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Series GSE211354 Query DataSets for GSE211354
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
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.
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.
Contributor(s) Stegmaier K, Alexe G
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Submission date Aug 16, 2022
Last update date Apr 19, 2024
Contact name Gabriela Alexe
Organization name Broad Institute
Department Computational Biology and Bioinformatics
Street address 415 Main St.
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
Platforms (2)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (54)
GSM6467273 KELLY cells, DMSO, 6 hours, replicate 1
GSM6467274 KELLY cells, DMSO, 6 hours, replicate 2
GSM6467275 KELLY cells, DMSO, 6 hours, replicate 3
This SubSeries is part of SuperSeries:
GSE211355 The SAGA complex maintains the oncogenic gene expression program in MYCN-amplified neuroblastoma
BioProject PRJNA869946

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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
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Raw data are available in SRA
Processed data are available on Series record

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