Abstract
Transcriptional regulatory elements (TREs) orchestrate gene expression programs fundamental to cellular identity and transitions between physiological and pathological states. Decoding the regulatory logic of human biology requires resolving where, when, and how these elements are transcriptionally engaged. Here, we profiled the active transcriptional regulatory landscape across all major organ systems and a broad spectrum of developmental and disease states using PRO-cap, a high-resolution method that captures nascent transcription start sites with unprecedented sensitivity and specificity. This atlas of active TREs highlights elements shaped by their cellular contexts and evolutionary constraints, sheds light on the genetic architecture of human traits and diseases, and reveals how patterns of transcription initiation and pausing encode regulatory logic. In cancer, nascent transcription enables the delineation of lineage-specific regulatory states, metastatic adaptations, and the co-option of pre-existing programs. Together, these findings establish nascent transcription as a core dimension of gene regulation, illuminating principles that govern development, physiology, and disease.