Selective RNA sequestration in biomolecular condensates directs cell fate transitions
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.
Authors
- Florencia Levin-Ferreyra (ORCID: https://orcid.org/0000-0003-0395-5331)
- Nevan J. Krogan (ORCID: https://orcid.org/0000-0003-4902-337X)
- Yingzhi Cui (ORCID: https://orcid.org/0009-0005-8475-3361)
- Emily J. Park (ORCID: https://orcid.org/0000-0001-8770-9239)
- Eduard Casas (ORCID: https://orcid.org/0000-0002-6001-1276)
- Patrizia Pessina (ORCID: https://orcid.org/0000-0002-4227-411X)
- Junchao Shi (ORCID: https://orcid.org/0000-0002-1548-5069)
- Srikanth Kodali (ORCID: https://orcid.org/0000-0001-9330-9880)
- Justin Brumbaugh (ORCID: https://orcid.org/0000-0002-9605-2010)
- Bruno Di Stefano (ORCID: https://orcid.org/0000-0003-2532-3087)
- Erica Stevenson (ORCID: https://orcid.org/0000-0001-7853-1854)
- Alicia Richards (ORCID: https://orcid.org/0000-0002-4869-2945)
- Danielle L. Swaney (ORCID: https://orcid.org/0000-0001-6119-6084)
- Alejandra Rivera Tostado
- Mika Nevo (ORCID: https://orcid.org/0000-0002-2385-4784)
- Xi Chen (ORCID: https://orcid.org/0000-0001-5947-3046)
- Qi Chen (ORCID: https://orcid.org/0000-0001-6353-9589)
- Qi-Long Ying (ORCID: https://orcid.org/0000-0001-5822-9498)
Institutions
- University of Southern California (US)
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- University of Colorado Boulder (US)
- University of Utah (US)
- Quantitative BioSciences (US)
- University of Colorado Cancer Center (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1038/s41587-025-02853-z
- Citations
- 4
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 3.22