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Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma [CRISPR/Cas9 screen]

ABSTRACT: Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma [CRISPR/Cas9 screen]

PROVIDER: PRJNA1150587 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30331609_1.fastq.gz	Fastqsanger.gz
	SRR30331609_2.fastq.gz	Fastqsanger.gz
	SRR30331610_1.fastq.gz	Fastqsanger.gz
	SRR30331610_2.fastq.gz	Fastqsanger.gz
	SRR30331611_1.fastq.gz	Fastqsanger.gz

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Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma [CRISPR/Cas9 screen]

Project description:Childhood neuroblastoma with MYCN-amplification is classified as high-risk and often relapses after intensive treatment regimen. Immune checkpoint blockade therapy shows limited efficacy in neuroblastoma patients and the cancer intrinsic immune regulatory network is poorly understood. Here, we leveraged genome-wide CRISPR/Cas9 screens in a human co-culture system and identified H2AFY as a resistance gene to nivolumab. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverted in vivo resistance to PD-1 blockade by eliciting concurrent activation of the adaptive and innate immunity. Analysis of single-cell RNA sequencing datasets revealed that H2AFY mRNA was enriched in adrenergic cancer cells and was associated with patient survival. Mapping of the epigenetic and translational landscape demonstrated that H2afy deletion promoted cell transition to a malignant mesenchymal-like state. With a multi-omics approach, we uncovered H2AFY-associated genes that were functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell state and immunogenicity in high-risk human neuroblastoma.

2024-08-22 | GSE275390 | GEO

Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma

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Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma [CUT&RUN]

2024-06-25 | GSE270196 | GEO

Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma

Project description:Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma

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Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma [CUT&RUN]

Project description:Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma [CUT&RUN]

| PRJNA1125401 | ENA

CRISPR-Cas9 RBM10 synthetic lethality screen

Project description:Genome-wide CRISPR-Cas9 knockout screen using TKOv1 sgRNA library was performed in isogenic RBM10-proficient and RBM10-deficient HCC827 cells.

2023-03-04 | E-MTAB-12724 | biostudies-arrayexpress

Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma.

Project description:Childhood neuroblastoma with MYCN amplification is classified as high risk and often relapses after intensive treatments. Immune checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in patients with neuroblastoma, and the cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody nivolumab. Analysis of single-cell RNA-Seq datasets reveals that H2AFY mRNA is enriched in adrenergic cancer cells and is associated with worse patient survival. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverts in vivo resistance to PD-1 blockade by eliciting activation of the adaptive and innate immunity. Mapping of the epigenetic and translational landscape demonstrates that H2afy deletion promotes cell transition to a mesenchymal-like state. With a multiomics approach, we uncovered H2AFY-associated genes that are functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell states and immunogenicity in high-risk neuroblastoma.

| S-EPMC11527455 | biostudies-literature

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2.

Project description:Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

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CRISPR-Cas9 RBM10 synthetic lethality screen

Project description:CRISPR-Cas9 RBM10 synthetic lethality screen

| PRJEB60386 | ENA

The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.

2023-05-10 | PXD039332 | Pride

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