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Sequential enhancer state remodelling defines human germline competence and specification [ATAC-seq]

ABSTRACT: Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours mesoderm and endoderm fates. Consistently, reducing the expression of the mesendodermal transcription factor OTX2 promotes the PGC fate. In hPGCs, SOX17 and TFAP2C initiate activation of enhancers to establish a core germline programme, including the transcriptional repressor PRDM1 and pluripotency factors POU5F1 and NANOG. We demonstrate that SOX17 enhancers are the critical components in the regulatory circuitry of germline competence. Furthermore, activation of upstream cis-regulatory elements by an optimized CRISPR activation system is sufficient for hPGC specification. We reveal an enhancer-linked germline transcription factor network that provides the basis for the evolutionary divergence of mammalian germlines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159649 | GEO | 2022/01/24

REPOSITORIES: GEO

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Sequential enhancer state remodelling defines human germline competence and specification [TF ChIP-seq]]

Project description:Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours mesoderm and endoderm fates. Consistently, reducing the expression of the mesendodermal transcription factor OTX2 promotes the PGC fate. In hPGCs, SOX17 and TFAP2C initiate activation of enhancers to establish a core germline programme, including the transcriptional repressor PRDM1 and pluripotency factors POU5F1 and NANOG. We demonstrate that SOX17 enhancers are the critical components in the regulatory circuitry of germline competence. Furthermore, activation of upstream cis-regulatory elements by an optimized CRISPR activation system is sufficient for hPGC specification. We reveal an enhancer-linked germline transcription factor network that provides the basis for the evolutionary divergence of mammalian germlines.

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SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate

Project description:Specification of primordial germ cells (PGCs) marks the beginning of the totipotent state. However, without a tractable experimental model, the mechanism of human PGC (hPGC) specification remains unclear. Here, we demonstrate specification of hPGC-like cells (hPGCLCs) from germline competent pluripotent stem cells. The characteristics of hPGCLCs are consistent with the embryonic hPGCs and a germline seminoma that share a CD38 cell-surface marker, which collectively defines likely progression of the early human germline. Remarkably, SOX17 is the key regulator of hPGC-like fate, whereas BLIMP1 represses endodermal and other somatic genes during specification of hPGCLCs. Notable mechanistic differences between mouse and human PGC specification could be attributed to their divergent embryonic development and pluripotent states, which might affect other early cell-fate decisions. We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information. RNA-Seq analysis to investigate transcriptomes of hPGC-like cells (hPGCLCs), fetal hPGCs, TCam-2 and hESCs

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SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate

2014-12-26 | GSE60138 | GEO

Depicting early human development and germ cell origin with porcine embryos

Project description:Human primordial germ cells (hPGCs), the precursors of sperm and eggs, originate in early postimplantation embryos. Since early human embryos cannot be investigated directly, we extended our recent in vitro model for hPGC fate, alongside direct analysis of early porcine embryos, which develop in a highly similar manner. Here we show that porcine PGCs (pPGCs) originate from the posterior pre-primitive streak epiblast in response to WNT and BMP-pSMAD signalling, followed by sequential induction of SOX17–BLIMP1 expression. This is reminiscent of our observations for the human in vitro counterpart. Mechanistic analysis in the culture model for hPGC specification and gastrulation shows that a balanced SOX17-BLIMP1 gene dosage is critical and sufficient for PGC specification; SOX17 subsequently induces definitive endoderm during gastrulation. We demonstrate that porcine embryos when combined with a tractable human model system can provide insights on early human development and mechanisms of early cell fate decisions.

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The TFAP2C-Regulated OCT4 Naive Enhancer Is Involved in Human Germline Formation

Project description:Human primordial germ cells (hPGCs) are the first embryonic progenitors in the germ cell lineage, yet the molecular mechanisms required for hPGC formation are not well characterized. To identify regulatory regions in hPGC development, we used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) to systematically characterize regions of open chromatin in hPGCs and hPGC-like cells (hPGCLCs) differentiated from human embryonic stem cells (hESCs). We discovered regions of open chromatin unique to hPGCs and hPGCLCs that significantly overlap with TFAP2C-bound enhancers identified in the naive ground state of pluripotency. Using CRISPR/Cas9, we show that deleting the TFAP2C-bound naive enhancer at the OCT4 locus (also called POU5F1) results in impaired OCT4 expression and a negative effect on hPGCLC identity.

2018-12-27 | GSE120648 | GEO

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Project description:The mechanism for human germ-cell specification, which sets out a complex program generating spermatozoa or oocytes, remains largely unknown. We established a system for inducing human primordial germ cell-like cells (hPGCLCs) from induced pluripotent stem cells (hiPSCs) via incipient mesoderm-like cells (iMeLCs). Here, we show that EOMESODERMIN (EOMES) elevates in iMeLCs through WNT signaling and is essential for activating SOX17, a key driver for hPGC(LC) specification, with the duration/dosage of the WNT signaling/EOMES expression dictating the germ-cell competence. Upon hPGCLC induction, BMP signaling activates TFAP2C independently from SOX17, and SOX17 and TFAP2C instate the hPGCLC program, including BLIMP1 expression, in an interdependent fashion. The hPGC(LC) specification program is highly consistent with the monkey program, but is divergent from the mouse one regarding key transcription factors and their hierarchy of actions. These findings delineate evolutionary divergence of mammalian germ-cell specification, providing a foundation for further human germ-cell development in vitro.

2018-02-21 | GSE99350 | GEO

Female human primordial germ cells display X-chromosome dosage compensation despite the absence of X-inactivation [Female]

Project description:X chromosome dosage compensation is one of the most important epigenetic events in female mammalian development. Although the mouse has served as the primary model to study how genetic equality is established between male and female mammals, it is now appreciated that these mechanisms are not fully conserved in humans. Using human primordial germ cells (hPGCs) as a model together with single cell RNA-sequencing, in vitro differentiation of hPGC like cells and human embryo attachment culture, we show that X-linked gene expression in female hPGCs is compensated to levels found in female somatic cells though a mechanism related to X chromosome dampening rather than X chromosome inactivation. Loss of dampening and decompensation of both X chromosomes occurs when female hPGCs enter meiosis and is coincident with loss of the long non-coding RNAs XIST and XACT. In contrast, differentiation of male hPGCs results in no change in compensation despite loss of XACT. Taken together, future studies of X-linked gene regulation and function in human germ cell development and fertility must take into account the unique and sexually dimorphic dosage compensation occurring during in the prenatal human germline prior to birth.

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