.8 Gb |
(http)(custom) |
TAR (of BED, BIGWIG, TDF) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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