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  1. AU="Tang, Walfred W C"
  2. AU=Hashitani Hikaru
  3. AU="Löw, Martina"
  4. AU="Robertson, Leon S"
  5. AU="Wright, Aaron T"
  6. AU="Jones, T. B."
  7. AU=Shirtliff Mark E.
  8. AU="Riis, Kamilla R"
  9. AU="Xu, Leyao"
  10. AU="Udayakumar, Karthikrajan Parasuraman"
  11. AU="Fry, Brian"

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  1. Artikel ; Online: Specification of human germ cell fate with enhanced progression capability supported by hindgut organoids.

    Alves-Lopes, João Pedro / Wong, Frederick C K / Tang, Walfred W C / Gruhn, Wolfram H / Ramakrishna, Navin B / Jowett, Geraldine M / Jahnukainen, Kirsi / Surani, M Azim

    Cell reports

    2023  Band 42, Heft 1, Seite(n) 111907

    Abstract: Human primordial germ cells (hPGCs), the precursors of sperm and eggs, are specified during weeks 2-3 after fertilization. Few studies on ex vivo and in vitro cultured human embryos reported plausible hPGCs on embryonic day (E) 12-13 and in an E16-17 ... ...

    Abstract Human primordial germ cells (hPGCs), the precursors of sperm and eggs, are specified during weeks 2-3 after fertilization. Few studies on ex vivo and in vitro cultured human embryos reported plausible hPGCs on embryonic day (E) 12-13 and in an E16-17 gastrulating embryo. In vitro, hPGC-like cells (hPGCLCs) can be specified from the intermediary pluripotent stage or peri-gastrulation precursors. Here, we explore the broad spectrum of hPGCLC precursors and how different precursors impact hPGCLC development. We show that resetting precursors can give rise to hPGCLCs (rhPGCLCs) in response to BMP. Strikingly, rhPGCLCs co-cultured with human hindgut organoids progress at a pace reminiscent of in vivo hPGC development, unlike those derived from peri-gastrulation precursors. Moreover, rhPGCLC specification depends on both EOMES and TBXT, not just on EOMES as for peri-gastrulation hPGCLCs. Importantly, our study provides the foundation for developing efficient in vitro models of human gametogenesis.
    Mesh-Begriff(e) Humans ; Male ; Semen ; Cell Differentiation ; Germ Cells ; Embryo, Mammalian ; Organoids
    Sprache Englisch
    Erscheinungsdatum 2023-01-05
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111907
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Epigenetic resetting in the human germ line entails histone modification remodeling.

    Gruhn, Wolfram H / Tang, Walfred W C / Dietmann, Sabine / Alves-Lopes, João P / Penfold, Christopher A / Wong, Frederick C K / Ramakrishna, Navin B / Surani, M Azim

    Science advances

    2023  Band 9, Heft 3, Seite(n) eade1257

    Abstract: Epigenetic resetting in the mammalian germ line entails acute DNA demethylation, which lays the foundation for gametogenesis, totipotency, and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to ... ...

    Abstract Epigenetic resetting in the mammalian germ line entails acute DNA demethylation, which lays the foundation for gametogenesis, totipotency, and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genes and transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCs exhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signatures at most genes and TEs and the acquisition of a neutral or paused epigenetic state without transcriptional activation. Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such as evolutionarily young TEs and some developmental genes, which require H3K9me3 and H3K27me3, respectively, for efficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presents an exemplary balanced system relying on local maintenance of heterochromatic features and a lack of inductive cues.
    Mesh-Begriff(e) Animals ; Humans ; Histone Code ; DNA Methylation ; DNA Transposable Elements/genetics ; Epigenesis, Genetic ; Germ Cells ; Mammals/genetics
    Chemische Substanzen DNA Transposable Elements
    Sprache Englisch
    Erscheinungsdatum 2023-01-18
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.ade1257
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Sequential enhancer state remodelling defines human germline competence and specification.

    Tang, Walfred W C / Castillo-Venzor, Aracely / Gruhn, Wolfram H / Kobayashi, Toshihiro / Penfold, Christopher A / Morgan, Michael D / Sun, Dawei / Irie, Naoko / Surani, M Azim

    Nature cell biology

    2022  Band 24, Heft 4, Seite(n) 448–460

    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 ...

    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.
    Mesh-Begriff(e) Animals ; Cell Differentiation/genetics ; Embryonic Development/genetics ; Endoderm ; Gastrulation ; Gene Expression Regulation, Developmental ; Germ Cells/metabolism ; Humans ; Mammals
    Sprache Englisch
    Erscheinungsdatum 2022-04-11
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-022-00878-z
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: A critical role of PRDM14 in human primordial germ cell fate revealed by inducible degrons.

