Volume 31, No 4, Apr 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 4, April 2021: 463-477   |  Open Access

ORIGINAL ARTICLES

Dissecting the epigenomic dynamics of human fetal germ cell development at single-cell resolution

Li Li^2,7,8 , Lin Li³ , Qingqing Li^1,2 , Xixi Liu¹ , Xinyi Ma¹ , Jun Yong¹ , Shuai Gao¹ , Xinglong Wu¹ , Yuan Wei^1,4 , Xiaoye Wang^1,4 , Wei Wang^1,4 , Rong Li^1,4 , Jie Yan^1,4 , Xiaohui Zhu^1,4 , Lu Wen^1,2 , Jie Qiao^1,4,5,6 , Liying Yan^1,4,5,* , Fuchou Tang^1,2,6,*

¹Beijing Advanced Innovation Center for Genomics, Department of Obstetrics and Gynecology, Third Hospital, School of Life Sciences, Peking University, Beijing 100871, China
²Biomedical Pioneering Innovation Center, Center for Reproductive Medicine, Ministry of Education, Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
³Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
⁴Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing 100191, China
⁵Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing 100191, China
⁶Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
⁷Present address: Stem Cell Program, Boston Children’s Hospital, Boston, MA 02115, USA
⁸Present address: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
These authors contributed equally: Li Li, Lin Li, Qingqing Li, Xixi Liu, Xinyi Ma Correspondence: Liying Yan(yanliyingkind@aliyun.com)Fuchou Tang(tangfuchou@pku.edu.cn)

Proper development of fetal germ cells (FGCs) is vital for the precise transmission of genetic and epigenetic information through generations. The transcriptional landscapes of human FGC development have been revealed; however, the epigenetic reprogramming process of FGCs remains elusive. Here, we profiled the genome-wide DNA methylation and chromatin accessibility of human FGCs at different phases as well as gonadal niche cells at single-cell resolution. First, we found that DNA methylation levels of FGCs changed in a temporal manner, whereas FGCs at different phases in the same embryo exhibited comparable DNA methylation levels and patterns. Second, we revealed the phase-specific chromatin accessibility signatures at the promoter regions of a large set of critical transcription factors and signaling pathway genes. We also identified potential distal regulatory elements including enhancers in FGCs. Third, compared with other hominid-specific retrotransposons, SVA_D might have a broad spectrum of binding capacity for transcription factors, including SOX15 and SOX17. Finally, using an in vitro culture system of human FGCs, we showed that the BMP signaling pathway promoted the cell proliferation of FGCs, and regulated the WNT signaling pathway by orchestrating the chromatin accessibility of its ligand genes. Our single-cell epigenomic atlas and functional assays provide valuable insights for understanding the strongly heterogeneous, unsynchronized, yet highly robust nature of human germ cell development.

https://doi.org/10.1038/s41422-020-00401-9

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