Appreciating What’s Unique about Every Stem Cell

Using single-cell techniques, the behaviors of individual stem cells are coming under ever-greater scrutiny. Such efforts are pushing the boundaries of technology development in cell biology and are getting to the heart of what defines cellular states, what drives cell-state changes, andwhat canwe learn about biological systems from cell-to-cell variability. A prime example of this trend comes from recent work by Takahashi et al. (2019), who have addressedwhether replication timing across the genome is stereotyped between individual cells of the same cell type, and their results raise questions about the potential role of replication timing in the decision-making of differentiating stem cells. Previous studies with bulk sequencing of cell populations have revealed the basic principle that regions that replicate early tend to be euchromatic, actively transcribed, and in the nuclear interior, whereas late-replicating regions tend to be heterochromatic and at the nuclear periphery. Takahashi et al. have now designed and tested an approach to profile earlyversus late-replicating regions at the single-cell level in mouse embryonic stem cells (mESCs), before and after differentiation and in an immortalized human retinal pigment epithelial cell line. Similar to another recent study by Dileep and Gilbert (2018), the authors find that overall genomewide replication timing is highly consistent between individual cells in a given state and that some regions exhibit more intrinsic variability than others. Going deeper, they reveal an interesting corollary: developmentally regulated genes exhibit higher-than-average variability in replication timing. Does this suggest a link between replication timing variability and developmental plasticity? The variability at these genes does in fact go away uponmESC differentiation. Future work may explore this facet of nuclear organization in