The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.

The nucleus is a highly organized and dynamic organelle, with hierarchical layers ranging from nucleosome positioning to chromatin domains and higher-order 3D genome topology. Viewed over time as the 4D nucleome, this organization enables precise and context-dependent transcriptional control. In the heart, dynamic nuclear architecture orchestrates precise transcriptional programmes that control lineage commitment and the establishment of cardiac cell types crucial not only for heart development, but also for postnatal function and adaptive responses. Correspondingly, transitions between developmental and disease states are accompanied by coordinated changes in genome organization, chromatin accessibility and transcription factor occupancy. These architectural programmes are modulated by mechanical and metabolic inputs, which further shape chromatin organization, nuclear positioning and epigenetic state. Deciphering the 4D nucleome of the heart can potentially provide new insights into disease mechanisms, regenerative strategies and precision cardiovascular medicine. In this Review, we highlight studies that define the fundamental principles of nuclear organization; explore nuclear and chromatin reorganization during cardiac development, disease and ageing; and discuss emerging methods to interrogate nuclear architecture. We also consider how mechanical and metabolic signals shape the 4D epigenome and examine their therapeutic and translational implications for cardiovascular health and disease.