In vitro reconstitution of epigenetic reprogramming in the human germ line

Yusuke Murase, Ryuta Yokogawa, Yukihiro Yabuta, Masahiro Nagano, Yoshitaka Katou, Manami Mizuyama, Ayaka Kitamura, Pimpitcha Puangsricharoen, Chika Yamashiro, Bo Hu, Ken Mizuta, Taro Tsujimura, Takuya Yamamoto, Kosuke Ogata, Yasushi Ishihama and Mitinori Saitou ()
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Yusuke Murase: Kyoto University
Ryuta Yokogawa: Kyoto University
Yukihiro Yabuta: Kyoto University
Masahiro Nagano: Kyoto University
Yoshitaka Katou: Kyoto University
Manami Mizuyama: Kyoto University
Ayaka Kitamura: Kyoto University
Pimpitcha Puangsricharoen: Kyoto University
Chika Yamashiro: Kyoto University
Bo Hu: Kyoto University
Ken Mizuta: Kyoto University
Taro Tsujimura: Kyoto University
Takuya Yamamoto: Kyoto University
Kosuke Ogata: Kyoto University
Yasushi Ishihama: Kyoto University
Mitinori Saitou: Kyoto University

Nature, 2024, vol. 631, issue 8019, 170-178

Abstract: Abstract Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency1. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here we establish a strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem-cell-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (about >1010-fold). Bone morphogenetic protein (BMP) signalling is a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK (ERK) pathway and both de novo and maintenance DNA methyltransferase activities, which probably promote replication-coupled, passive DNA demethylation. hPGCLCs deficient in TET1, an active DNA demethylase abundant in human germ cells2,3, differentiate into extraembryonic cells, including amnion, with de-repression of key genes that bear bivalent promoters. These cells fail to fully activate genes vital for spermatogenesis and oogenesis, and their promoters remain methylated. Our study provides a framework for epigenetic reprogramming in humans and an important advance in human biology. Through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, our results also represent a milestone for human in vitro gametogenesis research and its potential translation into reproductive medicine.

Date: 2024
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DOI: 10.1038/s41586-024-07526-6

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