Multiomics analysis reveals super enhancer associated GTSF1 and Schwann cell heterogeneity in neuroblastoma

Super-enhancers (SEs) contribute to oncogenic transcriptional programs in neuroblastoma (NB), but their relationship with nerve-associated microenvironmental remodeling remains unclear. This study integrated epigenomic, transcriptomic, dependency, single-cell, and clinical validation analyses to identify nerve-/Schwann-cell-associated candidate genes and characterize PNI-related cellular features in NB. H3K27ac ChIP-seq data were analyzed using ROSE2 to identify SEs, and transcription factor motifs were predicted using FIMO. SE-associated genes were integrated with differential expression, survival, and DepMap dependency data. Public single-cell RNA-seq data were analyzed using Seurat and CellChat. GTSF1 expression was validated in a neuroblastoma tissue microarray by immunofluorescence. We identified 477 super-enhancers (SEs) and 737 enriched transcription factors, among which CREBBP/EP300 emerged as central regulatory hubs. Integrated analysis of SE-associated genes, clinical datasets, and CRISPR dependency data prioritized GTSF1 as an SE-associated candidate gene with prognostic associations and a context-dependent CRISPR dependency signal in neuroblastoma models. Immunofluorescence analysis showed higher GTSF1 expression in neuroblastoma tissues than in adult adrenal reference tissues, with higher expression in tumors from patients with distant metastasis than in those without distant metastasis. A curated nerve-/Schwann-cell-associated transcriptional program was preferentially enriched in Schwann cells. CellChat analysis further identified prominent computationally inferred Schwann-cell-associated communication, including MDK-associated signaling. This study identifies GTSF1 as a candidate SE-associated gene in NB and suggests that Schwann cells may participate in nerve-associated and MDK-centered microenvironmental communication.