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Reconstituting the transcriptome and DNA methylome landscapes of human implantation

ABSTRACT: Implantation is a milestone event during mammalian embryogenesis. Implantation failure is a nonnegligible cause of human early pregnancy loss. Due to the extreme difficulty of obtaining in vivo human early post-implantation embryos, it remains elusive how the gene regulatory network and epigenetic mechanisms control human embryo implantation. Here, combining an in vitro culture system for human post-implantation development and single-cell omics sequencing technologies, over 8,000 individual cells from 65 human peri-implantation embryos were systematically analyzed. Unsupervised dimensionality reduction and clustering algorithm of the transcriptome data show stepwise implantation routes for the epiblast (EPI), primitive endoderm (PE), and trophectoderm (TE) lineages, suggesting robust preparation for the proper establishment of a mother-to-offspring connection during implantation. Female embryos showed initiation of random X chromosome inactivation based on analysis of parental allele-specific expression of X chromosome-linked genes during implantation. Surprisingly, by the single-cell Trio-Seq (scTrio-Seq) analysis, the genome re-methylation of PE lineage was shown to be much slower than those of both EPI and TE lineages during implantation process, indicating distinct DNA methylome re-establishment features between EPI and PE although both of which were derived from inner cell mass (ICM). Collectively, our work paves the way for understanding the complex molecular mechanisms that regulate human embryo implantation, offering new insights and future efforts in early embryonic development and reproductive medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109555 | GEO | 2019/07/11

REPOSITORIES: GEO

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Project description:Differentiation of totipotent embryonic cells into the first cell lineages (trophectoderm (TE) and inner cell mass (ICM), and further into epiblast (EPI) and primitive endoderm (PE)), although well studied, is only beginning to be understood at the molecular level. An in depth understanding of the regulation of these early differentiation events would enable improvements in the quality of in vitro produced embryos, as well as the study and application of bovine embryonic stem cells. The objective of this work was to perform single cell RNASeq on bovine blastocysts derived in vivo (IVV), in vitro in a conventional in vitro production system (IVC), and in vitro in reduced nutrient media (IVR). All in vitro culture was serum free. In vivo embryonic cells could be assigned based on Leiden clustering analysis, although there was some overlap in expression of marker genes. The two TE groups identified clearly separated in a uniform manifold approximation and projection (UMAP) plot from EPI groups. Putative epiblast cells could be identified. In in vitro embryos produced in a conventional system, considerable overlap in expression of marker genes made Leiden clustering difficult, but a selected count could be used for UMAP to tentatively identify one TE, 2 EPI and 2 PE groups. In assigned cell types we observed higher expression of the identifying marker genes, but some marker genes were expressed in all cell types. In IVC embryos, TE markers clustered while PE and EPI marker genes overlapped. In IVR embryos, again there was considerable overlap between marker gene expression. Like IVC embryos, TE was easily identified by clustering in IVR, but EPI and PE were too similar to distinguish. In summary, the methods used here could partially distinguish putative cell types in bovine blastocysts, although marker gene expression was not always discreet. This may not be surprising given differentiation events are in progress in the blastocyst stage embryo. TE cells were more easily distinguished than EPI and PE cells, which would support this hypothesis.

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Reconstituting the transcriptome and DNA methylome landscapes of human implantation

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