Mechanical Heterogeneity and the Nuclear Mechanome: Towards an Omics-Level Understanding of Nuclear Function
The cell nucleus is increasingly recognized as a mechanosensitive organelle whose mesoscale mechanical heterogeneity (100 nm 10 um) is inseparable from genome regulation yet remains weakly integrated into systems biology and omics frameworks. Here we synthesize experimental and theoretical advances that define a nuclear mechanome: a multidimensional state of mechanical observables spanning lamins, chromatin, nucleoplasm and condensates, and varying across space, time, and cells. We review how intranuclear gradients, chromatin domains and phase-separated bodies generate viscoelastic, poroelastic and plastic niches that shape transcription, replication, DNA repair, epigenetic metabolism, and clonal selection, with particular emphasis on cancer, laminopathies and ageing. We survey invasive, optical and high throughput mechanophenotyping techniques, together with continuum, shell polymer, mesoscopic and non-equilibrium models, as a toolkit for mechanomic mapping. Finally, we outline a research agenda towards standardized mechanical descriptors, tissue-level mechano multi omic atlases and mechanotherapeutic strategies that explicitly target nuclear mechanotypes as potential biomarkers that can define cellular identity, explain plasticity, and help predict pathological states or the evolution of several diseases.