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| Status |
Public on Oct 25, 2022 |
| Title |
HDAC1 regulates the chromatin landscape to control transcriptional dependencies in chronic lymphocytic leukemia [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome wide occupancy of HDAC1, BRD4, H3K27Ac and H3K9Ac signals with chromatin accessibility, Pol2 occupancy and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers (SEs) marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression in CLL. Targeting HDACs reduced BRD4 and Pol2 engagement to downregulate the transcript and proteins levels of specific oncogenic driver genes in CLL such as BLK, a key mediator of the B-cell receptor pathway, core transcription factors such as PAX5 and IKZF3 and the anti-apoptotic gene, BCL2. Concurrently, HDAC1, when recruited in the absence of super-enhancers repressed target gene expression. HDAC inhibition reversed silencing of a defined set of protein coding and noncoding RNA genes. We focused on a specific set of microRNA genes and show that their upregulation was inversely correlated with the expression of CLL specific survival, transcription factor and signaling genes. Our findings identify that the transcriptional activator and repressor functions of HDACs cooperate within the same tumor to establish the transcriptional dependencies essential for survival in CLL.
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| Overall design |
CLL Cells were treated with vehicle (DMSO) or with abexinostat (0.4 mM) for 6 h before being harvested and processed for chromatin innunoprecipitation (ChIP) with the HDAC1, BRD4, H3K9Ac, H3K27Ac and RNA Pol II antibodies.
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| Contributor(s) |
Yilmaz AS, Ozer HG, Sampath D |
| Citation(s) |
36287107 |
| |
| Submission date |
Oct 21, 2022 |
| Last update date |
Feb 01, 2023 |
| Contact name |
Ayse Selen Yilmaz |
| E-mail(s) |
[email protected]
|
| Organization name |
OSU
|
| Department |
Biomedical Informatics
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| Lab |
Bioinformatics shared Resource
|
| Street address |
1800 Cannon Drive
|
| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43210 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (31)
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| This SubSeries is part of SuperSeries: |
| GSE216290 |
HDAC1 regulates the chromatin landscape to control transcriptional dependencies in chronic lymphocytic leukemia |
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| Relations |
| BioProject |
PRJNA892939 |
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