Abstract
In mouse, X-chromosome inactivation (XCI) can either be imprinted or random. Imprinted XCI (iXCI) is considered unstable and depending on continuous Xist expression, whereas random XCI (rXCI) is stably maintained even in the absence of Xist. Here we have systematically examined epigenetic modifications associated with the inactive X-chromosome (Xi) in Trophoblast Stem cells, eXtra-Embryonic Endoderm Cells, undifferentiated and differentiated Epiblast Like Stem Cells in order to understand intrinsic differences in epigenetic mechanisms involved in silencing of the inactive X-chromosome in lineages presenting iXCI and rXCI. Whereas euchromatic histone modifications are predominantly lost from the Xi territory in all cell types, the accumulation of heterochromatic modifications diverges in between the analysed cell lineages. Particularly, only the Xi of multipotent Trophoblast (iXCI) and Epiblast stem cells (rXCI) display a visible accumulation of Polycomb Repressive Complexes (PRCs), in contrast to the Xi in differentiated Epiblast Like Stem Cells and eXtra-embryonic Endoderm cells. Despite this, the histone modifications catalysed by PRCs, ubH2AK119 and H3K27me3, remain the best heterochromatic markers for the Xi in all assessed lineages. Heterochromatic chromatin modifications associated with the Xi are a reflection of the epigenetic landscape of the entire genome of the assessed cell regardless whether XCI is imprinted or random.
Highlights
Sex determination in mammals is determined by the presence of the male sex determining gene SRY located on the Y-chromosome
Previous studies indicate that the first epigenetic changes observed on the Xist coated X are related to loss of histone modifications, H3K4me2, H3K9ac, H4ac, H4K16ac and RNA polymerase II, all associated with active chromatin
What governs stability of XCI cannot be determined by the assessment of the presence or absence of histone modifications or classified depending on whether XCI is random or imprinted
Summary
Sex determination in mammals is determined by the presence of the male sex determining gene SRY located on the Y-chromosome. In the female mouse embryo, Xist starts to be expressed during early embryogenesis from the 2-cell stage onwards, leading to silencing in cis. This form of XCI is referred as imprinted XCI (iXCI), as it exclusively leads to XCI of the paternally derived X-chromosome. We have systematically characterized histone modifications associated with the inactivated X-chromosome (Xi) in trophoblast stem (TS) cells, eXtra-embryonic Endoderm (XEN) cells, in vitro derived Epiblast Like Stem Cells (EpiLCs) and to mesoderm differentiated EpiLCs. The obtained data were completed with reported data of chromatin modifications on the Xi in pre-implantation embryos (Table 1) and cell lineages directly derived from the pre- and early post-implantation embryo (Table 2). This study has generated a comprehensive overview of the epigenetic landscape of the Xi in different cell lineages presenting either iXCI or rXCI
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