Signaling pathways drive cell fate transitions largely by changing gene expression. However, the mechanisms for rapid and selective transcriptome rewiring in response to signaling cues remain elusive. Here we use deep learning to deconvolve both the sequence determinants and the trans-acting regulators that trigger extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase kinase (MEK)-induced decay of the naive pluripotency mRNAs. Timing of decay is coupled to embryo implantation through ERK–MEK phosphorylation of LIN28A, which repositions pLIN28A to the highly A+U-rich 3′ untranslated region (3′UTR) termini of naive pluripotency mRNAs. Interestingly, these A+U-rich 3′UTR termini serve as poly(A)-binding protein (PABP)-binding hubs, poised for signal-induced convergence with LIN28A. The multivalency of AUU motifs determines the efficacy of pLIN28A–PABP convergence, which enhances PABP 3′UTR binding, decreases the protection of poly(A) tails and activates mRNA decay to enable progression toward primed pluripotency. Thus, the signal-induced convergence of LIN28A with PABP–RNA hubs drives the rapid selection of naive mRNAs for decay, enabling the transcriptome remodeling that ensures swift developmental progression.

信号通路主要通过改变基因表达来驱动细胞命运转变。然而，响应信号线索的快速和选择性转录组重新布线的机制仍然难以捉摸。在这里，我们使用深度学习来解卷积序列决定簇和反式作用调节因子，这些调节因子触发细胞外信号调节激酶（ERK）-丝裂原激活蛋白激酶激酶（MEK）诱导的初始多能性 mRNA 的衰减。通过 LIN28A 的 ERK-MEK 磷酸化，衰变时间与胚胎植入相结合，从而将 pLIN28A 重新定位到初始多能性 mRNA 高度 A+U 丰富的 3' 非翻译区 (3'UTR) 末端。有趣的是，这些富含 A+U 的 3'UTR 末端充当多聚 (A) 结合蛋白 (PABP) 结合中心，准备好与 LIN28A 进行信号诱导的汇聚。 AUU 基序的多价性决定了 pLIN28A-PABP 收敛的功效，这增强了 PABP 3'UTR 结合，减少了 Poly(A) 尾部的保护，并激活 mRNA 衰变，从而能够向引发的多能性发展。因此，信号诱导的 LIN28A 与 PABP-RNA 中枢的融合驱动了初始 mRNA 的快速选择以进行衰退，从而实现转录组重塑，从而确保快速的发育进程。