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| Status |
Public on Apr 19, 2024 |
| Title |
The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pediatric cancers are frequently driven by fusion or amplification events that result in aberrant transcription factor activity. As transcription factors themselves remain challenging to target, an emerging therapeutic approach for these cancers is to target epigenetic complexes that help maintain oncogenic transcriptional programs. It is therefore critical to identify the complete set of epigenetic modulators maintaining the oncogenic epigenetic landscape of pediatric cancers. Here, we used functional genomic screens to identify epigenetic complexes critical for viability in cell line models of MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We identified multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies in MYCN-amplified neuroblastoma. Integrating ChIP-seq, ATAC-seq, and RNA-seq with targeted protein-degradation and gene editing tools, we characterized the DNA recruitment sites of the SAGA complex in neuroblastoma, and the consequences of SAGA complex lysine acetyltransferase (KAT) activity loss on histone acetylation and gene expression. We demonstrate that loss of SAGA KAT activity suppresses MYC and MYCN gene expression programs and impairs cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable with a KAT2A/KAT2B proteolysis targeting chimera molecule that demonstrated significant activity in vitro and in vivo. Our findings expand our understanding of the histone modifying complexes that maintain the oncogenic transcriptional state in this disease and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.
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| Overall design |
Investigate alterations in gene expression after TADA2B loss (degradation dTAG v1 TADA2B vs. DMSO at 6 hours, 24 hours, and 72 hours; CRISPR TADA2B knock-out vs. control at 7 days and 12 days) and after KAT2A/KAT2B loss (GSK-699-1 vs. DMSO at 6 hours, 24 hours, and 72 hours) in KELLY neuroblastoma cells. Three replicates per condition.
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| Contributor(s) |
Stegmaier K, Alexe G |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Aug 16, 2022 |
| Last update date |
Apr 19, 2024 |
| Contact name |
Gabriela Alexe |
| E-mail(s) |
galexe@broadinstitute.org
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| Organization name |
Broad Institute
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| Department |
Computational Biology and Bioinformatics
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| Street address |
415 Main St.
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (2) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (54)
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| GSM6467273 |
KELLY cells, DMSO, 6 hours, replicate 1 |
| GSM6467274 |
KELLY cells, DMSO, 6 hours, replicate 2 |
| GSM6467275 |
KELLY cells, DMSO, 6 hours, replicate 3 |
| GSM6467276 |
KELLY cells, dTAG v1 TADA2B, 6 hours, replicate 1 |
| GSM6467277 |
KELLY cells, dTAG v1 TADA2B, 6 hours, replicate 2 |
| GSM6467278 |
KELLY cells, dTAG v1 TADA2B, 6 hours, replicate 3 |
| GSM6467279 |
KELLY cells, DMSO, 24 hours, replicate 1 |
| GSM6467280 |
KELLY cells, DMSO, 24 hours, replicate 2 |
| GSM6467281 |
KELLY cells, DMSO, 24 hours, replicate 3 |
| GSM6467282 |
KELLY cells, dTAG v1 TADA2B, 24 hours, replicate 1 |
| GSM6467283 |
KELLY cells, dTAG v1 TADA2B, 24 hours, replicate 2 |
