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. IJcken, John W. M. Martens, Tilman Borggrefe, Edith Heard and Joost Gribnau ()
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Teresa Robert-Finestra: Erasmus University Medical Center, Oncode Institute
Beatrice F. Tan: Erasmus University Medical Center, Oncode Institute
Hegias Mira-Bontenbal: Erasmus University Medical Center, Oncode Institute
Erika Timmers: Erasmus University Medical Center, Oncode Institute
Cristina Gontan: Erasmus University Medical Center, Oncode Institute
Sarra Merzouk: Erasmus University Medical Center, Oncode Institute
Benedetto Daniele Giaimo: University of Giessen
François Dossin: European Molecular Biology Laboratory, Director’s Research
Wilfred F. J. IJcken: Erasmus University Medical Center
John W. M. Martens: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Tilman Borggrefe: University of Giessen
Edith Heard: European Molecular Biology Laboratory, Director’s Research
Joost Gribnau: Erasmus University Medical Center, Oncode Institute

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27294-5

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