miR-290 cluster (red) and miR-302 cluster (green) expression during mouse embryonic development. Cells within dotted line are embryonic tissue and outside of dotted line are extraembryonic tissue. Sorting experiments confirmed that the yellow represents expression of both clusters in the same cell.

Two miRNA Clusters Reveal Alternative Paths in Late-Stage Reprogramming


Figure 1b in this paper is one my favorite images. Prior to this study, we had demonstrated that when overexpressed, microRNAs from the miR-290 and miR-302 clusters enhance the efficiency and specificity of reprogramming somatic cells to a pluripotent state, and other labs had demonstrated that the miR-302 cluster can even induce iPSC formation on its own. Motivated by this powerful phenotype, Ron Parchem wanted to investigate the role of the endogenous clusters during both reprogramming and normal development. He constructed a beautiful system by generating live fluorescent reporters for each cluster. Figure 1b shows the expression of these reporters during mouse embryonic development, highlighting his fascinating discovery that the expression of the two clusters can be used to mark not only the naive and primed stem cells of the blastocyst and epiblast, respectively, but also a transient third pluripotent state where both clusters are active. This ordered differentiation also occurs during in vitro stem cell differentiation. In contrast, although the endogenous activation of either cluster is predictive of successful downstream reprogramming, the process of dedifferentiation is not similarly ordered, but can take alternative paths.

Model of three states of pluripotency, a naive state (red), a primed state (green), and an intermediate state (yellow). Differentiation both during development and in vivo passes through each state in an ordered manner. During de-differentiation, however, there are alternatvie routes to reach the the naive (red) state, that do not required passing back through the primed or intermediate pluripotency states.



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