Genetic and epigenetic features direct differential efficiency of Xist-mediated silencing at X-chromosomal and autosomal locations

Agnese Loda, Johannes H. Brandsma, Ivaylo Vassilev, Nicolas Servant, Friedemann Loos, Azadeh Amirnasr, Erik Splinter, Emmanuel Barillot, Raymond A. Poot, Edith Heard and Joost Gribnau ()
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Agnese Loda: Erasmus University Medical Center
Johannes H. Brandsma: Erasmus University Medical Center
Ivaylo Vassilev: Bioinformatics and Computational Systems Biology of Cancer
Nicolas Servant: Bioinformatics and Computational Systems Biology of Cancer
Friedemann Loos: Centre de Recherche des Cordeliers
Azadeh Amirnasr: Erasmus University Medical Center
Erik Splinter: Cergentis B.V.
Emmanuel Barillot: Bioinformatics and Computational Systems Biology of Cancer
Raymond A. Poot: Erasmus University Medical Center
Edith Heard: Institut Curie
Joost Gribnau: Erasmus University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Xist is indispensable for X chromosome inactivation. However, how Xist RNA directs chromosome-wide silencing and why some regions are more efficiently silenced than others remains unknown. Here, we explore the function of Xist by inducing ectopic Xist expression from multiple different X-linked and autosomal loci in mouse aneuploid and female diploid embryonic stem cells in which Xist-mediated silencing does not lead to lethal functional monosomy. We show that ectopic Xist expression faithfully recapitulates endogenous X chromosome inactivation from any location on the X chromosome, whereas long-range silencing of autosomal genes is less efficient. Long interspersed elements facilitate inactivation of genes located far away from the Xist transcription locus, and genes escaping X chromosome inactivation show enrichment of CTCF on X chromosomal but not autosomal loci. Our findings highlight important genomic and epigenetic features acquired during sex chromosome evolution to facilitate an efficient X chromosome inactivation process.

Date: 2017
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DOI: 10.1038/s41467-017-00528-1

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