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SPEN integrates transcriptional and epigenetic control of X-inactivation

Author

Listed:
  • François Dossin

    (European Molecular Biology Laboratory, Director’s Unit)

  • Inês Pinheiro

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Jan J. Żylicz

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne
    University of Cambridge)

  • Julia Roensch

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Samuel Collombet

    (European Molecular Biology Laboratory, Director’s Unit)

  • Agnès Le Saux

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Tomasz Chelmicki

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Mikaël Attia

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Varun Kapoor

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Ye Zhan

    (University of Massachusetts Medical School)

  • Florent Dingli

    (Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique)

  • Damarys Loew

    (Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique)

  • Thomas Mercher

    (Université Paris-Sud)

  • Job Dekker

    (University of Massachusetts Medical School
    Howard Hughes Medical Institute)

  • Edith Heard

    (European Molecular Biology Laboratory, Director’s Unit
    Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

Abstract

Xist represents a paradigm for the function of long non-coding RNA in epigenetic regulation, although how it mediates X-chromosome inactivation (XCI) remains largely unexplained. Several proteins that bind to Xist RNA have recently been identified, including the transcriptional repressor SPEN1–3, the loss of which has been associated with deficient XCI at multiple loci2–6. Here we show in mice that SPEN is a key orchestrator of XCI in vivo and we elucidate its mechanism of action. We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and in embryonic stem cells. SPEN is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI. We show that SPEN is immediately recruited to the X chromosome upon the upregulation of Xist, and is targeted to enhancers and promoters of active genes. SPEN rapidly disengages from chromatin upon gene silencing, suggesting that active transcription is required to tether SPEN to chromatin. We define the SPOC domain as a major effector of the gene-silencing function of SPEN, and show that tethering SPOC to Xist RNA is sufficient to mediate gene silencing. We identify the protein partners of SPOC, including NCoR/SMRT, the m6A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in the regulation of transcription initiation and elongation. We propose that SPEN acts as a molecular integrator for the initiation of XCI, bridging Xist RNA with the transcription machinery—as well as with nucleosome remodellers and histone deacetylases—at active enhancers and promoters.

Suggested Citation

  • François Dossin & Inês Pinheiro & Jan J. Żylicz & Julia Roensch & Samuel Collombet & Agnès Le Saux & Tomasz Chelmicki & Mikaël Attia & Varun Kapoor & Ye Zhan & Florent Dingli & Damarys Loew & Thomas M, 2020. "SPEN integrates transcriptional and epigenetic control of X-inactivation," Nature, Nature, vol. 578(7795), pages 455-460, February.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7795:d:10.1038_s41586-020-1974-9
    DOI: 10.1038/s41586-020-1974-9
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    Citations

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    Cited by:

    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.
    2. Lisa-Marie Appel & Vedran Franke & Melania Bruno & Irina Grishkovskaya & Aiste Kasiliauskaite & Tanja Kaufmann & Ursula E. Schoeberl & Martin G. Puchinger & Sebastian Kostrhon & Carmen Ebenwaldner & M, 2021. "PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    3. Andrew Keniry & Natasha Jansz & Linden J. Gearing & Iromi Wanigasuriya & Joseph Chen & Christian M. Nefzger & Peter F. Hickey & Quentin Gouil & Joy Liu & Kelsey A. Breslin & Megan Iminitoff & Tamara B, 2022. "BAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. 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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