Scientific Updates

Fuchou Tang and colleagues reconstituted the transcriptome and methylome landscapes of human implantation at single-cell resolution

Human embryonic development starts from a fertilized egg and forms a free-floating blastocyst, containing an outer TE and an ICM. The mature ICM is composed of the pluripotent EPI covered by a layer of PE (also known as hypoblast). The EPI, PE and TE then give rise to the embryo proper, yolk sac and placenta, respectively. By embryonic day 6-7 (post-fertilization), the embryo will implant into the uterus to form a gastrula, followed by organogenesis. 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.

To decode the multidimensional elements regulating cell fate and functional switch during human implantation, Tang Lab and Jie Qiao Group from Peking University Third Hospital applied an in vitro simulation of embryo development strategy established by Magdalena Zernicka-Goetz group to make a prospective exploration on the almost completely unknown field of human embryo implantation. Combining the optimized in vitro culture system to mimic the implantation process and single-cell omics technologies, they reconstituted the transcriptome and DNA methylome landscapes of human implantation at single-cell resolution and uncovered a serial of key developmental events, which previously was a black box in human.

Fig. 1 Immunofluorescence images of human embryos at different developmental stages

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.

Fig. 2 Transcriptome dynamics at post-implantation stages

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).

Fig. 4 Lineage-specific dynamics of the DNA methylome in human peri-implantation embryos

Collectively, this 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.

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