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.
Highlights
In mammals, dosage compensation of X-linked gene products between XX females and XY males is achieved by the transcriptional inactivation of all but one X chromosome per diploid cell in females early in embryogenesis
Imprinted X chromosome inactivation (XCI) is found in Eutherians like mice, rats [3,4,5] and, less extensively characterized, bovines [6], exclusively in extraembryonic tissues
The process of XCI has been best studied in the mouse, where it has been shown to be triggered by expression in cis of the noncoding Xist gene exclusively from the future inactive X (Xi), and to occur in two waves in the female pre-implantation embryo
Summary
Dosage compensation of X-linked gene products between XX females and XY males is achieved by the transcriptional inactivation of all but one X chromosome per diploid cell in females early in embryogenesis. The process of XCI has been best studied in the mouse, where it has been shown to be triggered by expression in cis of the noncoding Xist gene exclusively from the future inactive X (Xi), and to occur in two waves in the female pre-implantation embryo (reviewed in [7]). Imprinted XCI becomes evident as early as in the 4-cell stage [8,9,10], where expression of Xist exclusively from the paternal X (Xp) results in its inactivation. Cells from the epiblast reactivate the paternal Xi , and go through a second round of XCI, this time randomly choosing the paternal or the maternal X as the inactive one [9,11]
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