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; Édith Heard; Joost H. Gribnau

doi:10.1038/s41467-021-27294-5

Developmental BiologyNature CommunicationsDec 1, 2021

Peer-reviewed journal article

SPEN is Required for Xist Upregulation during Initiation of X Chromosome Inactivation

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

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 the 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 the initiation of the XCI process.

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