Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [iCLIP]

The naïve pluripotent epiblast cells become polarized into a rosette-like structure, followed by irreversible transition into primed pluripotency during one of the fastest morphological switches termed lumenogenesis. This requires rapid decay of pluripotency-associated mRNAs, but the underlying mechanism remains unknown. Guided by machine learning and metabolic RNA sequencing, we identified RNA binding proteins (RBPs), especially LIN28A, as primary mRNA decay factors. To understand if RBP dynamics steer embryogenesis, we used mRNA-RBP interactome capture during naïve-rosette-epiblast-gastrulation progression. We identified a dramatic increase in LIN28A mRNA binding, driven by its nucleolus-to-cytoplasm translocation during the naïve-primed pluripotency transition. Cytoplasmic LIN28A binds to 3’UTRs of pluripotency-associated mRNAs to directly stimulate their decay, and thereby progression to lumenogenesis. Accordingly, forced nuclear retention of LIN28A impeded lumenogenesis, causing an unforeseen embryonic multiplication and impaired gastrulation. This reveals selective mRNA decay, driven by nucleo-cytoplasmic RBP translocation, as an intrinsic mechanism for cell identity switch that controls embryonic timing of lumenogenesis.