Female mice lacking Xist RNA show partial dosage compensation and survive to term

Abstract

X-chromosome inactivation (XCI) compensates for differences in X-chromosome number between male and female mammals. XCI is orchestrated by Xist RNA, whose expression in early development leads to transcriptional silencing of one X chromosome in the female. Knockout studies have established a requirement for Xist with inviability of female embryos that inherit an Xist deletion from the father. Here, we report that female mice lacking Xist RNA can, surprisingly, develop and survive to term. Xist-null females are born at lower frequency and are smaller at birth, but organogenesis is mostly normal. Transcriptomic analysis indicates significant overexpression of hundreds of X-linked genes across multiple tissues. Therefore, Xist-null mice can develop to term in spite of a deficiency of dosage compensation. However, the degree of X-autosomal dosage imbalance was less than anticipated (1.14-fold to 1.36-fold). Thus, partial dosage compensation can be achieved without Xist, supporting the idea of inherent genome balance. Nevertheless, to date, none of the mutant mice has survived beyond weaning stage. Sudden death is associated with failure of postnatal organ maturation. Our data suggest Xist-independent mechanisms of dosage compensation and demonstrate that small deviations from X-autosomal balance can have profound effects on overall fitness.

Human Embryonic Stem Cells Do Not Change Their X Inactivation Status during Differentiation

“…In female mammals, X-to-autosome dosage compensation is achieved by X-chromosome inactivation and current evidence indicates that this process is essential for female embryonic development and adult homeostasis (Schulz and Heard, 2013; Yang et al, 2016). The prevailing model therefore suggests that human primed female ESCs and iPSCs undergo XCI during differentiation, but the literature on the state of the X in undifferentiated PSCs and upon differentiation has remained controversial (Anguera et al, 2012; Barakat et al, 2015; Hall et al, 2008; Hoffman et al, 2005; Kim et al, 2014; Lengner et al, 2010; Mekhoubad et al, 2012; Nazor et al, 2012; Pomp et al, 2011; Shen et al, 2008; Silva et al, 2008; Tchieu et al, 2010; Tomoda et al, 2012; Vallot et al, 2015; Xie et al, 2016).…”

“…The silencing of the X-chromosome is accompanied by heterochromatin formation and stably maintained throughout the lifetime of the organism (Augui et al, 2011; Disteche, 2012). Genetic approaches have indicated that XCI is necessary for development and adult homeostasis (Schulz and Heard, 2013; Yang et al, 2016). …”

Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

“…It is likely that a strategy that effectively reactivates MeCP2 will, at least to some extent, reactivate other loci on the Xi. Even though undesirable side effects resulting from such a nonselective reactivation of the Xi might hinder use of MeCP2 reactivation for therapeutic purposes, a recent study demonstrating grossly normal organogenesis of XIST-deficient female mice suggests that partial deficiency in dosage compensation is surprisingly well tolerated and compatible with both cellular and organismal viability (22,47).…”

Genetic Intersection of Tsix and Hedgehog Signaling during the Initiation of X-Chromosome Inactivation

“…Rapid and faithful XCI is critical to development, as persistence of two active X chromosomes results in a dosage imbalance that compromises development (Takagi and Abe, 1990; Schulz et al, 2014; Yang et al, 2016). Because XCI occurs synchronously in ~20 cells of the epiblast, we hypothesize that intercellular communication between the epiblast and surrounding extraembryonic cells may help coordinate the timing of this process, most likely through a signal transduction pathway.…”