Dynamic changes in paternal X-chromosome activity during imprinted X-chromosome inactivation in mice

Abstract

In mammals, X-chromosome dosage compensation is achieved by inactivating one of the two X chromosomes in females. In mice, X inactivation is initially imprinted, with inactivation of the paternal X (Xp) chromosome occurring during preimplantation development. One theory is that the Xp is preinactivated in female embryos, because of its previous silence during meiosis in the male germ line. The extent to which the Xp is active after fertilization and the exact time of onset of X-linked gene silencing have been the subject of debate. We performed a systematic, single-cell transcriptional analysis to examine the activity of the Xp chromosome for a panel of X-linked genes throughout early preimplantation development in the mouse. Rather than being preinactivated, we found the Xp to be fully active at the time of zygotic gene activation, with silencing beginning from the 4-cell stage onward. X-inactivation patterns were, however, surprisingly diverse between genes. Some loci showed early onset (4 -8-cell stage) of X inactivation, and some showed extremely late onset (postblastocyst stage), whereas others were never fully inactivated. Thus, we show that silencing of some X-chromosomal regions occurs outside of the usual time window and that escape from X inactivation can be highly lineage specific. These results reveal that imprinted X inactivation in mice is far less concerted than previously thought and highlight the epigenetic diversity underlying the dosage compensation process during early mammalian development.dosage compensation ͉ epigenetics ͉ imprinting ͉ mouse development ͉ X inactivation

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

“…Initiation of XCI is controlled by the non-coding Xist transcript 8,9 , which coats the chromosome in cis and triggers gene silencing. During murine pre-implantation development, Xist is maternally repressed and paternally expressed, consistent with its role in regulating imprinted XCI 3,4,6,9,10 . By the epiblast stage, the imprint is lost or ignored, Xp has been reactivated and Xist can be upregulated randomly, from either Xp or the maternally derived X chromosome, Xm.…”

“…In mice, however, XCI is also imprinted initially, with silencing of Xp from the 4-8-cell stage [3][4][5][6] . Xp remains inactive in the trophectoderm 7 but is reactivated in the inner cell mass 5,6 (ICM) with subsequent random XCI in epiblast cells.…”

Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?

“…It has been proposed that imprinted inactivation of the paternal X chromosome in the pre-implantation embryo is established via a continuation of the PMSC state [108], [106]. However, this view remains controversial, as several studies indicated that imprinted X inactivation is initiated in the early embryo either in a Xist-dependent or Xist-independent manner [109], [110], [111]. In addition, the maternal X chromosome harbors a strong imprint that prevents its inactivation in early mouse embryos [112], [113].…”

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

“…However, both X-chromosomes are active after embryonic genome activation (Patrat et al 2009), and XCI is not fully accomplished during early development, which leads to an upregulation of X-linked genes in female embryos. The developmental stage at which XCI is accomplished is not clear and may differ greatly between species ).…”