Selective RNA sequestration in biomolecular condensates directs cell fate transitions

Patrizia Pessina^#^{1

2

3

4}, Mika Nevo^#^{5

6

7}, Junchao Shi⁸, Srikanth Kodali^{1

2

3

4}, Eduard Casas^{5

6

7}, Yingzhi Cui^{1

2

3

4}, Alicia L Richards^{9

10

11}, Emily J Park^{1

2

3

4}, Xi Chen¹², Florencia Levin-Ferreyra^{1

2

3

4}, Alejandra Rivera Tostado^{1

2

3

4}, Erica Stevenson^{9

10

11}, Nevan J Krogan^{9

10

11}, Danielle L Swaney^{9

10

11}, Qilong Ying¹², Qi Chen⁸, Justin Brumbaugh^{13

14

15

16}, Bruno Di Stefano^{17

18

19

20}

Affiliations

¹ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.
² Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
³ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
⁴ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
⁶ University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA.
⁷ Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Molecular Medicine Program, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁹ J. David Gladstone Institutes, San Francisco, CA, USA.
¹⁰ Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
¹¹ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA. justin.brumbaugh@colorado.edu.
¹⁴ University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA. justin.brumbaugh@colorado.edu.
¹⁵ Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. justin.brumbaugh@colorado.edu.
¹⁶ BioFrontiers Institute, University of Colorado, Boulder, CO, USA. justin.brumbaugh@colorado.edu.
¹⁷ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.
¹⁸ Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.
¹⁹ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.
²⁰ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.

^# Contributed equally.

PMID: 41152623
DOI: 10.1038/s41587-025-02853-z

Selective RNA sequestration in biomolecular condensates directs cell fate transitions

Patrizia Pessina et al. Nat Biotechnol. 2025.

. 2025 Oct 28.

doi: 10.1038/s41587-025-02853-z. Online ahead of print.

Authors

Affiliations

¹ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.
² Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
³ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
⁴ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁵ Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
⁶ University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA.
⁷ Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Molecular Medicine Program, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁹ J. David Gladstone Institutes, San Francisco, CA, USA.
¹⁰ Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.
¹¹ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹³ Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA. justin.brumbaugh@colorado.edu.
¹⁴ University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA. justin.brumbaugh@colorado.edu.
¹⁵ Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. justin.brumbaugh@colorado.edu.
¹⁶ BioFrontiers Institute, University of Colorado, Boulder, CO, USA. justin.brumbaugh@colorado.edu.
¹⁷ Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.
¹⁸ Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.
¹⁹ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.
²⁰ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. bruno.distefano@bcm.edu.

^# Contributed equally.

PMID: 41152623
DOI: 10.1038/s41587-025-02853-z

Abstract

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.

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Conflict of interest statement

Competing interests: N.J.K.’s laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche and Rezo Therapeutics. N.J.K. is the president and is on the board of directors of Rezo Therapeutics, and he is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, GEn1E Lifesciences and Interline Therapeutics. N.J.K. also has financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Interline Therapeutics, Rezo Therapeutics, GEn1E Lifesciences and Twist Bioscience (all within the last 36 months). The other authors declare no competing interests.

Update of

Selective RNA sequestration in biomolecular condensates directs cell fate transitions.
Pessina P, Nevo M, Shi J, Kodali S, Casas E, Cui Y, Richards AL, Park EJ, Chen X, Levin-Ferreyra F, Stevenson E, Krogan NJ, Swaney DL, Ying Q, Chen Q, Brumbaugh J, Di Stefano B. Pessina P, et al. bioRxiv [Preprint]. 2025 May 10:2025.05.08.652299. doi: 10.1101/2025.05.08.652299. bioRxiv. 2025. Update in: Nat Biotechnol. 2025 Oct 28. doi: 10.1038/s41587-025-02853-z. PMID: 40654687 Free PMC article. Updated. Preprint.

References

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Selective RNA sequestration in biomolecular condensates directs cell fate transitions

Affiliations

Selective RNA sequestration in biomolecular condensates directs cell fate transitions

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources