From 3D to 4D: spatiotemporal genome architecture and functional genomics in cardiovascular disease

The human genome is highly organized within the nucleus and is remodeled across physiological and disease states. Enabled by rapidly advancing technologies for mapping three-dimensional chromatin architecture, recent works have begun to define how three-dimensional chromatin architecture changes in the cardiovascular system and how these changes influence gene regulation. Here, we summarize the hierarchical folding features of 3D chromatin architecture and discuss major sequencing- and imaging-based strategies for mapping chromatin organization, including emerging single-cell and multimodal approaches that extend static 3D maps toward a spatiotemporal 4D nucleome perspective. We highlight how genetic variants, structural variants, mechanical forces, metabolic-inflammatory stress and lamina-genome disruption reshape chromatin topology in heart development, aging and cardiovascular diseases. Representative examples across cardiovascular diseases illustrate how altered enhancer-promoter communication, chromatin insulation and nuclear positioning can contribute to pathogenic gene regulation. Finally, we discuss the therapeutic potential of 3D genome engineering and propose that the near-term translational value of cardiovascular 3D genomics lies primarily in improving disease-gene nomination and therapeutic target prioritization, while direct manipulation of chromatin architecture remains a promising but technically challenging frontier.