eTRex Reveals Oncogenic Transcriptional Regulatory Programs Across Human Cancers

Abstract

Transcriptional regulators (TRs) are essential proteins that regulate gene transcription, and their dysregulation defines the oncogenic transcriptional regulatory programs that drive tumor-specific gene expression. Existing pan-cancer resources summarize these programs by aggregating signals across individual datasets, neglecting the context-specific features that capture the diversity of transcriptional regulation underlying cancer heterogeneity. By developing a variational Bayesian hierarchical model named eTRex (epigenomics-based Transcriptional Regulator explorer) and applying it to 4,819 cancer-related ATAC-seq datasets, we provide a comprehensive pan-cancer atlas of functional TR profiles that preserve the context-specific features of each dataset. This study reveals both common regulators across diverse malignancies and those with highly specific roles. We extensively validated these findings using independent CRISPR/Cas9 screening, mutation, and transcriptomic datasets. Collectively, this pan-cancer atlas of functional TR profiles represents a comprehensive, biologically interpretable resource for uncovering transcriptional regulatory programs, identifying biomarkers, prioritizing therapeutic targets in oncology, and is freely accessible through an interactive web portal.