Unveiling karyoskeletal dynamics in chromatin organization and gene regulation in haematopoietic cell physiology and pathology

Chromatin organization and gene regulation are essential for maintaining homeostatic haematopoiesis, the tightly regulated process by which haematopoietic stem and progenitor cells generate diverse blood lineages. Growing evidence identifies karyoskeletal proteins, particularly nuclear actin and its associated scaffolding networks, as central regulators of nuclear function. These proteins influence transcription through interactions with chromatin-remodelling complexes, shape three-dimensional genome architecture, facilitate DNA repair and modulate polycomb-mediated gene repression, thereby governing blood cell identity and lineage commitment. Dysregulation of nuclear structural proteins contributes to haematological malignancies, including leukaemia and myelodysplastic syndromes. In this review, we synthesize current understanding of how karyoskeletal proteins integrate structural and regulatory roles to control chromatin dynamics and gene expression in the lympho-haematopoietic system. We highlight recent insights into their roles in three-dimensional genome organization, epigenetic regulation, polycomb-dependent repression and stemness in both normal and pathological contexts and discuss how nuclear actin modulates these processes in cancer pathogenesis. Collectively, this review underscores how emerging concepts in nuclear architecture reveal karyoskeletal proteins as pivotal determinants of transcriptional regulation and haematopoietic function.