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X-chromosome inactivation patterns in human extraembryonic and fetal tissues Peñaherrera Arcos, Maria Serena

Abstract

X-chromosome inactivation (XCI) compensates for dosage of X-linked genes in female mammals. XCI is generally random and clonally inherited in embryonic tissues, XCI patterns in the placenta appear to be distinct and vary among different mammalian species. The aim of this thesis was to further our understanding of XCI patterns in human placentae with three main goals: 1) To determine if XCI shows a parental bias in human placenta as it does in mouse and other mammals, XCI patterns were studied in amnion, chorion, trophoblast and mesenchyme of 14 normal female term placentae, and 11 first trimester placentae using methylation based assays (AR and FMR-1). XCI patterns were heterogeneous within most term placentae, in both direction and degree of skewing, indicating that there is no clear parental bias to XCI in term placentae. However, a trend towards the preferential inactivation of the paternally derived X was observed in trophoblast of first trimester placentae. Investigation of a placenta with a paternally derived X/autosome translocation also supports the idea that preferential inactivation of the paternal X is probably not a requirement for normal development in humans as it is in mice. 2) To determine whether all or most X-linked genes are hypomethylated in human extraembryonic tissues, XCI was studied in 20 CVS samples, using methylation-based assays for 7 X-linked genes (MAOA, ARAF, AR, XIST, DXS6673E, GRIA3E and FMR-1). Incomplete methylation was observed for all genes except XIST. The low methylation suggests either gene derepression, or that an alternative mechanism of silencing is involved in gene regulation in placenta. 3) To use XCI studies to understand the characteristics of cell dynamics in cases of trisomy preferentially confined to the placenta, I studied XCI in embryonic and extraembryonic tissues from 25 such cases. Extremely skewed XCI was found in diploid fetal but not placental tissues of most of these individuals. This may result from the selective elimination of trisomic cells from the embryonic precursor cell pool subsequent to XCI. A significant correlation between high levels of skewing and abnormal fetal outcome was evident, suggesting that when high levels of trisomy are found in the placenta, there is an increased probability of "hidden" trisomy mosaicism in the fetus.

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