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

Teresa Robert-Finestra, Beatrice F. Tan, Hegias Mira-Bontenbal, Erika Timmers, Cristina Gontan, Sarra Merzouk, Benedetto Daniele Giaimo, François Dossin, Wilfred F.J. van IJcken, John W.M. Martens, Tilman Borggrefe, Edith Heard, Joost Gribnau*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number7000
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2021

Bibliographical note

Funding Information:
We thank Anniek Meesters and Esther Sleddens-Linkels for technical help; Kristian Helin for providing the EZH2 antibody; Martine M. Jaegle for sharing with us a floxed-puromycin resistance cassette; Joana Carvalho Moreira de Mello for her input in R plotting; and all the members of the Erasmus MC Developmental Biology department for useful discussions. T.R.F. is supported by an Erasmus MC grant (Mrace). T.R.F., B.F.T., H.M.B., E.T., and J.G. are supported by the Oncode Institute and a ZonMW Top subsidy (91215046). B.D.G. is supported by a research grant of the University Medical Center Giessen and Marburg (UKGM) and by a Prize of the Justus Liebig University Giessen. The work was further supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—TRR 81/3-109546710 and BO1639/9-393040308, and the Von Behring‐Röntgen foundation and Excellence Cluster for Cardio Pulmonary System (ECCPS) in Giessen to T.B.

Publisher Copyright:
© 2021, The Author(s).


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