RNA sequestration regulates cell fate (Human)

Recent studies have highlighted the significance of RNA condensates in governing various aspects of cellular RNA processing. Nonetheless, the functional roles and composition of RNA condensates in the context of cell fate specification have remained elusive. In this study, we conducted a comprehensive characterization of the coding and non-coding transcriptome within cytoplasmic condensates known as P-bodies across diverse developmental contexts and vertebrate species. Notably, our investigation unveiled that the dissolution of RNA condensates reprograms both human and mouse pluripotent stem cells into a blastomere-like state. Mechanistically, we observed a high enrichment of untranslated fate-instructive RNAs within P-bodies, subject to cell type-specific sequestration. Employing degron systems, we demonstrated that the acute loss of P-bodies facilitates the translation of stored mRNAs. Furthermore, our research identifies the AGO-miRNAs molecular node as central in orchestrating RNA sequestration in P-bodies in a context-dependent manner. Perturbing AGO proteins, RNA 3’ UTR length, or expression of selected miRNAs, profoundly reshapes the localization of RNAs within cells. Collectively, our findings illuminate how RNA processing within condensates drives essential aspects of lineage-specific cell fate trajectories across vertebrate species.