Epigenetic predisposition to reprogramming fates in somatic cells

Reprogramming to pluripotency is a low-efficiency process at the population level. Despite notable advances to molecularly characterize key steps, several fundamental aspects remain poorly understood, including when the potential to reprogram is first established. Here, we apply live-cell imaging combined with a novel statistical approach to infer when somatic cells become fated to generate downstream pluripotent progeny. By tracing cell lineages from several divisions before factor induction through to pluripotent colony formation, we find that pre-induction sister cells acquire similar outcomes. Namely, if one daughter cell contributes to a lineage that generates induced pluripotent stem cells (iPSCs), its paired sibling will as well. This result suggests that the potential to reprogram is predetermined within a select subpopulation of cells and heritable, at least over the short term. We also find that expanding cells over several divisions prior to factor induction does not increase the per-lineage likelihood of successful reprogramming, nor is reprogramming fate correlated to neighboring cell identity or cell-specific reprogramming factor levels. By perturbing the epigenetic state of somatic populations with Ezh2 inhibitors prior to factor induction, we successfully modulate the fraction of iPSC-forming lineages. Our results therefore suggest that reprogramming potential may in part reflect preexisting epigenetic heterogeneity that can be tuned to alter the cellular response to factor induction. Synopsis The potential of mouse embryonic fibroblasts (MEFs) to generate iPSCs is determined before OKSM induction and symmetrically maintained over the short term. Epigenetic perturbations of MEFs can alter their future response to reprogramming. The potential to generate iPSC colonies is shared between sister lineages emanating from a pre-induction cell division. Cell-specific OKSM levels or local niche effects do not explain preference toward iPSC fate. Perturbing H3K27 or H3K4 methylation marks prior to OKSM induction increases the number of iPSC lineages. The potential of Mouse Embryonic Fibroblasts (MEFs) to generate iPSCs is determined before OKSM induction and symmetrically maintained over the short term. Epigenetic perturbations of MEFs can alter their future response to reprogramming.