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Phase separation drives X-chromosome inactivation: a hypothesis

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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.

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

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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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  2. Alexandros Armaos
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  3. Christoph Neumayer
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  4. Philip Avner
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  5. Mitchell Guttman
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  6. Gian Gaetano Tartaglia
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Corresponding authors

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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