Germline stem cells in human

Cheng, Hanhua; Shang, Dantong; Zhou, Rongjia

doi:10.1038/s41392-022-01197-3

Cited by 24 publications

(20 citation statements)

References 541 publications

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“…Previous studies have focused on the transcription factors involved in the regulatory mechanisms for human germ cell development. In humans, SOX17-BLIMP1 is the central specifier of early germ cell fate, and many other key genes like EOMES and TFAP2C are critical regulators involved in the unique transcriptional program of hPGCs [ 21 , 22 , 45 ]. The transcriptome and DNA methylome data of hPGCs reveal the global erasure of DNA methylation in the germline genome, which is not completely correlated with the global changes in gene expression [ 5 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

The balance between NANOG and SOX17 mediated by TET proteins regulates specification of human primordial germ cell fate

Fang

Long

et al. 2022

Cell Biosci

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Background Human primordial germ cells (hPGCs) initiate from the early post-implantation embryo at week 2–3 and undergo epigenetic reprogramming during development. However, the regulatory mechanism of DNA methylation during hPGC specification is still largely unknown due to the difficulties in analyzing early human embryos. Using an in vitro model of hPGC induction, we found a novel function of TET proteins and NANOG in the hPGC specification which was different from that discovered in mice. Methods Using the CRISPR–Cas9 system, we generated a set of TET1, TET2 and TET3 knockout H1 human embryonic stem cell (hESC) lines bearing a BLIMP1-2A-mKate2 reporter. We determined the global mRNA transcription and DNA methylation profiles of pluripotent cells and induced hPGC-like cells (hPGCLCs) by RNA-seq and whole-genome bisulfite sequencing (WGBS) to reveal the involved signaling pathways after TET proteins knockout. ChIP-qPCR was performed to verify the binding of TET and NANOG proteins in the SOX17 promoter. Real-time quantitative PCR, western blot and immunofluorescence were performed to measure gene expression at mRNA and protein levels. The efficiency of hPGC induction was evaluated by FACS. Results In humans, TET1, TET2 and TET3 triple-knockout (TKO) human embryonic stem cells (hESCs) impaired the NODAL signaling pathway and impeded hPGC specification in vitro, while the hyperactivated NODAL signaling pathway led to gastrulation failure when Tet proteins were inactivated in mouse. Specifically, TET proteins stimulated SOX17 through the NODAL signaling pathway and directly regulates NANOG expression at the onset of hPGCLCs induction. Notably, NANOG could bind to SOX17 promoter to regulate its expression in hPGCLCs specification. Furthermore, in TKO hESCs, DNMT3B-mediated hypermethylation of the NODAL signaling-related genes and NANOG/SOX17 promoters repressed their activation and inhibited hPGCLC induction. Knockout of DNMT3B in TKO hESCs partially restored NODAL signaling and NANOG/SOX17 expression, and rescued hPGCLC induction. Conclusion Our results show that TETs-mediated oxidation of 5-methylcytosine modulates the NODAL signaling pathway and its downstream genes, NANOG and SOX17, by promoting demethylation in opposition to DNMT3B-mediated methylation, suggesting that the epigenetic balance of DNA methylation and demethylation in key genes plays a fundamental role in early hPGC specification.

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Section: Discussionmentioning

confidence: 99%

The balance between NANOG and SOX17 mediated by TET proteins regulates specification of human primordial germ cell fate

Fang

Long

et al. 2022

Cell Biosci

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“…The second decision arises once the gonads have formed, determining whether they will differentiate into testes or ovaries. Despite the extensive knowledge about the epigenetic regulation of these processes (Cheng et al, 2022 ; Strome and Updike, 2015 ), our understanding of the TFs or GRNs that orchestrate the repression of alternative fates remains limited.…”

Section: Cell and Tissue Specificity Of Alternative Fate Repression: ...mentioning

confidence: 99%

Canalizing cell fate by transcriptional repression

Lim,

Domsch,

Mall

et al. 2024

Mol Syst Biol

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Precision in the establishment and maintenance of cellular identities is crucial for the development of multicellular organisms and requires tight regulation of gene expression. While extensive research has focused on understanding cell type-specific gene activation, the complex mechanisms underlying the transcriptional repression of alternative fates are not fully understood. Here, we provide an overview of the repressive mechanisms involved in cell fate regulation. We discuss the molecular machinery responsible for suppressing alternative fates and highlight the crucial role of sequence-specific transcription factors (TFs) in this process. Depletion of these TFs can result in unwanted gene expression and increased cellular plasticity. We suggest that these TFs recruit cell type-specific repressive complexes to their cis-regulatory elements, enabling them to modulate chromatin accessibility in a context-dependent manner. This modulation effectively suppresses master regulators of alternative fate programs and their downstream targets. The modularity and dynamic behavior of these repressive complexes enables a limited number of repressors to canalize and maintain major and minor cell fate decisions at different stages of development.

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“…Though recent study about ovarian stem cell challenges the concept of unrenewed follicular pool, it is suggested to make only a minor difference in normal aging process due to its rarity [19]. However, as the success achieved by the use of female germline stem cells of human for oogenesis in vitro [20], these cells have the potential to be applied to fertility preservation in the future [21].…”

Section: Definitionmentioning

confidence: 99%

Mechanisms of ovarian aging in women: a review

Wang

Xiang

2023

J Ovarian Res

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Ovarian aging is a natural and physiological aging process characterized by loss of quantity and quality of oocyte or follicular pool. As it is generally accepted that women are born with a finite follicle pool that will go through constant decline without renewing, which, together with decreased oocyte quality, makes a severe situation for women who is of advanced age but desperate for a healthy baby. The aim of our review was to investigate mechanisms leading to ovarian aging by discussing both extra- and intra- ovarian factors and to identify genetic characteristics of ovarian aging. The mechanisms were identified as both extra-ovarian alternation of hypothalamic–pituitary-ovarian axis and intra-ovarian alternation of ovary itself, including telomere, mitochondria, oxidative stress, DNA damage, protein homeostasis, aneuploidy, apoptosis and autophagy. Moreover, here we reviewed related Genome-wide association studies (GWAS studies) from 2009 to 2021 and next generation sequencing (NGS) studies of primary ovarian insufficiency (POI) in order to describe genetic characteristics of ovarian aging. It is reasonable to wish more reliable anti-aging interventions for ovarian aging as the exploration of mechanisms and genetics being progressing.

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Germline stem cells in human

Cited by 24 publications

References 541 publications

The balance between NANOG and SOX17 mediated by TET proteins regulates specification of human primordial germ cell fate

The balance between NANOG and SOX17 mediated by TET proteins regulates specification of human primordial germ cell fate

Canalizing cell fate by transcriptional repression

Mechanisms of ovarian aging in women: a review

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