Abstract
BackgroundDuring early mouse development, two extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE) and the primitive endoderm (PrE). Epigenetic changes known to take place during these early stages include changes in DNA methylation and modified histones, as well as dynamic changes in gene expression.ResultsIn order to understand the role and extent of chromatin-based changes for lineage commitment within the embryo, we examined the epigenetic profiles of mouse embryonic stem (ES), trophectoderm stem (TS) and extra-embryonic endoderm (XEN) stem cell lines that were derived from the inner cell mass (ICM), TE and PrE, respectively. As an initial indicator of the chromatin state, we assessed the replication timing of a cohort of genes in each cell type, based on data that expressed genes and acetylated chromatin domains, generally, replicate early in S-phase, whereas some silent genes, hypoacetylated or condensed chromatin tend to replicate later. We found that many lineage-specific genes replicate early in ES, TS and XEN cells, which was consistent with a broadly 'accessible' chromatin that was reported previously for multiple ES cell lines. Close inspection of these profiles revealed differences between ES, TS and XEN cells that were consistent with their differing lineage affiliations and developmental potential. A comparative analysis of modified histones at the promoters of individual genes showed that in TS and ES cells many lineage-specific regulator genes are co-marked with modifications associated with active (H4ac, H3K4me2, H3K9ac) and repressive (H3K27me3) chromatin. However, in XEN cells several of these genes were marked solely by repressive modifications (such as H3K27me3, H4K20me3). Consistent with TS and XEN having a restricted developmental potential, we show that these cells selectively reprogramme somatic cells to induce the de novo expression of genes associated with extraembryonic differentiation.ConclusionsThese data provide evidence that the diversification of defined embryonic and extra-embryonic lineages is accompanied by chromatin remodelling at specific loci. Stem cell lines from the ICM, TE and PrE can each dominantly reprogramme somatic cells but reset gene expression differently, reflecting their separate lineage identities and increasingly restricted developmental potentials.
Highlights
IntroductionTwo extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE) and the primitive endoderm (PrE)
During early mouse development, two extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE) and the primitive endoderm (PrE)
ES, trophectoderm stem (TS) and extra-embryonic endoderm (XEN) cell lines have similar but distinct replication timing profiles In order to directly compare the epigenetic profiles of extra-embryonic stem cell lines with those of pluripotent cell lines, we initially assessed the replication timing of a panel of developmental genes in OS25, B1 and IM8A1 cell lines
Summary
Two extra-embryonic lineages form alongside the future embryo: the trophectoderm (TE) and the primitive endoderm (PrE). The outer, polar cells of the late morula change morphology to form an epithelial monolayer of cells - the trophectoderm (TE), which mediates the implantation and initiation of placentation, while the inner apolar cells become the inner cell mass (ICM) and contain the founder cells of the embryo proper. By the early blastocyst stage (E3.5), these two tissues are morphologically distinct - the outer polarized epithelium, the TE, enclosing the ICM, which is itself heterogeneous [2]. Lineage studies have shown that the cells of the EPI are pluripotent and give rise to all tissues of the fetus plus extra-embryonic mesoderm. Besides providing growth support and protection within the uterus, the extra-embryonic TE and PrE are sources of signals to the embryonic lineages to promote correct patterning and differentiation [3]
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