Abstract
An open chromatin architecture devoid of compact chromatin is thought to be associated with pluripotency in embryonic stem cells. Establishing this distinct epigenetic state may also be required for somatic cell reprogramming. However, there has been little direct examination of global structural domains of chromatin during the founding and loss of pluripotency that occurs in preimplantation mouse development. Here, we used electron spectroscopic imaging to examine large-scale chromatin structural changes during the transition from one-cell to early postimplantation stage embryos. In one-cell embryos chromatin was extensively dispersed with no noticeable accumulation at the nuclear envelope. Major changes were observed from one-cell to two-cell stage embryos, where chromatin became confined to discrete blocks of compaction and with an increased concentration at the nuclear envelope. In eight-cell embryos and pluripotent epiblast cells, chromatin was primarily distributed as an extended meshwork of uncompacted fibres and was indistinguishable from chromatin organization in embryonic stem cells. In contrast, lineage-committed trophectoderm and primitive endoderm cells, and the stem cell lines derived from these tissues, displayed higher levels of chromatin compaction, suggesting an association between developmental potential and chromatin organisation. We examined this association in vivo and found that deletion of Oct4, a factor required for pluripotency, caused the formation of large blocks of compact chromatin in putative epiblast cells. Together, these studies show that an open chromatin architecture is established in the embryonic lineages during development and is sufficient to distinguish pluripotent cells from tissue-restricted progenitor cells.
Highlights
The initial steps of mouse preimplantation development involve an ordered series of cleavage divisions to form an 8-cell embryo
Using correlative light and electron spectroscopic imaging (ESI) to directly observe large-scale alterations or ‘‘remodelling’’ of global chromatin organization, we have found that dramatic changes in the chromatin landscape are associated with each stage from one-cell to postimplantation embryos (Figure 8)
A minimal degree of concentration of chromatin occurs at the surfaces of the nucleolar precursor body (NPB) and at the nuclear envelope
Summary
The initial steps of mouse preimplantation development involve an ordered series of cleavage divisions to form an 8-cell embryo. Trophectoderm (TE) and primitive endoderm (PE) cells generate the extraembryonic tissues, whereas epiblast (EPI) cells are pluripotent and give rise to the embryo itself. When EPI cells are removed from the embryo and explanted into culture they give rise to embryonic stem (ES) cells, which retain epiblast identity and potency [2]. The genome of eukaryotic cells is organised into euchromatin, which is generally permissive for gene activation, and heterochromatin, which is largely gene-poor or transcriptionally silenced. It is presumed that chromatin compaction can influence transcriptional activities by regulating accessibility to transcription factors and DNA interactions [3,4,5]. The location of the chromosome within the nucleus is thought to control gene activity, with the nuclear periphery associated with transcriptionally repressed chromatin [6,7,8,9]. Nuclear architecture can be altered by a number of distinct pathways including ATP-dependent nucleosome remodelling, linker histone proteins, histone variants and covalent modifications to the histones and DNA [10]
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