IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v578y2020i7795d10.1038_s41586-020-1974-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-1974-9
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-1974-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:578:y:2020:i:7795:d:10.1038_s41586-020-1974-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.