The bimodally expressed microRNA miR‐142 gates exit from pluripotency

A stem cell's decision to self‐renew or differentiate is thought to critically depend on signaling cues provided by its environment. It is unclear whether stem cells have the intrinsic capacity to control their responsiveness to environmental signals that can be fluctuating and noisy. Using a novel single‐cell microRNA activity reporter, we show that miR‐142 is bimodally expressed in embryonic stem cells, creating two states indistinguishable by pluripotency markers. A combination of modeling and quantitative experimental data revealed that mESCs switch stochastically between the two miR‐142 states. We find that cells with high miR‐142 expression are irresponsive to differentiation signals while cells with low miR‐142 expression can respond to differentiation cues. We elucidate the molecular mechanism underpinning the bimodal regulation of miR‐142 as a double‐negative feedback loop between miR‐142 and KRAS/ERK signaling and derive a quantitative description of this bistable system. miR‐142 switches the activation status of key intracellular signaling pathways thereby locking cells in an undifferentiated state. This reveals a novel mechanism to maintain a stem cell reservoir buffered against fluctuating signaling environments. Synopsis The bimodally expressed microRNA miR‐142 defines two stochastically interconverting states of pluripotent embryonic stem cells: a state competent to differentiate and a state irresponsive to differentiation signals akin to a stem cell reservoir. Bimodal miR‐142 expression creates two functionally distinct pluripotent states miR‐142 regulates ERK and AKT signaling miR‐142 expression locks embryonic stem cells in an undifferentiated state Stochastic miR‐142 state switching maintains a pluripotent stem cell reservoir Graphical Abstract The bimodally expressed microRNA miR‐142 defines two stochastically interconverting states of pluripotent embryonic stem cells: a state competent to differentiate and a state irresponsive to differentiation signals akin to a stem cell reservoir.