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Phase separation drives X-chromosome inactivation: a hypothesis

Nature Structural & Molecular Biology volume 26, pages 331–334 (2019)Cite this article

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The long non-coding RNA Xist induces heterochromatinization of the X chromosome by recruiting repressive protein complexes to chromatin. Here we gather evidence, from the literature and from computational analyses, showing that Xist assemblies are similar in size, shape and composition to phase-separated condensates, such as paraspeckles and stress granules. Given the progressive sequestration of Xist’s binding partners during X-chromosome inactivation, we formulate the hypothesis that Xist uses phase separation to perform its function.

The ability of protein and RNA to interact affects the formation of membrane-less organelles, such as paraspeckles and stress granules, which are involved in various biological functions1, including RNA processing and responses to environmental changes2,3,4. As studied by confocal microscopy5 and super-resolution approaches6, these assemblies appear as round foci that are in dynamic exchange with their environment. They form when locally saturated molecules separate into two phases, a process known as ‘liquid–liquid phase separation’ (LLPS)7.

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Fig. 1: Supporting evidence that Xist might form a phase-separated compartment.
Fig. 2: XCI model.

References

  1. Chujo, T. et al. EMBO J. 36, 1447–1462 (2017).

    Article  CAS  Google Scholar 

  2. Maharana, S. et al. Science 360, 918–921 (2018).

    Article  CAS  Google Scholar 

  3. Yamazaki, T. et al. Mol. Cell 70, 1038–1053.e1037 (2018).

    Article  CAS  Google Scholar 

  4. Cid-Samper, F. et al. Cell Rep. 25, 3422–3434.e3427 (2018).

    Article  CAS  Google Scholar 

  5. Mao, Y. S., Sunwoo, H., Zhang, B. & Spector, D. L. Nat. Cell Biol. 13, 95–101 (2011).

    Article  CAS  Google Scholar 

  6. West, J. A. et al. J. Cell Biol. 214, 817–830 (2016).

    Article  CAS  Google Scholar 

  7. Shin, Y. & Brangwynne, C. P. Science 357, eaaf4382 (2017).

    Article  Google Scholar 

  8. Bolognesi, B. et al. Cell Rep. 16, 222–231 (2016).

    Article  CAS  Google Scholar 

  9. Tartaglia, G. G. et al. J. Mol. Biol. 380, 425–436 (2008).

    Article  CAS  Google Scholar 

  10. Cerase, A. et al. Proc. Natl Acad. Sci. USA 111, 2235–2240 (2014).

    Article  CAS  Google Scholar 

  11. Smeets, D. et al. Epigenetics Chromatin 7, 8 (2014).

    Article  Google Scholar 

  12. Cirillo, D. et al. Nat. Methods 14, 5–6 (2016).

    Article  Google Scholar 

  13. Markmiller, S. et al. Cell 172, 590–604.e513 (2018).

    Article  CAS  Google Scholar 

  14. Pintacuda, G., Young, A. N. & Cerase, A. Front. Mol. Biosci. 4, 90 (2017).

    Article  Google Scholar 

  15. Delli Ponti, R., Marti, S., Armaos, A. & Tartaglia, G. G. Nucleic Acids Res. 45, e35 (2017).

    Article  Google Scholar 

  16. Van Nostrand, E. L. et al. Nat. Methods 13, 508–514 (2016).

    Article  Google Scholar 

  17. Naganuma, T. et al. EMBO J. 31, 4020–4034 (2012).

    Article  CAS  Google Scholar 

  18. Jain, S. et al. Cell 164, 487–498 (2016).

    Article  CAS  Google Scholar 

  19. Cerase, A., Pintacuda, G., Tattermusch, A. & Avner, P. Genome Biol. 16, 166 (2015).

    Article  Google Scholar 

  20. Pintacuda, G. et al. Mol. Cell 68, 955–969.e910 (2017).

    Article  CAS  Google Scholar 

  21. Klus, P. et al. Bioinformatics 30, 1601–1608 (2014).

    Article  CAS  Google Scholar 

  22. Ng, K. et al. Mol. Biol. Cell 22, 2634–2645 (2011).

    Article  CAS  Google Scholar 

  23. Almeida, M. et al. Science 356, 1081–1084 (2017).

    Article  CAS  Google Scholar 

  24. Engreitz, J. M. et al. Science 341, 1237973 (2013).

    Article  Google Scholar 

  25. Zylicz, J. J. et al. Cell 176, 182–197.e123 (2019).

    Article  CAS  Google Scholar 

  26. Isono, K. et al. Dev. Cell 26, 565–577 (2013).

    Article  CAS  Google Scholar 

  27. Chen, C. K. et al. Science 354, 468–472 (2016).

    Article  CAS  Google Scholar 

  28. Wutz, A. & Jaenisch, R. Mol. Cell 5, 695–705 (2000).

    Article  CAS  Google Scholar 

  29. Csankovszki, G., Nagy, A. & Jaenisch, R. J. Cell Biol. 153, 773–784 (2001).

    Article  CAS  Google Scholar 

  30. Moindrot, B. et al. Cell Rep. 12, 562–572 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all members of the Avner, Tartaglia and Guttman groups, as well as Greta Pintacuda and Kathrin Plath for critical reading of the manuscript. P.A. was funded by an EMBL grant (50800), and A.C. was funded by an EMBL fellowship and a Rett Syndrome Research Trust (RSRT) grant. The research leading to these results has been supported by the European Research Council (RIBOMYLOME_309545), the Spanish Ministry of Economy, Industry, and Competitiveness (BFU2014-55054-P and BFU2017-86970-P) and “Fundació La Marató de TV3” (PI043296). M.G. was funded by a Caltech grant. We acknowledge support from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya.

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Author notes

  1. Andrea Cerase

    Present address: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

  2. These authors contributed equally: Andrea Cerase, Alexandros Armaos.

Authors and Affiliations

  1. EMBL-Rome, Monterotondo, Italy

    Andrea Cerase & Philip Avner

  2. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain

    Alexandros Armaos & Gian Gaetano Tartaglia

  3. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Christoph Neumayer & Mitchell Guttman

  4. ICREA and UPF, Barcelona, Spain

    Gian Gaetano Tartaglia

  5. Department of Biology ‘Charles Darwin’, Sapienza University of Rome, Rome, Italy

    Gian Gaetano Tartaglia

  6. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy

    Gian Gaetano Tartaglia

Authors
  1. Andrea Cerase
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Correspondence to Andrea Cerase, Mitchell Guttman or Gian Gaetano Tartaglia.

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Cerase, A., Armaos, A., Neumayer, C. et al. Phase separation drives X-chromosome inactivation: a hypothesis. Nat Struct Mol Biol 26, 331–334 (2019). https://doi.org/10.1038/s41594-019-0223-0

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