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The role of KLF4 in the development of human primordial germ cell

ABSTRACT: Primordial germ cells (PGCs) are the founder cells that develop into mature gametes. PGCs emerge during weeks 2-3 of human embryo development. Pluripotency genes are reactivated during PGCs specification, including Kruppel-like factor KLF4, but its precise role in PGC development is unknown. Here, we investigated the role of KLF4 in PGC development using our in vitro model for human PGC-like cells (hPGCLCs). We show that depletion of KLF4 using acute protein degradation strategies reduced the efficiency of hPGCLC specification. We conducted transcriptome analysis of KLF4-depleted hPGCLCs, and observed downregulation of genes involved in pattern specification, stem cell differentiation, and epigenetic modifications. Notably, KLF4 depletion led to the derepression of some somatic genes related to endodermal and neuronal differentiation. In PGCLCs, the KLF4 Cut&Run results showed significant co-enrichment with SP and STAT motifs, prominently localized to promoter regions. This represents a distinct binding pattern compared to that observed in naive embryonic stem cells. Our study reveals that KLF4 contributes to the differentiation and maintenance of human PGCLCs by comprehensively regulating both gene activation and repression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271818 | GEO | 2025/01/29

REPOSITORIES: GEO

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Project description:The generation of properly functioning gametes in vitro, a key goal in developmental/reproductive biology, requires multi-step reconstitutions of complex germ cell development. Based on the logic of primordial germ cell (PGC)-specification, we demonstrate here the generation of PGC-like cells (PGCLCs) in mice with robust capacity for spermatogenesis from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) through epiblast-like cells (EpiLCs), a cellular state highly similar to pre-gastrulating epiblasts, but distinct from epiblast stem cells (EpiSCs). The global transcription profiles, epigenetic reprogramming, and cellular dynamics during PGCLC induction from EpiLCs are a meticulous capture of those associated with PGC specification from the epiblasts. Furthermore, we identify Integrin-beta 3 and SSEA1 as markers that purify PGCLCs with spermatogenic capacity free from tumorigenic undifferentiated cells. With the reconstitution of PGC specification pathway from the naive inner cell mass state, our study defines a paradigm for the essential step of in vitro gametogenesis. We performed this analysis to reveal the characters of the cells that we created in this study, epiblast-like cells (EpiLCs) and primordial germ cells-like cells (PGCLCs). Because EpiLCs were induced from embryonic stem cells (ESCs), and equivalent to pre-gastrulating epiblast (embryonic day [E] 5.5-6.0) in vivo (embryo), ESCs and epiblast were included in this analysis. Epiblast stem cells (EpiSCs) are a culture cell type derived from epiblast, and were also included. PGCLCs were supposed to be equivalent to E9.5 PGCs based on reporter fluorescent transgene expressions and epigenetic properties, and therefore E9.5 PGCs were also inckuded in this analysis. Because epiblast and E9.5 PGCs are of a small number of cells in embryos (a few hundred to thousand cells), cDNAs were amplified with a quantitative global PCR method (Kurimoto et al., 2006, Nucleic Acids Research) for microarray analyses. We took two biological replicate for each cell type.

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The role of KLF4 in the development of human primordial germ cell

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