Foundation model reveals the shared organization of transcription and topologically associating domains

Abstract

The three-dimensional organization of chromatin into topologically associating domains (TADs) may impact gene regulation by bringing distant genes into contact. However, studies of TADs function and their influence on transcription have been constrained by ambiguities in TAD boundary definitions and challenges in directly measuring their regulatory effects. We overcome these limitations by developing species-level consensus TAD maps for human and mouse using a bag-of-genes approach that exposes emergent regulatory structure. To quantify TAD-mediated gene relationships, we leverage a generative AI foundation model computed from 33 million transcriptomes to define a contextual similarity metric, revealing higher-order gene relationships elusive to co-expression analysis. We find that TADs are regions of elevated gene co-regulation, and our analytical framework directly leads to testable hypotheses about chromatin organization across cellular states. We discover that the TAD-linked enhancement of transcriptional context is strongest in early developmental stages and systematically declines with aging. Investigation of cancer cells show distinct patterns of TAD usage that shift with chemotherapy treatment. Enhancing our understanding of cellular plasticity in differentiation and disease, these findings suggest that chromatin organization may act through probabilistic mechanisms rather than deterministic rules. Software availabilityhttps://singhlab.net/tadmap