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| Status |
Public on Apr 06, 2020 |
| Title |
Alteration of CTCF associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Other
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| Summary |
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.
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| Overall design |
We have finished the RNA-SEQ, ATAC-seq, ChIP-seq and HiC-seq to investigate the role of TAL1 transcription and CTCF boundaries in leukemogenesis. Jurkat leukemia cells and K562 cells were used to perform the RNA-seq, ATAC-seq, 4Cseq, CHIP-seq and HiC-seq analysis.
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| Contributor(s) |
Luo H, Huang S |
| Citation(s) |
32086528 |
| Submission date |
Aug 02, 2019 |
| Last update date |
Apr 06, 2020 |
| Contact name |
Suming Huang |
| E-mail(s) |
huanglabseq@hotmail.com
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| Organization name |
Penn State University
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| Department |
Pediatrics
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| Street address |
500 University Dr.
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| City |
Hershey |
| State/province |
PA |
| ZIP/Postal code |
17033 |
| Country |
USA |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA558386 |
| SRA |
SRP217227 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE135320_RAW.tar |
3.9 Mb |
(http)(custom) |
TAR (of BED, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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