Nonstochastic Reprogramming from a Privileged Somatic Cell State

Abstract

SUMMARY Reprogramming somatic cells to induced pluripotency by Yamanaka factors is usually slow and inefficient, and is thought to be a stochastic process. We identified a privileged somatic cell state, from which acquisition of pluripotency could occur in a non-stochastic manner. Subsets of murine hematopoietic progenitors are privileged, whose progeny cells predominantly adopt the pluripotent fate with activation of endogenous Oct4 locus after 4–5 divisions in reprogramming conditions. Privileged cells display an ultrafast cell cycle of ~8 hours. In fibroblasts, a subpopulation cycling at a similar ultrafast speed is observed after 6 days of factor expression, and is increased by p53-knockdown. This ultrafast-cycling population accounts for >99% of the bulk reprogramming activity in wildtype or p53-knockdown fibroblasts. Our data demonstrate that the stochastic nature of reprogramming can be overcome in a privileged somatic cell state, and suggest that cell cycle acceleration toward a critical threshold is an important bottleneck for reprogramming.

Cell Type-Specific Expression Profile and Signaling Requirements in Early Hematopoietic Reprogramming

“…This result is consistent with the recent finding that nonstochastic reprogramming was observed in hematopoietic cells [29].…”

Two distinct modes for propagation of histone PTMs across the cell cycle

“…We further envision that this mode of PTM maintenance could explain how cell cycle speed and withdrawal impact on cellular plasticity. DNA replication could be instrumental to reset epigenetic states (Tsubouchi et al 2013), and, by revealing how histone PTMs are maintained across the cell cycle, our findings pave the way to understanding how cellular identity and reprogramming potential are connected with cell proliferation (Guo et al 2014). …”

The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters

“…Reprogramming by exogenous factors is nowadays considered as a multistep process in which cells must overcome a series of roadblocks to ultimately acquire pluripotency [3,4], though under certain conditions it can also be deterministic [5][6][7]. Two fundamental reprogramming roadblocks are the activation of a p53-mediated response that promotes apoptosis and cell senescence, and the inefficient removal of preexisting somatic-like epigenetic marks.…”