A comparative single-cell multi-omic atlas links intrinsic regulatory programs to microenvironmental signaling in pediatric brain tumors
Abstract
Pediatric brain tumors often carry few recurrent genetic alterations, placing regulatory mechanisms at the center of their pathogenesis. Yet how epigenetic states and microenvironmental cues rewire developmental programs remains poorly defined. Here we present a large-scale single-cell multi-omic atlas profiling chromatin accessibility and gene expression simultaneously in 127,478 cells from 37 patients spanning four major pediatric brain cancer types: diffuse high-grade glioma, circumscribed low-grade glioma, medulloblastoma, and ependymoma. We identified more than 330,000 candidate cis-regulatory elements (cCREs) and 58,000 peak-gene links, reconstructing a regulatory hierarchy from cancer-type-specific enhancers to subtype-restricted domains of regulatory chromatin (DORCs). Integrating these links with transcription factor (TF) motifs and gene expression defined regulons that distinguished cancer types, molecular subtypes, and intratumoral states more effectively than TF expression or motif accessibility alone, and selected regulon activities were associated with clinical outcomes. To integrate these intrinsic programs to their microenvironmental context, we developed SIREN, a computational framework that links extracellular signals to TF regulons in recipient cells. SIREN nominated candidate immune-tumor signaling relationships associated with cancer-type- and cell-state-specific oncogenic programs. Together, this atlas provides an enabling resource for tracing pediatric brain tumor regulation from CREs to malignant cell states and candidate microenvironmental inputs, while prioritizing regulatory mechanisms for functional investigation.
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