miR-203 facilitates timely cell fate transitions via epigenetic modulation during early embryogenesis

Commonly expressed at developmental transitions, microRNAs operate as fine tuners of gene expression to facilitate cell fate acquisition and lineage segregation. Nevertheless, how they might regulate the earliest developmental transitions in early mammalian embryogenesis remains obscure. Here, in a strictly in vivo approach based on novel genetically engineered mouse models and single-cell RNA sequencing, we identify miR-203 as a critical regulator of timely progression in preimplantation mouse embryos. Genetically engineered mouse models including a new embryonic reporter (eE-Reporter) transgenic mouse carrying MERVL-Tomato and Sox2-GFP transgenes show that loss of miR-203 slows down early preimplantation development leading to the accumulation of embryos with high expression of totipotency-associated markers, including MERVL endogenous retroviral elements. A combination of single-cell transcriptional studies and epigenetic analyses identified histone acetylases including the central coactivator and histone acetyltransferase EP300 as critical miR-203 targets in the control of cell specification in early embryos. These data suggest that miR-203 carves the epigenetic rewiring required for early developmental transitions, allowing a timely and correctly paced development, at least partially by fine-tuning EP300 levels.