Abstract
Abstract Introduction: Trimethylation of Histone 3 Lysine 27 (H3K27) is widely understood to be a mark associated with gene repression and linked to gene silencing during development. Neuroblastoma, a developmental pediatric extracranial solid malignancy, has a relatively silent mutational landscape. Therefore, epigenetic modifications, including H3K27me3 mediated repression, could explain underlying developmental origins and the wide clinical heterogeneity observed. While previous studies have focused on the role of distinct super enhancer histone marks and their core regulatory circuits, less is understood about repressive control. We aimed to therefore investigate the role of H3K27me3-mediated repression in Neuroblastoma patients. Methods: Genome-wide H3K27me3 ChIP-Seq profiles were obtained from 48 diagnostic tissue biopsies covering all clinical and molecular patient subgroups. Transcriptome sequencing, ChIP-Seq of additional histone marks and WES/WGS was also performed on the same samples and on a panel of Neuroblastoma cell line models, with multiomics integrative analysis to validate findings. HMCAN, deepTools, DiffBind and ROSE packages were used to analyze the ChIP-seq data. Results: A comparison of H3K27me3 regions across all patient ChIP-Seq profiles, identified commonly repressed genes specific to Neuroblastoma. These genes are enriched in development and differentiation pathways, with significantly lower RNA expression levels than other publicly available pediatric tumor datasets. When compared to publicly available single cell RNAseq of the healthy adrenal medulla, we can further highlight a potential role of H3K27me3-mediated repression in regulating cell lineage commitment and differentiation ability. In addition, we identified that patient samples cluster into their clinical subgroups based on H3K27me3 patterns and differentially repressed genes, specifically between MYCN-amplified and non-amplified high-risk groups. A CRISPR screen to further validate the functional role of these repressed genes is being carried out. Conclusions: To our knowledge, this study shows for the first time that understanding of H3K27me3 mediated repression in Neuroblastoma, can uncover new insights into both disease development and clinical subclassifications. This knowledge will be important when considering future potential novel treatment options. Citation Format: Charlotte Butterworth, Alexandra Saint-Charles, Yasmine Iddir, Jaydutt Bhalshankar, Angela Bellini, Charles Bobin, Elisa Wecht, Young-Gyu Park, Caroline Louis, Virginie Raynal, Dominique Plantaz, Hervé Sartelet, Valérie Combaret, Gaelle Pierron, Isabelle Janoueix-Lerosey, Kai-Oliver Henrich, Olivier Delattre, Frank Westermann, Gudrun Schleiermacher. Study of spatial and temporal epigenetic heterogeneity in neuroblastoma suggests role of H3K27me3-mediated repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2847.
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