Schematic of paper summary. miR-294 and miR-181 each sensitize fibroblasts to epigenetic reprogramming through simultaneous inhibition of ot least fourteen and eleven targets, respectively. Targets with known functional modules are depicted here.
MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells
Published 2013 in Nature Structural & Molecular Biology
Robert L Judson, Tobias S Greve, Ronald J Parchem, Robert Blelloch
This paper reports on four intertwined lines of experiments and conclusions that, although interdependent, are individually interesting.
The miR-181 family can facilitate reprogramming into iPSCs and their endogenous expression is an important downstream tranient step during Oct4, Sox2 & Klf4 - driven reprogramming. This is a straight-forward but unexpected conclusion as miR-181 has also been shown to induce differentiation when overexpressed in ESCs.
The miR-181 family, as well as the previously identified miR-294 / miR-302 miRNAs, enhance reprogramming during the early stages of the process, through destabilization of the fibroblastic program. They play a role in the initiation of the process, but not thereafter.
The verified targets of both microRNA families constitute a gene set enriched for cooperative genetic interactions. This paper contains one of the first published functional genetic interaction maps in a mammalian system.
These miRNAs have their effect on reprogramming through simultaneous regulation of at least three signaling pathways.
What does this all mean?
Together, these observations, combined with previously published studies, suggest an interesting model, whereby aberrantly expressed microRNAs destabilize a cell’s endogenous program through co-inhibition of many genes involved in several different cellular processes. This destabilization then sensitizes a cell to epigenetic reprogramming. In the case of miR-294 / miR-302, this destabilization is sufficient to permit changes in the growth media to fully reprogram fibroblasts to a pluripotent state. In the case or miR-181, a miRNA normally expressed in the brain and immune system, both the fibroblast program and the pluripotency program are destabilized, such that transient expression aids in OSK-induced de-differentiation, but prolonged expression has deleterious effects. Regardless of whether this proves to be the correct model to explain these data, the study does show that microRNAs are excellent tools for discovering novel functional genetic interactions.