Loda Agnese, Brandsma Johannes H, Vassilev Ivaylo, Servant Nicolas, Loos Friedemann, Amirnasr Azadeh, Splinter Erik, Barillot Emmanuel, Poot Raymond A, Heard Edith, Gribnau Joost
Department of Developmental Biology, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Mammalian Developmental Epigenetics group, Institut Curie, CNRS UMR 3215, INSERM, U934, Paris, France.
Nat Commun. 2017 Sep 25;8(1):690. doi: 10.1038/s41467-017-00528-1.
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.Xist RNA is required for X chromosome inactivation but it is not well understood how Xist silences some regions more efficiently than others. Here, the authors induce ectopic Xist expression from multiple different X-linked and autosomal loci in cells to explore Xist function.
Xist对于X染色体失活至关重要。然而，Xist RNA如何指导全染色体范围的沉默以及为何某些区域比其他区域更有效地被沉默仍不清楚。在此，我们通过在小鼠非整倍体和雌性二倍体胚胎干细胞中从多个不同的X连锁和常染色体位点诱导异位Xist表达来探索Xist的功能，在这些细胞中Xist介导的沉默不会导致致死性的功能性单体。我们表明，异位Xist表达能忠实地重现X染色体上任何位置的内源性X染色体失活，而常染色体基因的远距离沉默效率较低。长散在元件促进远离Xist转录位点的基因失活，并且逃避X染色体失活的基因在X染色体位点而非常染色体位点上显示出CTCF的富集。我们的研究结果突出了性染色体进化过程中获得的重要基因组和表观遗传特征，以促进高效的X染色体失活过程。Xist RNA是X染色体失活所必需的，但目前尚不清楚Xist如何比其他区域更有效地沉默某些区域。在此，作者在细胞中从多个不同的X连锁和常染色体位点诱导异位Xist表达以探索Xist的功能。
