Manipulation of the nucleoscaffold potentiates cellular reprogramming kinetics

Somatic cell fate is an outcome set by the activities of specific transcription factors and the chromatin landscape and is maintained by gene silencing of alternate cell fates through physical interactions with the nuclear scaffold. Here, we evaluate the role of the nuclear scaffold as a guardian of cell fate in human fibroblasts by comparing the effects of transient loss (knockdown) and mutation (progeria) of functional Lamin A/C, a core component of the nuclear scaffold. We observed that Lamin A/C deficiency or mutation disrupts nuclear morphology, and the mechanical properties of the nucleus when measured by a microfluidic cellular squeezing device. We also show that transient loss of Lamin A/C promotes opening of previously silenced heterochromatin domains and increases access to DNA in lamina-associated domains. These alterations in Lamin A/C resulted in acceleration of the kinetics of cellular reprogramming to pluripotency, while genetic mutation of Lamin A/C into progerin was found to induce a senescent phenotype that inhibits the induction of reprogramming genes. Our results highlight the physical role of the nuclear scaffold in safeguarding cellular fate.