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

Agnese Loda (1) , Johannes H Brandsma (1) , Ivaylo Vassilev (2) , Nicolas Servant (2) , Friedemann Loos (3) , Azadeh Amirnasr (1) , Erik Splinter (4) , Emmanuel Barillot (2) , Raymond A Poot (1) , Edith Heard (5, 6) , Joost Gribnau (1)

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]
2 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
3 CRC - Centre de Recherche des Cordeliers
4 Cergentis
5 Génétique et Biologie du Développement
6 Collège de France - Chaire Epigénétique et mémoire cellulaire

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 inacti-vation 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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Agnese Loda, Johannes H Brandsma, Ivaylo Vassilev, Nicolas Servant, Friedemann Loos, et al.. Genetic and epigenetic features direct differential efficiency of Xist-mediated silencing at X-chromosomal and autosomal locations. Nature Communications, 2017, 8, pp.690. ⟨10.1038/s41467-017-00528-1⟩. ⟨hal-01617984⟩