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Single-cell RNA-seq reveals distinct dynamic behavior of sex chromosomes during early human embryogenesis

By Qing Zhou, Taifu Wang, Lizhi Leng, Wei Zheng, Jinrong Huang, Fang Fang, Ling Yang, Jian Wang, Huanming Yang, Fang Chen, Ge Lin, Wen-Jing Wang, Karsten Kristiansen

Posted 01 Aug 2018
bioRxiv DOI: 10.1101/382085 (published DOI: 10.1002/mrd.23162)

Background: Several animal and human studies have demonstrated that sex affects kinetics and metabolism during early embryo development. However, the mechanism governing these differences at the molecular level is unknown, warranting a systematic profiling of gene expression in males and females during embryogenesis. Findings: We performed comprehensive analyses of gene expression comparing male and female embryos using available single-cell RNA-sequencing data of 1607 individual cells from 99 human preimplantation embryos, covering development stages from 4-cell to late blastocyst (E2 to E7). Consistent chromosome-wide transcription of autosomes was observed, while sex chromosomes showed significant differences after embryonic genome activation (EGA). Differentially expressed genes (DE genes) in male and female embryos mainly involved in the cell cycle, protein translation and metabolism. The Y chromosome was initially activated by pioneer genes, RPS4Y1 and DDX3Y, while the two X chromosomes in female were widely activated after EGA. Expression of X-linked genes in female significantly declined at the late blastocyst stage, especially in trophectoderm cells, revealing a rapid process of dosage compensation. Conclusions: We observed imbalanced expression from sex chromosomes in male and female embryos during EGA, with dosage compensation occurring first in female trophectoderm cells. Studying the effect of sex differences during human embryogenesis, as well as understanding the mechanism of X chromosome inactivation and its correlation with early miscarriage, will provide a basis for advancing assisted reproductive technology (ART) and thereby improve the treatment of infertility and possibly enhance reproductive health. Key words: single-cell RNA-seq, embryogenesis, sex differences, dosage compensation

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