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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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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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Competing interests

The authors declare no competing interests.

Correspondence to Andrea Cerase or Mitchell Guttman or Gian Gaetano Tartaglia.

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