Combinatorial microRNA activity is essential for the transition of pluripotent cells from proliferation into dormancy

Abstract

SUMMARYDormancy is a key feature of stem cell function in adult tissues as well as embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring1,2. How these processes are coordinated to successfully transition cells to the resting dormant state remains unclear. Here we show that microRNA activity, which is otherwise dispensable for pre-implantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in loss of pluripotent cells. Through integration of high-sensitivity small RNA expression profiling of individual embryos and protein expression of miRNA targets with public data of protein-protein interactions, we constructed the miRNA-mediated regulatory network of mouse early embryos specific to diapause. We find that individual miRNAs contribute to the combinatorial regulation by the network and the perturbation of the network compromises embryo survival in diapause. Without miRNAs, nuclear and cytoplasmic bodies show aberrant expression, concurrent with splicing defects. We identified the nutrient-sensitive transcription factor TFE3 as an upstream regulator of diapause-specific miRNAs, linking cytoplasmic mTOR activity to nuclear miRNA biogenesis. Our results place miRNAs as a critical regulatory layer for the molecular rewiring of early embryos to establish dormancy.

TET activity safeguards pluripotency throughout embryonic dormancy

“…Embryonic diapause has remained an enigma since its discovery in 1854. Recent progress [3][4][5][6]8,28,[53][54][55][56][57] started to illuminate the regulation of dormancy at the cellular level, yet we are missing answers to at least two critical questions: (1) Is low anabolic activity sufficient to induce diapause at the cellular level? (2) If not, which other mechanisms ensure faithful propagation of this dormant state?…”

“…This phenomenon, known as embryonic diapause, allows the preservation of the embryo for weeks to months in a reversibly dormant state 1 . Establishment of dormancy entails low anabolic activity and repression of transcriptional and translational programs [2][3][4][5][6] . A key feature of dormancy is the ability to revert back to proliferation without compromising the developmental potential and cell fate.…”