Patrizia Pessina, Mika Nevo, Junchao Shi, Srikanth Kodali, Eduard Casas, Yingzhi Cui, Alicia Richards, Emily J. Park, Xi Chen, Florencia Levin-Ferreyra, Alejandra Rivera Tostado, Erica Stevenson, Nevan J. Krogan, Danielle L. Swaney, Qi-Long Ying, Qi Chen, Justin Brumbaugh, Bruno Di Stefano
Controlling stem cell differentiation is a longstanding goal in biomedical research. Here we explore how cell fate is influenced by RNA condensates, specifically P-bodies, which modulate gene expression posttranscriptionally. We profiled the transcriptomes of biomolecular condensates in diverse developmental contexts spanning multiple vertebrate species. Our analyses revealed conserved, cell type-specific sequestration of untranslated RNAs encoding cell fate regulators. P-body RNA contents do not reflect active gene expression in each cell type but are enriched for translationally repressed transcripts characteristic of the preceding developmental stage. Mechanistically, P-body contents are controlled by microRNAs and can be profoundly reshaped by perturbing AGO2 or polyadenylation site usage. Applying these insights to stem cell differentiation, we show that manipulating P-body assembly or microRNA activity can direct naive mouse and human pluripotent stem cells toward totipotency or primed human embryonic cells toward the germ cell lineage. Our findings link cell fate decisions to RNA condensates across vertebrates and provide a means of controlling cell identity.