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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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.

Original languageEnglish
Article number7000
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 1 Dec 2021

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