In vitro reconstitution of epigenetic reprogramming in the human germ line

Author:

Murase Yusuke,Yokogawa RyutaORCID,Yabuta Yukihiro,Nagano Masahiro,Katou Yoshitaka,Mizuyama ManamiORCID,Kitamura Ayaka,Puangsricharoen Pimpitcha,Yamashiro ChikaORCID,Hu Bo,Mizuta KenORCID,Tsujimura Taro,Yamamoto Takuya,Ogata KosukeORCID,Ishihama YasushiORCID,Saitou MitinoriORCID

Abstract

AbstractEpigenetic 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.

Publisher

Springer Science and Business Media LLC

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