Phase separation drives X-chromosome inactivation: a hypothesis

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.

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

References

  1. 1.

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

    CAS  Article  Google Scholar 

  2. 2.

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

    CAS  Article  Google Scholar 

  3. 3.

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

    CAS  Article  Google Scholar 

  4. 4.

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

    CAS  Article  Google Scholar 

  5. 5.

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

    CAS  Article  Google Scholar 

  6. 6.

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

    CAS  Article  Google Scholar 

  7. 7.

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

    Article  Google Scholar 

  8. 8.

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

    CAS  Article  Google Scholar 

  9. 9.

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

    CAS  Article  Google Scholar 

  10. 10.

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

    CAS  Article  Google Scholar 

  11. 11.

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

    Article  Google Scholar 

  12. 12.

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

    Article  Google Scholar 

  13. 13.

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

    CAS  Article  Google Scholar 

  14. 14.

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

    Article  Google Scholar 

  15. 15.

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

    Article  Google Scholar 

  16. 16.

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

    Article  Google Scholar 

  17. 17.

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

    CAS  Article  Google Scholar 

  18. 18.

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

    CAS  Article  Google Scholar 

  19. 19.

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

    Article  Google Scholar 

  20. 20.

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

    CAS  Article  Google Scholar 

  21. 21.

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

    CAS  Article  Google Scholar 

  22. 22.

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

    CAS  Article  Google Scholar 

  23. 23.

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

    CAS  Article  Google Scholar 

  24. 24.

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

    Article  Google Scholar 

  25. 25.

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

    CAS  Article  Google Scholar 

  26. 26.

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

    CAS  Article  Google Scholar 

  27. 27.

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

    CAS  Article  Google Scholar 

  28. 28.

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

    CAS  Article  Google Scholar 

  29. 29.

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

    CAS  Article  Google Scholar 

  30. 30.

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

    CAS  Article  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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Correspondence to Andrea Cerase or 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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