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Single-Cell Sequencing Offers Hints to Molecular Dynamics of Human Embryo Implantation

NEW YORK – New research is revealing some of the transcriptional shifts, cell lineage activity, regulatory network changes, DNA methylation dynamics, and other molecular features that mark human embryo implantation — a process that can go awry in ways that lead to early pregnancy loss. 

"Collectively, our work provides insights into the complex molecular mechanisms that regulate the implantation of human embryos, and helps to advance future efforts to understanding early embryonic development and reproductive medicine," co-senior and co-corresponding authors Fuchou Tang and Jie Qiao, obstetrics and gynecology researchers at Peking University, and their colleagues wrote in their study, published online today in Nature.

In the hopes of better understanding implantation and potential problems with it, a team from China did single-cell sequencing on thousands of individual cells from 65 human embryos grown in an in vitro culture system. Based on features found in cells profiled before, during, and after implantation, the investigators looked at everything from X chromosome inactivation in female embryos to the molecular trajectories of trophectoderm cells on the outer portion of the embryo, pluripotent epiblast cells from the embryo's inner cell mass, and primitive endoderm cells that surround the epiblast cells.

"Principal component analysis and pseudo-time analysis revealed that all three lineages presented their own developmental continuity, suggesting that there are stepwise implantation routes," the authors reported, noting that gene expression patterns observed in the developing embryos "indicated that the embryo started preparing for mother-fetal interactions during implantation."

For their study, the researchers started by applying a 'triple omics' single-cell sequencing strategy called scTrio-seq to more than 2,000 pre-implantation embryos at six days post-fertilization. They also assessed more than 9,000 individual cells obtained from post-implantation embryos grown in their in vitro culture system at eight, 10, 12, and 14 days after fertilization. After quality control steps, the team included almost 3,200 individual cells in its comparison of the trophectoderm, pluripotent epiblast, and primitive endoderm lineages.

From the gene expression clusters, cell lineage clues, copy number patterns, methylation dynamics, and other insights gleaned from the scTrio-seq data, for example, the researchers suggest that re-methylation of the genome after implantation occurs more quickly in cells from the trophectoderm and epiblast lineages than in primitive endoderm lineage cells.

"The patterns of hypermethylated gene body and hypomethylated promoter regions were shared in all of the three lineages," the authors noted, though they also found that "DNA re-methylation has clear genomic element-specific and cell lineage-specific features during implantation."

Using parental sequence data and an analysis of allele-specific expression for X-linked genes in the female embryos, meanwhile, the team got a glimpse at the early stages of X chromosome inactivation in the in vitro culture system. 

The authors warned that "many potential differences may exist between in vivo and in vitro implantation systems," but suggested that the current approach "provides a potential basis for the development of better strategies to mimic this unique process in vitro."