Translational specialization in pluripotency by RBPMS poises future lineage-decisions

The blueprints for developing organs are preset at the early stages of embryogenesis. Transcriptional and epigenetic mechanisms are proposed to preset developmental trajectories. However, we reveal that the competence for future cardiac fate of human embryonic stem cells (hESCs) is preset in pluripotency by a specialized mRNA translation circuit controlled by RBPMS. RBPMS is recruited to active ribosomes in hESCs to control the translation of essential factors needed for cardiac commitment program, including WNT signaling. Consequently, RBPMS loss specifically and severely impedes cardiac mesoderm specification leading to patterning and morphogenesis defects in human cardiac organoids. Mechanistically, RBPMS specializes mRNA translation, selectively via 3UTR binding and globally by promoting translation initiation. Accordingly, RBPMS loss causes translation initiation defects highlighted by aberrant retention of the EIF3 complex and depletion of EIF5A from mRNAs, thereby abrogating ribosome recruitment. We reveal how future fate trajectories are preprogrammed during embryogenesis by specialized mRNA translation. Teaser: Cardiac fate competence is preprogrammed in pluripotency by specialized mRNA translation of factors initiating cardiogenesis