    Sybirna, Anastasiya / Tang, Walfred W C / Pierson Smela, Merrick / Dietmann, Sabine / Gruhn, Wolfram H / Brosh, Ran / Surani, M Azim

    Nature communications

    2020  Band 11, Heft 1, Seite(n) 1282

    Abstract: PRDM14 is a crucial regulator of mouse primordial germ cells (mPGCs), epigenetic reprogramming and pluripotency, but its role in the evolutionarily divergent regulatory network of human PGCs (hPGCs) remains unclear. Besides, a previous knockdown study ... ...

    Abstract PRDM14 is a crucial regulator of mouse primordial germ cells (mPGCs), epigenetic reprogramming and pluripotency, but its role in the evolutionarily divergent regulatory network of human PGCs (hPGCs) remains unclear. Besides, a previous knockdown study indicated that PRDM14 might be dispensable for human germ cell fate. Here, we decided to use inducible degrons for a more rapid and comprehensive PRDM14 depletion. We show that PRDM14 loss results in significantly reduced specification efficiency and an aberrant transcriptome of hPGC-like cells (hPGCLCs) obtained in vitro from human embryonic stem cells (hESCs). Chromatin immunoprecipitation and transcriptomic analyses suggest that PRDM14 cooperates with TFAP2C and BLIMP1 to upregulate germ cell and pluripotency genes, while repressing WNT signalling and somatic markers. Notably, PRDM14 targets are not conserved between mouse and human, emphasising the divergent molecular mechanisms of PGC specification. The effectiveness of degrons for acute protein depletion is widely applicable in various developmental contexts.
    Mesh-Begriff(e) Animals ; CRISPR-Cas Systems/genetics ; Cell Differentiation ; Cell Lineage ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Gene Expression Regulation ; Germ Cells/cytology ; Germ Cells/metabolism ; HEK293 Cells ; Humans ; Indoleacetic Acids/pharmacology ; Mice ; Promoter Regions, Genetic/genetics ; Protein Binding ; Proteolysis ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcriptome/genetics
    Chemische Substanzen DNA-Binding Proteins ; Indoleacetic Acids ; PRDM14 protein, human ; Prdm14 protein, mouse ; RNA-Binding Proteins ; Transcription Factors
    Sprache Englisch
    Erscheinungsdatum 2020-03-09
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-15042-0
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis.

    Irie, Naoko / Tang, Walfred W C / Azim Surani, M

    Reproductive medicine and biology

    2014  Band 13, Heft 4, Seite(n) 203–215

    Abstract: Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms. How germ cells acquire this ability has been of considerable interest. In mammals, ...

    Abstract Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms. How germ cells acquire this ability has been of considerable interest. In mammals, primordial germ cells (PGCs), the precursors of sperm and oocytes, are specified around the time of gastrulation. PGCs are induced by signals from the surrounding extra-embryonic tissues to the equipotent epiblast cells that give rise to all cell types. Currently, the mechanism of PGC specification in mammals is best understood from studies in mice. Following implantation, the epiblast cells develop as an egg cylinder while the extra-embryonic ectoderm cells which are the source of important signals for PGC specification are located over the egg cylinder. However, in most cases, including humans, the epiblast cells develop as a planar disc, which alters the organization and the source of the signaling for cell fates. This, in turn, might have an effect on the precise mechanism of PGC specification in vivo as well as in vitro using pluripotent embryonic stem cells. Here, we discuss how the key early embryonic differences between rodents and other mammals may affect the establishment of the pluripotency network in vivo and in vitro, and consequently the basis for PGC specification, particularly from pluripotent embryonic stem cells in vitro.
    Sprache Englisch
    Erscheinungsdatum 2014-06-10
    Erscheinungsland Japan
    Dokumenttyp Journal Article
    ZDB-ID 2185775-1
    ISSN 1447-0578 ; 1445-5781
    ISSN (online) 1447-0578
    ISSN 1445-5781
    DOI 10.1007/s12522-014-0184-2
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Author Correction: Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.

    Floros, Vasileios I / Pyle, Angela / Dietmann, Sabine / Wei, Wei / Tang, Walfred W C / Irie, Naoko / Payne, Brendan / Capalbo, Antonio / Noli, Laila / Coxhead, Jonathan / Hudson, Gavin / Crosier, Moira / Strahl, Henrik / Khalaf, Yacoub / Saitou, Mitinori / Ilic, Dusko / Surani, M Azim / Chinnery, Patrick F

    Nature cell biology

    2022  Band 25, Heft 1, Seite(n) 194

    Sprache Englisch
    Erscheinungsdatum 2022-12-15
    Erscheinungsland England
    Dokumenttyp Published Erratum
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-022-01046-z
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Primordial germ-cell development and epigenetic reprogramming in mammals.

