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

doi:10.1038/s41467-021-27294-5

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 journal › Article › Academic › peer-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 language	English
Article number	7000
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27294-5
Publication status	Published - 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.

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© 2021, The Author(s).

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SPEN is required for Xist upregulation during initiation of X chromosome inactivationFinal published version, 6.6 MBLicence: CC BY

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Robert-Finestra, T., Tan, B. F., Mira-Bontenbal, H., Timmers, E., Gontan, C., Merzouk, S., Giaimo, B. D., Dossin, F., van IJcken, W. F. J., Martens, J. W. M., Borggrefe, T., Heard, E., & Gribnau, J. (2021). SPEN is required for Xist upregulation during initiation of X chromosome inactivation. Nature Communications, 12(1), Article 7000. https://doi.org/10.1038/s41467-021-27294-5

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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.",

author = "Teresa Robert-Finestra and Tan, {Beatrice F.} and Hegias Mira-Bontenbal and Erika Timmers and Cristina Gontan and Sarra Merzouk and Giaimo, {Benedetto Daniele} and Fran{\c c}ois Dossin and {van IJcken}, {Wilfred F.J.} and Martens, {John W.M.} and Tilman Borggrefe and Edith Heard and Joost Gribnau",

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‐R{\"o}ntgen foundation and Excellence Cluster for Cardio Pulmonary System (ECCPS) in Giessen to T.B. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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AU - Robert-Finestra, Teresa

AU - Tan, Beatrice F.

AU - Mira-Bontenbal, Hegias

AU - Timmers, Erika

AU - Gontan, Cristina

AU - Merzouk, Sarra

AU - Giaimo, Benedetto Daniele

AU - Dossin, François

AU - van IJcken, Wilfred F.J.

AU - Martens, John W.M.

AU - Borggrefe, Tilman

AU - Heard, Edith

AU - Gribnau, Joost

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N2 - 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.

AB - 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.

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

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