| GSM6467284 |
KELLY cells, dTAG v1 TADA2B, 24 hours, replicate 3 |
| GSM6467285 |
KELLY cells, DMSO, 72 hours, replicate 1 |
| GSM6467286 |
KELLY cells, DMSO, 72 hours, replicate 2 |
| GSM6467287 |
KELLY cells, DMSO, 72 hours, replicate 3 |
| GSM6467288 |
KELLY cells, dTAG v1 TADA2B, 72 hours, replicate 1 |
| GSM6467289 |
KELLY cells, dTAG v1 TADA2B, 72 hours, replicate 2 |
| GSM6467290 |
KELLY cells, dTAG v1 TADA2B, 72 hours, replicate 3 |
| GSM6467291 |
KELLY cells, CRISPR LACZ, 7 days, replicate 1 |
| GSM6467292 |
KELLY cells, CRISPR LACZ, 7 days, replicate 2 |
| GSM6467293 |
KELLY cells, CRISPR LACZ, 7 days, replicate 3 |
| GSM6467294 |
KELLY cells, CRISPR sg2 TADA2B, 7 days, replicate 1 |
| GSM6467295 |
KELLY cells, CRISPR sg2 TADA2B, 7 days, replicate 2 |
| GSM6467296 |
KELLY cells, CRISPR sg2 TADA2B, 7 days, replicate 3 |
| GSM6467297 |
KELLY cells, CRISPR sg4 TADA2B, 7 days, replicate 1 |
| GSM6467298 |
KELLY cells, CRISPR sg4 TADA2B, 7 days, replicate 2 |
| GSM6467299 |
KELLY cells, CRISPR sg4 TADA2B, 7 days, replicate 3 |
| GSM6467300 |
KELLY cells, CRISPR LACZ, 12 days, replicate 1 |
| GSM6467301 |
KELLY cells, CRISPR LACZ, 12 days, replicate 2 |
| GSM6467302 |
KELLY cells, CRISPR LACZ, 12 days, replicate 3 |
| GSM6467303 |
KELLY cells, CRISPR sg4 TADA2B, 12 days, replicate 1 |
| GSM6467304 |
KELLY cells, CRISPR sg4 TADA2B, 12 days, replicate 2 |
| GSM6467305 |
KELLY cells, CRISPR sg4 TADA2B, 12 days, replicate 3 |
| GSM6467306 |
KELLY cells, CRISPR sg5 TADA2B, 12 days, replicate 1 |
| GSM6467307 |
KELLY cells, CRISPR sg5 TADA2B, 12 days, replicate 2 |
| GSM6467308 |
KELLY cells, CRISPR sg5 TADA2B, 12 days, replicate 3 |
| GSM7871829 |
PROTAC-RNA, KELLY cells, DMSO, 6 hours, replicate 1 |
| GSM7871830 |
PROTAC-RNA, KELLY cells, DMSO, 6 hours, replicate 2 |
| GSM7871831 |
PROTAC-RNA, KELLY cells, DMSO, 6 hours, replicate 3 |
| GSM7871832 |
PROTAC-RNA. KELLY cells, GSK-699-1, 6 hours, replicate 1 |
| GSM7871833 |
PROTAC-RNA. KELLY cells, GSK-699-1, 6 hours, replicate 2 |
| GSM7871834 |
PROTAC-RNA. KELLY cells, GSK-699-1, 6 hours, replicate 3 |
| GSM7871835 |
PROTAC-RNA, KELLY cells, DMSO, 24 hours, replicate 1 |
| GSM7871836 |
PROTAC-RNA, KELLY cells, DMSO, 24 hours, replicate 2 |
| GSM7871837 |
PROTAC-RNA, KELLY cells, DMSO, 24 hours, replicate 3 |
| GSM7871838 |
PROTAC-RNA, KELLY cells, GSK-699-1, 24 hours, replicate 1 |
| GSM7871839 |
PROTAC-RNA, KELLY cells, GSK-699-1, 24 hours, replicate 2 |
| GSM7871840 |
PROTAC-RNA, KELLY cells, GSK-699-1, 24 hours, replicate 3 |
| GSM7871841 |
PROTAC-RNA, KELLY cells, DMSO, 72 hours, replicate 1 |
| GSM7871842 |
PROTAC-RNA, KELLY cells, DMSO, 72 hours, replicate 2 |
| GSM7871843 |
PROTAC-RNA, KELLY cells, DMSO, 72 hours, replicate 3 |
| GSM7871844 |
PROTAC-RNA, KELLY cells, GSK-699-1, 72 hours, replicate 1 |
| GSM7871845 |
PROTAC-RNA, KELLY cells, GSK-699-1, 72 hours, replicate 2 |
| GSM7871846 |
PROTAC-RNA, KELLY cells, GSK-699-1, 72 hours, replicate 3 |
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| This SubSeries is part of SuperSeries: |
| GSE211355 |
The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma |
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| Relations |
| BioProject |
PRJNA869946 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE211354_RNASeq_all_samples_hg38_counts.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
| GSE211354_RNASeq_all_samples_hg38_log2TPMplus1.txt.gz |
4.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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