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Three lncRNAs promote PUM protein condensation and germline differentiation

Author

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  • Roni Falk

    (The Hebrew University of Jerusalem)

  • Noa Gilad

    (The Hebrew University of Jerusalem)

  • Hanna Achache

    (The Hebrew University of Jerusalem)

  • Yisrael Rappaport

    (The Hebrew University of Jerusalem)

  • Roni Halfon

    (The Hebrew University of Jerusalem)

  • Reut Shabtai

    (The Hebrew University of Jerusalem)

  • Hasan Ishtayeh

    (The Hebrew University of Jerusalem)

  • Laura Wolovelsky

    (The Hebrew University of Jerusalem)

  • Oren Ram

    (The Hebrew University of Jerusalem)

  • Yonatan B. Tzur

    (The Hebrew University of Jerusalem)

Abstract

Long non-coding RNAs (lncRNAs) are abundant in gonads, yet most knockout models show no fertility defects, leaving their role unclear. Here, we identify overlapping functions of three lncRNAs in Caenorhabditis elegans fertility. These lncRNAs bind and sequester FBF-2, a regulator that inhibits germ cell differentiation. Combined deletion of the lncRNAs reduces progenitor cell number and overall progeny, reflecting additive effects. In lncRNA mutants, pro-meiotic transcripts—normally destabilized by FBF-2—are significantly reduced. FBF-2 localizes to both the cytoplasm and peri-nuclear condensates in germ cells, but its peri-nuclear condensation and association with P granules—phase-separated, evolutionarily conserved structures—are diminished in lncRNA mutants. Our findings suggest that these lncRNAs cooperatively promote fertility by spatially restricting FBF-2 within granules, thus reducing its activity and allowing the expression of differentiation-promoting transcripts. The requirement for multiple knockouts to reveal this phenotype highlights the redundancy and combinatorial function of lncRNAs in regulating germline development.

Suggested Citation

  • Roni Falk & Noa Gilad & Hanna Achache & Yisrael Rappaport & Roni Halfon & Reut Shabtai & Hasan Ishtayeh & Laura Wolovelsky & Oren Ram & Yonatan B. Tzur, 2025. "Three lncRNAs promote PUM protein condensation and germline differentiation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61652-x
    DOI: 10.1038/s41467-025-61652-x
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    References listed on IDEAS

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    1. Mathias Munschauer & Celina T. Nguyen & Klara Sirokman & Christina R. Hartigan & Larson Hogstrom & Jesse M. Engreitz & Jacob C. Ulirsch & Charles P. Fulco & Vidya Subramanian & Jenny Chen & Monica Sch, 2018. "Publisher Correction: The NORAD lncRNA assembles a topoisomerase complex critical for genome stability," Nature, Nature, vol. 563(7733), pages 32-32, November.
    2. Mathias Munschauer & Celina T. Nguyen & Klara Sirokman & Christina R. Hartigan & Larson Hogstrom & Jesse M. Engreitz & Jacob C. Ulirsch & Charles P. Fulco & Vidya Subramanian & Jenny Chen & Monica Sch, 2018. "The NORAD lncRNA assembles a topoisomerase complex critical for genome stability," Nature, Nature, vol. 561(7721), pages 132-136, September.
    3. Sarah L. Crittenden & David S. Bernstein & Jennifer L. Bachorik & Beth E. Thompson & Maria Gallegos & Andrei G. Petcherski & Gary Moulder & Robert Barstead & Marvin Wickens & Judith Kimble, 2002. "A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans," Nature, Nature, vol. 417(6889), pages 660-663, June.
    4. Mahmoud M. Elguindy & Joshua T. Mendell, 2021. "NORAD-induced Pumilio phase separation is required for genome stability," Nature, Nature, vol. 595(7866), pages 303-308, July.
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