Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development

Abstract

X-chromosome inactivation (XCI) in female mammals allows dosage compensation for X-linked gene products between the sexes1. The developmental regulation of this process has been extensively investigated in mice, where the X chromosome of paternal origin (Xp) is silenced during early embryogenesis owing to imprinted expression of the regulatory RNA, Xist (X-inactive specific transcript). Paternal XCI is reversed in the inner cell mass of the blastocyst and random XCI subsequently occurs in epiblast cells. Here we show that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homologue is not subject to imprinting and XCI begins later than in mice. Furthermore,Xist is upregulated on both X chromosomes in a high proportion of rabbit andhuman embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosome-wide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Our study demonstrates the remarkable diversity in XCI regulation and highlights differences between mammals in their requirement for dosage compensation during early embryogenesis

Xist Deficiency and Disorders of X-Inactivation in Rabbit Embryonic Stem Cells Can Be Rescued by Transcription-Factor-Mediated Conversion

“…Our data suggest two possibilities. First, rabbits and humans may share a similar molecular mechanism of XCI regulation [31]. If so, it will be very interesting to investigate the evolutionary importance of XCI during development.…”

The origin and evolution of vertebrate sex chromosomes and dosage compensation

“…In mouse, XIST is transcribed exclusively from the future inactive X (Xi), and spreads in cis from the X inactivation centre to coat the whole X, triggering silencing (reviewed in Okamoto and Heard, 2009). However, in humans XIST upregulation at the blastomere stage precedes XCI, implying that the choice of which X becomes inactivated occurs downstream of XIST upregulation (Okamoto et al, 2011).…”

Inactivation du chromosome X chez l’humain

“…Si cette inactivation est dans l'ensemble conservée chez tous les mammifères euthériens, des différences importantes existent, notamment chez l'humain. Chez l'homme, les stades précoces de l'inactivation du X n'ont été que très peu caractérisés, mais une étude sur des embryons humains surnuméraires issus de fécondation in vitro (FIV) a montré que chacun des deux chromosomes X était recouvert par l'ARN de XIST et pourtant toujours actif [4] (Figure 1). Ces résultats indiquent que le processus d'inactivation n'est pas strictement dépendant de XIST chez l'humain, contrairement à ce qui a été montré …”