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SPEN is required for Xist upregulation during initiation of X chromosome inactivation

Author

Listed:
  • Teresa Robert-Finestra

    (Erasmus University Medical Center, Oncode Institute)

  • Beatrice F. Tan

    (Erasmus University Medical Center, Oncode Institute)

  • Hegias Mira-Bontenbal

    (Erasmus University Medical Center, Oncode Institute)

  • Erika Timmers

    (Erasmus University Medical Center, Oncode Institute)

  • Cristina Gontan

    (Erasmus University Medical Center, Oncode Institute)

  • Sarra Merzouk

    (Erasmus University Medical Center, Oncode Institute)

  • Benedetto Daniele Giaimo

    (University of Giessen)

  • François Dossin

    (European Molecular Biology Laboratory, Director’s Research)

  • Wilfred F. J. IJcken

    (Erasmus University Medical Center)

  • John W. M. Martens

    (Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center)

  • Tilman Borggrefe

    (University of Giessen)

  • Edith Heard

    (European Molecular Biology Laboratory, Director’s Research)

  • Joost Gribnau

    (Erasmus University Medical Center, Oncode Institute)

Abstract

At initiation of X chromosome inactivation (XCI), Xist is monoallelically upregulated from the future inactive X (Xi) chromosome, overcoming repression by its antisense transcript Tsix. Xist recruits various chromatin remodelers, amongst them SPEN, which are involved in silencing of X-linked genes in cis and establishment of the Xi. Here, we show that SPEN plays an important role in initiation of XCI. Spen null female mouse embryonic stem cells (ESCs) are defective in Xist upregulation upon differentiation. We find that Xist-mediated SPEN recruitment to the Xi chromosome happens very early in XCI, and that SPEN-mediated silencing of the Tsix promoter is required for Xist upregulation. Accordingly, failed Xist upregulation in Spen−/− ESCs can be rescued by concomitant removal of Tsix. These findings indicate that SPEN is not only required for the establishment of the Xi, but is also crucial in initiation of the XCI process.

Suggested Citation

  • Teresa Robert-Finestra & Beatrice F. Tan & Hegias Mira-Bontenbal & Erika Timmers & Cristina Gontan & Sarra Merzouk & Benedetto Daniele Giaimo & François Dossin & Wilfred F. J. IJcken & John W. M. Mart, 2021. "SPEN is required for Xist upregulation during initiation of X chromosome inactivation," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27294-5
    DOI: 10.1038/s41467-021-27294-5
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    1. Milan Kumar Samanta & Srimonta Gayen & Clair Harris & Emily Maclary & Yumie Murata-Nakamura & Rebecca M. Malcore & Robert S. Porter & Patricia M. Garay & Christina N. Vallianatos & Paul B. Samollow & , 2022. "Activation of Xist by an evolutionarily conserved function of KDM5C demethylase," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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