Random X Inactivation and Extensive Mosaicism in Human Placenta Revealed by Analysis of Allele-Specific Gene Expression along the X Chromosome

Abstract

Imprinted inactivation of the paternal X chromosome in marsupials is the primordial mechanism of dosage compensation for X-linked genes between females and males in Therians. In Eutherian mammals, X chromosome inactivation (XCI) evolved into a random process in cells from the embryo proper, where either the maternal or paternal X can be inactivated. However, species like mouse and bovine maintained imprinted XCI exclusively in extraembryonic tissues. The existence of imprinted XCI in humans remains controversial, with studies based on the analyses of only one or two X-linked genes in different extraembryonic tissues. Here we readdress this issue in human term placenta by performing a robust analysis of allele-specific expression of 22 X-linked genes, including XIST, using 27 SNPs in transcribed regions. We show that XCI is random in human placenta, and that this organ is arranged in relatively large patches of cells with either maternal or paternal inactive X. In addition, this analysis indicated heterogeneous maintenance of gene silencing along the inactive X, which combined with the extensive mosaicism found in placenta, can explain the lack of agreement among previous studies. Our results illustrate the differences of XCI mechanism between humans and mice, and highlight the importance of addressing the issue of imprinted XCI in other species in order to understand the evolution of dosage compensation in placental mammals.

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

“…In human embryos, XIST expression is detected from the 4-8-cell stage and XCI has been proposed to follow kinetics similar to those in mouse 21 , although it does not seem to be imprinted in extra-embryonic tissues 22,23 . To investigate this further, we examined in vitro conceived pre-implantation human embryos ( Fig.…”

The Human Placental Methylome

“…It was also reported that this site was unmethylated in microdissected stromal tissue from placenta and umbilical cord (Looijenga et al 1999). Second, the villous trees of the placenta grow in a highly clonal manner (see below), creating extensive site-tosite differences in XCI status (Moriera de Mello et al 2010;Peñaherrera et al 2012). Last, the average level of skewing over multiple sampled sites shows little correlation with skewing observed in fetal somatic tissues (Peñaherrera et al 2012).…”

Species-specific differences in X chromosome inactivation in mammals

“…Some studies demonstrated that X-inactivation was also imprinted in the human placenta (Harrison & Warburton 1986), whereas other studies reported that it was random (Moreira de Mello et al 2010). It should be mentioned, however, that in contrast to mice, an extra X chromosome(s) can be maternal or paternal in origin in Klinefelter syndrome patients (47, XXY).…”