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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275390 | GEO | 2024/08/22

REPOSITORIES: GEO

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Project description:In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of the factor occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner across most active cis-regulatory promoters and enhancers. MYCN shutdown globally reduces histone acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. We establish that MYCN load at the promoter and proximal enhancers predicts transcriptional responsiveness to MYCN shutdown and that MYCN enhancer binding occurs prominently at the most strongly occupied and down-regulated genes, suggesting a role for these tissue specific elements in predicating MYCN responsive âtargetâ genes. At these invaded enhancers, we identify the lineage specific bHLH TWIST1 as a key collaborator and dependency of oncogenic MYCN. These data suggest that MYCN enhancer invasion helps shape transcriptional amplification of the neuroblastoma gene expression program to promote tumorigenesis. ChIP-Seq in SHEP21, BE2C, KELLY, and NGP neuroblastoma cell lines for H3K27ac, H3K4me3, RNA PolII, MYCN, BRD4, or TWIST1

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

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