Poised PABP-RNA hubs implement signal-dependent mRNA decay in development

Abstract Changes in gene expression implement signalling pathways to drive cell fate transitions 1,2 . However, the mechanisms for rapid and selective transcriptome rewiring in response to signalling cues remain elusive 3-6 . Here we use deep learning to deconvolve both the sequence determinants and trans-acting regulators that trigger clearance of the naïve pluripotency programme. We show that A/U-rich 3’UTR termini serve as hubs for poised PABP binding to license selective mRNA decay. Timing of decay is coupled to embryo implantation via ERK/MEK phosphorylation of LIN28A, repositioning pLIN28A to the PABP-RNA hubs at 3’UTR termini. Multivalency of AUU-motifs determines the efficacy of pLIN28A-PABP convergence, enhancing PABP 3’UTR binding selectively, decreasing the protection of polyA tails and activating mRNA decay to enable progression towards primed pluripotency. Collectively, PABP-RNA hubs are poised for signal-induced convergence with the regulator LIN28A, which selects naïve mRNAs for decay, thus enabling the switch-like capacity of its phosphorylation in ensuring swift developmental progression.