Developmental regulation of X-chromosome inactivation

Abstract

With the emergence of sex--determination by sex chromosomes, which differ in composition and number between males and females, appeared the need to equalize X--chromosomal gene dosage between the sexes. Mammals have devised the strategy of X--chromosome inactivation (XCI), in which one of the two X--chromosomes is rendered transcriptionally silent in females. In the mouse, the best--studied model organism with respect to XCI, this inactivation process occurs in different forms, imprinted and random, interspersed by periods of X--chromosome reactivation (XCR), which is needed to switch between the different modes of XCI. In this review, I describe the recent advances with respect to the developmental control of XCI and XCR and in particular their link to differentiation and pluripotency. Furthermore, I review the mechanisms, which influence the timing and choice, with which one of the two X--chromosomes is chosen for inactivation during random XCI. This has an impact on how females are mosaics with regard to which X--chromosome is active in different cells, which has implications on the severity of diseases caused by X--linked mutations.

Single-Cell RNA-Seq Reveals Cellular Heterogeneity of Pluripotency Transition and X Chromosome Dynamics during Early Mouse Development

“…In the mouse, imprinted silencing of the paternal X chromosome (Xp) is initiated at the 4to 8-cell stage, after the zygotic genome is activated (Borensztein et al, 2017b;Deng et al, 2014;Mak et al, 2004;Okamoto et al, 2004). While Xp silencing continues in the extraembryonic lineages, Xp is reactivated in the EPI, followed by random X-inactivation (XCI) after implantation (Payer, 2016). Recently, X chromosome reactivation (XCR) during pregastrula development has been ascertained by showing the contrasting level of X chromosome expression between male and female cells (Mohammed et al, 2017).…”

Allele-specific RNA imaging shows that allelic imbalances can arise in tissues through transcriptional bursting

“…This latter expression pattern has been termed random monoallelic expression, and certainly, genes with such an expression profile exist: most X-linked genes are expressed only from one X chromosome due to random X-chromosome inactivation (X. Galupa and Heard 2015;Payer 2016) , and a similar pattern has also been shown for some autosomal genes, such as olfactory receptors or antigen receptors (Monahan and Lomvardas 2015;Brady, Steinel, and Bassing 2010; . Understanding random monoallelic expression is of particular interest given that quantitative cell-to-cell differences or spatial heterogeneity in allele-specific gene expression have the potential to modify phenotypic outcome if the two alleles harbor different functional variants, as has been described for both X-linked (eg.…”

Characterization of X-Chromosome Gene Expression in Bovine Blastocysts Derived by In vitro Fertilization and Somatic Cell Nuclear Transfer

“…In contrast to embryonic lineage cells, extra-embryonic cells (i.e., TE cells) maintain the silenced paternal X chromosome throughout embryogenesis. Meanwhile, XCR can be induced during reprogramming of differentiated cells toward pluripotency by nuclear transfer, cell fusion, or ectopic expression of reprogramming factors (for a review, see Pasque and Plath, 2015; Payer, 2016; Vallot et al, 2016). Recently, it was shown that during the early period of reprogramming in hybrid cells between human fibroblasts and mouse embryonic stem cells, human nuclei undergo a loss of XIST and XCI-associated histone marks from the inactive X chromosome to accomplish XCR, although some regions on the X chromosome are refractory to reprogramming (Cantone et al, 2016).…”