Nuclear periphery and its mechanical regulation in cell fate transitions

Cell fate changes require rewiring of transcriptional programs to generate functionally specialized cell states. Reconfiguration of transcriptional networks requires overcoming epigenetic barriers imposed by silenced heterochromatin in order to activate lineage-specific genes. Further, cell fate decisions are made in a tissue-specific context, where cells are physically linked to each other as well as to the connective tissue environment. Here, cells are continuously exposed to a multitude of mechanical forces emanating from cellular dynamics in their local microenvironments, for example through cell movements, cell divisions, tissue contractions, or fluid flow. Through their ability to deform cellular structures and activate receptors, mechanical forces can be sensed at the plasma membrane, but also at the nuclear periphery through direct or cytoskeleton-mediated deformation of the nuclear envelope. This deformation and the associated signaling is capable of triggering changes in the mechanical state of the nuclear membranes, the organization and rigidity of the underlying nuclear lamina, compaction state of chromatin, and ultimately transcription. This review focuses on the role of nuclear architecture, particularly the nuclear lamina-chromatin interface, and its mechanical regulation in cell fate decisions as well as its physiological role in development and cellular reprogramming.