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Systematic allelic analysis defines the interplay of key pathways in X chromosome inactivation

Author

Listed:
  • Tatyana B. Nesterova

    (University of Oxford)

  • Guifeng Wei

    (University of Oxford)

  • Heather Coker

    (University of Oxford)

  • Greta Pintacuda

    (University of Oxford
    Harvard University)

  • Joseph S. Bowness

    (University of Oxford)

  • Tianyi Zhang

    (University of Oxford)

  • Mafalda Almeida

    (University of Oxford)

  • Bianca Bloechl

    (University of Oxford)

  • Benoit Moindrot

    (University of Oxford
    I2BC Paris-Sud University)

  • Emma J. Carter

    (University of Oxford)

  • Ines Alvarez Rodrigo

    (University of Oxford
    University of Oxford)

  • Qi Pan

    (University of Oxford)

  • Ying Bi

    (University of Oxford)

  • Chun-Xiao Song

    (University of Oxford)

  • Neil Brockdorff

    (University of Oxford)

Abstract

Xist RNA, the master regulator of X chromosome inactivation, acts in cis to induce chromosome-wide silencing. Whilst recent studies have defined candidate silencing factors, their relative contribution to repressing different genes, and their relationship with one another is poorly understood. Here we describe a systematic analysis of Xist-mediated allelic silencing in mouse embryonic stem cell-based models. Using a machine learning approach we identify distance to the Xist locus and prior gene expression levels as key determinants of silencing efficiency. We go on to show that Spen, recruited through the Xist A-repeat, plays a central role, being critical for silencing of all except a subset of weakly expressed genes. Polycomb, recruited through the Xist B/C-repeat, also plays a key role, favouring silencing of genes with pre-existing H3K27me3 chromatin. LBR and the Rbm15/m6A-methyltransferase complex make only minor contributions to gene silencing. Together our results provide a comprehensive model for Xist-mediated chromosome silencing.

Suggested Citation

  • Tatyana B. Nesterova & Guifeng Wei & Heather Coker & Greta Pintacuda & Joseph S. Bowness & Tianyi Zhang & Mafalda Almeida & Bianca Bloechl & Benoit Moindrot & Emma J. Carter & Ines Alvarez Rodrigo & Q, 2019. "Systematic allelic analysis defines the interplay of key pathways in X chromosome inactivation," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11171-3
    DOI: 10.1038/s41467-019-11171-3
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    Cited by:

    1. 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.

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