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In vitro reconstitution of epigenetic reprogramming in the human germ line
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In vitro reconstitution of epigenetic reprogramming in the human germ line
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Journal Article
In vitro reconstitution of epigenetic reprogramming in the human germ line
2024
Overview
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 totipotency
1
. 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 >10
10
-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 cells
2
,
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.
A new strategy that involves signalling-molecule-driven differentiation can induce epigenetic reprogramming of human pluripotent stem cell-derived primordial germ cell-like cells to pro-spermatogonia and oogonia-like cells with massive propagation and high efficiency.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 13/31
/ 13/51
/ 13/95
/ 38/23
/ 38/91
/ Amnion
/ Bone Morphogenetic Proteins - metabolism
/ Cells
/ Cellular Reprogramming - genetics
/ DNA
/ Female
/ Gene Expression Regulation, Developmental
/ Genes
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mixed Function Oxygenases - deficiency
/ Oogonia
/ Pluripotent Stem Cells - cytology
/ Pluripotent Stem Cells - metabolism
/ Promoter Regions, Genetic - genetics
/ Science
