In vitro reconstitution of epigenetic reprogramming in the human germ line [EM-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA967721 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24451400_1.fastq.gz | Fastqsanger.gz | |||
| SRR24451400_2.fastq.gz | Fastqsanger.gz | |||
| SRR24451401_1.fastq.gz | Fastqsanger.gz | |||
| SRR24451401_2.fastq.gz | Fastqsanger.gz | |||
| SRR24451402_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency. However, the mechanism of epigenetic reprogramming in humans remains unknown. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>10(10)-fold). Strikingly, bone morphogenetic protein (BMP) signaling is the key driver of these processes. Mechanistically, BMP signaling attenuates the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, promoting replication-coupled, passive DNA demethylation. On the other hand, tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells, plays a dual role in hPGCLC differentiation: safeguarding hPGCLCs against differentiation into amnion-like cells by repressing key genes with bivalent promoters, and facilitating coordinated activation of genes vital for spermatogenesis and oogenesis by demethylating their promoters. Our study uncovers the principle of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.
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Project description:In vitro reconstitution of epigenetic reprogramming in the human germ line
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Project description:Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency. However, the mechanism of epigenetic reprogramming in humans remains unknown. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>10(10)-fold). Strikingly, bone morphogenetic protein (BMP) signaling is the key driver of these processes. Mechanistically, BMP signaling attenuates the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, promoting replication-coupled, passive DNA demethylation. On the other hand, tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells, plays a dual role in hPGCLC differentiation: safeguarding hPGCLCs against differentiation into amnion-like cells by repressing key genes with bivalent promoters, and facilitating coordinated activation of genes vital for spermatogenesis and oogenesis by demethylating their promoters. Our study uncovers the principle of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.
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Project description:Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency. However, the mechanism of epigenetic reprogramming in humans remains unknown. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>10(10)-fold). Strikingly, bone morphogenetic protein (BMP) signaling is the key driver of these processes. Mechanistically, BMP signaling attenuates the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, promoting replication-coupled, passive DNA demethylation. On the other hand, tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells, plays a dual role in hPGCLC differentiation: safeguarding hPGCLCs against differentiation into amnion-like cells by repressing key genes with bivalent promoters, and facilitating coordinated activation of genes vital for spermatogenesis and oogenesis by demethylating their promoters. Our study uncovers the principle of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.
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Project description: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.
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Project description:Mammalian male germ-cell development consists of three distinct phases: primordial germ cell (PGC) development, male germ-cell specification for spermatogonium development, and ensuing spermatogenesis. Here, we show an in vitro reconstitution of whole male germ-cell development by pluripotent stem cells (PSCs). Mouse embryonic stem cells (mESCs) are induced into PGC-like cells (mPGCLCs), which are expanded for epigenetic reprogramming. In reconstituted testes under an optimized condition, such mPGCLCs differentiate into spermatogonium-like cells with proper developmental transitions, gene expression, and cell-cycle dynamics and are expanded robustly as germline stem cell-like cells (GSCLCs) with an appropriate androgenetic epigenome. Importantly, GSCLCs show vigorous spermatogenesis, not only upon transplantation into testes in vivo but also under an in vitro culture of testis transplants, and the resultant spermatids contribute to fertile offspring. By uniting faithful recapitulations of the three phases of male germ-cell development, our study creates a paradigm for the in vitro male gametogenesis by PSCs.
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Project description:Mammalian male germ-cell development consists of three distinct phases: primordial germ cell (PGC) development, male germ-cell specification for spermatogonium development, and ensuing spermatogenesis. Here, we show an in vitro reconstitution of whole male germ-cell development by pluripotent stem cells (PSCs). Mouse embryonic stem cells (mESCs) are induced into PGC-like cells (mPGCLCs), which are expanded for epigenetic reprogramming. In reconstituted testes under an optimized condition, such mPGCLCs differentiate into spermatogonium-like cells with proper developmental transitions, gene expression, and cell-cycle dynamics and are expanded robustly as germline stem cell-like cells (GSCLCs) with an appropriate androgenetic epigenome. Importantly, GSCLCs show vigorous spermatogenesis, not only upon transplantation into testes in vivo but also under an in vitro culture of testis transplants, and the resultant spermatids contribute to fertile offspring. By uniting faithful recapitulations of the three phases of male germ-cell development, our study creates a paradigm for the in vitro male gametogenesis by PSCs.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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