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 genetically engineered mouse models and single-cell RNA sequencing, we identify microRNA-203 (miR-203) as a critical regulator of timely progression in preimplantation mouse embryos. Genetically engineered mouse models including a generated embryonic reporter (early embryo reporter) transgenic mouse carrying murine endogenous retrovirus-L (MERVL)-Tomato and SRY-box 2 (Sox2)-green fluorescent protein 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.