A proteocistromic atlas of 216 human disease-relevant transcription factors

Abstract Transcription factors (TFs) execute regulatory programs by integrating signaling inputs with chromatin context, yet their activity has typically been examined either through chromatin occupancy or protein-protein interactions (PPIs), leaving unclear how regulatory information is jointly implemented on the genome. Here, we construct a comprehensive proteocistromic atlas of 216 human TFs within a unified cellular context by integrating affinity-based proteomics with ChIP-seq, mapping over 30,000 high-confidence TF-centered PPIs and showing that TF binding spans 11.66% of the human genome. We develop a quantitative proteocistromic score that integrates DNA-binding activity with effector-domain connectivity, enabling stratification of TFs by functional regulatory potency. High-scoring TFs are enriched for lineage-specifying factors and master regulators of cell fate. These TFs preferentially assemble into cooperative pairs that co-occupy shared regulatory elements, revealing coordinated control modules central to developmental and oncogenic pathways. Within these highly active TF clusters, allele-specific binding events preferentially colocalize with eQTLs and GWAS lead variants, particularly at proximal regulatory elements, directly linking TF binding asymmetry to genetically driven transcriptional varaition. Network-level analyses further delineate synergistic TF pairs and higher-order TF communities that are selectively rewired across cancer cohorts, nominating context-dependent regulatory hubs with biomarker and therapeutic potential. By anchoring genetic variation and transcriptional control within a unified proteocistromic reference, this study defines general organizational principles of TF function on chromatin and establishes proteocistromics as a scalable framework for connecting TF binding, protein interaction networks, and human disease risk.