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| Status |
Public on Sep 14, 2023 |
| Title |
CUT&RUN profiling of histone H3K27ac and H3K27me3 localization after pharmacological inhibition of EZH2 and BET proteins |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
NUT carcinoma (NC), an aggressive carcinoma, is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and when fused to NUT forms very large super-enhancers, termed megadomains. Targeting BRD4-NUT with BET bromodomain inhibitors (BETi) are a promising treatment, but limited as monotherapy. To identify additional dependencies in NC, we performed a genetic rescue screen in NC cells depleted of BRD4-NUT and identified EZH2 as a top correlated hit. Indeed, inhibition of EZH2 using the clinical compound, tazemetostat (taz), potently blocked growth of NC cells, and when combined with BETi was highly synergistic. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on megadomain-associated genes. CDKN2A was identified as the only amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-CAS9 screen. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort.
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| Overall design |
CUT&RUN to assess histone H3K27ac and H3K27me3 localization after tazemetostat (EPZ-6438; EZH2 inhibitor) alone or tazemetostate combined with ABBV-075 (BET inhibitor) treatment of 10-15 and PER-403 cells, two NUT carcinoma cell lines.
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| Contributor(s) |
Hawkins CE, Ponne C, Le Q, Lemieux ME, French CA, Eagen KP |
| Citation(s) |
37747726 |
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| Submission date |
Mar 30, 2023 |
| Last update date |
Jan 11, 2024 |
| Contact name |
Kyle Eagen |
| E-mail(s) |
[email protected]
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| Organization name |
Baylor College of Medicine
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| Department |
Department of Molecular and Cellular Biology
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| Lab |
Eagen Lab
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| Street address |
1 Baylor Plaza
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| City |
Houston |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA950247 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE228533_10-15.H3K27ac.MEGADOMAINS.bed.gz |
3.0 Kb |
(ftp)(http) |
BED |
| GSE228533_10-15.H3K27ac.notMEGADOMAINS.bed.gz |
328.8 Kb |
(ftp)(http) |
BED |
| GSE228533_10-15.H3K27me3.MEGADOMAINS.bed.gz |
7.0 Kb |
(ftp)(http) |
BED |
| GSE228533_10-15.H3K27me3.notMEGADOMAINS.bed.gz |
379.6 Kb |
(ftp)(http) |
BED |
| GSE228533_PER-403.H3K27ac.MEGADOMAINS.bed.gz |
4.6 Kb |
(ftp)(http) |
BED |
| GSE228533_PER-403.H3K27ac.notMEGADOMAINS.bed.gz |
572.3 Kb |
(ftp)(http) |
BED |
| GSE228533_PER-403.H3K27me3.MEGADOMAINS.bed.gz |
12.1 Kb |
(ftp)(http) |
BED |
| GSE228533_PER-403.H3K27me3.notMEGADOMAINS.bed.gz |
770.7 Kb |
(ftp)(http) |
BED |
| GSE228533_RAW.tar |
2.9 Gb |
(http)(custom) |
TAR (of BW) |
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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