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| Status |
Public on Jun 09, 2022 |
| Title |
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [Cut & Run] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Transcriptional coregulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and lymphoid malignancies. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the turnover of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Several of the degraded NuRD complex subunits are themselves lineage-specific cancer dependencies, providing motivation to develop paralog-selective HDAC degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.
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| Overall design |
Profiling genomic localization of HDAC2, HDAC2-dTAG, MBD3, CHD4 in BE(2)-C wild-type cells at steady state and compare change of H3K9ac and H3K27ac with HDAC2 degradation in BE(2)-C-HDAC2-dTAG cells by CUT&RUN.
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| Contributor(s) |
Erb MA, Zhang Y |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
May 11, 2022 |
| Last update date |
Jun 10, 2022 |
| Contact name |
Yuxiang Zhang |
| E-mail(s) |
zyx2719@gmail.com
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| Organization name |
The Scripps Research Institute
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| Department |
Chemistry
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| Lab |
Erb Lab
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| Street address |
10550 N. Torrey Pines Rd.
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| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
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| Platforms (1) |
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| Samples (12)
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| GSM6131583 |
BE2C-WT, CHD4 |
| GSM6131584 |
BE2C-WT, IgG control for MBD3, CHD4 |
| GSM6131585 |
BE2C-HDAC2-dTAG, HA |
| GSM6131586 |
BE2C-HDAC2-dTAG, IgG control for HA |
| GSM6131587 |
BE2C-HDAC2-dTAG, H3K9ac, DMSO (0.1%), 2 h |
| GSM6131588 |
BE2C-HDAC2-dTAG, H3K9ac, dTAG-13 (500 nM), 2 h |
| GSM6131589 |
BE2C-HDAC2-dTAG, H3K27ac, DMSO (0.1%), 2 h |
| GSM6131590 |
BE2C-HDAC2-dTAG, H3K27ac, dTAG-13 (500 nM), 2 h |
| GSM6131591 |
BE2C-HDAC2-dTAG, IgG control for H3K9ac, H3K27ac |
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| This SubSeries is part of SuperSeries: |
| GSE202706 |
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities |
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| Relations |
| BioProject |
PRJNA837078 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE202703_RAW.tar |
383.8 Mb |
(http)(custom) |
TAR (of BED, WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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