    Leitch, Harry G / Tang, Walfred W C / Surani, M Azim

    Current topics in developmental biology

    2013  Band 104, Seite(n) 149–187

    Abstract: Primordial germ cells (PGCs) are the embryonic precursors of the gametes and represent the founder cells of the germline. Specification of PGCs is a critical divergent point during embryogenesis. Whereas the somatic lineages will ultimately perish, cells ...

    Abstract Primordial germ cells (PGCs) are the embryonic precursors of the gametes and represent the founder cells of the germline. Specification of PGCs is a critical divergent point during embryogenesis. Whereas the somatic lineages will ultimately perish, cells of the germline have the potential to form a new individual and hence progress to the next generation. It is therefore critical that the genome emerges intact and carrying the appropriate epigenetic information during its passage through the germline. To ensure this fidelity of transmission, PGC development encompasses extensive epigenetic reprogramming. The low cell numbers and relative inaccessibility of PGCs present a challenge to those seeking mechanistic understanding of the crucial developmental and epigenetic processes in this most fascinating of lineages. Here, we present an overview of PGC development in the mouse and compare this with the limited information available for other mammalian species. We believe that a comparative approach will be increasingly important to uncover the extent to which mechanisms are conserved and reveal the critical steps during PGC development in humans.
    Mesh-Begriff(e) Animals ; Cellular Reprogramming/genetics ; Epigenesis, Genetic ; Germ Cells/cytology ; Germ Cells/metabolism ; Humans ; Mammals/embryology ; Mammals/genetics ; Models, Biological ; Signal Transduction/genetics
    Sprache Englisch
    Erscheinungsdatum 2013-04-15
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1557-8933 ; 0070-2153
    ISSN (online) 1557-8933
    ISSN 0070-2153
    DOI 10.1016/B978-0-12-416027-9.00005-X
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Tracing the emergence of primordial germ cells from bilaminar disc rabbit embryos and pluripotent stem cells.

    Kobayashi, Toshihiro / Castillo-Venzor, Aracely / Penfold, Chris A / Morgan, Michael / Mizuno, Naoaki / Tang, Walfred W C / Osada, Yasuyuki / Hirao, Masao / Yoshida, Fumika / Sato, Hideyuki / Nakauchi, Hiromitsu / Hirabayashi, Masumi / Surani, M Azim

    Cell reports

    2021  Band 37, Heft 2, Seite(n) 109812

    Abstract: Rabbit embryos develop as bilaminar discs at gastrulation as in humans and most other mammals, whereas rodents develop as egg cylinders. Primordial germ cells (PGCs) appear to originate during gastrulation according to many systematic studies on ... ...

    Abstract Rabbit embryos develop as bilaminar discs at gastrulation as in humans and most other mammals, whereas rodents develop as egg cylinders. Primordial germ cells (PGCs) appear to originate during gastrulation according to many systematic studies on mammalian embryos. Here, we show that rabbit PGC (rbPGC) specification occurs at the posterior epiblast at the onset of gastrulation. Using newly derived rabbit pluripotent stem cells, we show robust and rapid induction of rbPGC-like cells in vitro with WNT and BMP morphogens, which reveals SOX17 as the critical regulator of rbPGC fate as in several non-rodent mammals. We posit that development as a bilaminar disc is a crucial determinant of the PGC regulators, regardless of the highly diverse development of extraembryonic tissues, including the amnion. We propose that investigations on rabbits with short gestation, large litters, and where gastrulation precedes implantation can contribute significantly to advances in early mammalian development.
    Mesh-Begriff(e) Animals ; Bone Morphogenetic Proteins/genetics ; Bone Morphogenetic Proteins/metabolism ; Cell Differentiation ; Cell Lineage ; Cell Movement ; Cells, Cultured ; Embryonic Stem Cells/metabolism ; Embryonic Stem Cells/physiology ; Female ; Gastrulation ; Gene Expression Regulation, Developmental ; Germ Layers/cytology ; Male ; Mice, Inbred NOD ; Mice, SCID ; Pluripotent Stem Cells/metabolism ; Pluripotent Stem Cells/physiology ; Rabbits ; SOXF Transcription Factors/genetics ; SOXF Transcription Factors/metabolism ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; Wnt Signaling Pathway ; Mice
    Chemische Substanzen Bone Morphogenetic Proteins ; SOXF Transcription Factors ; Wnt Proteins
    Sprache Englisch
    Erscheinungsdatum 2021-10-13
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109812
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Specification and epigenetic programming of the human germ line.

    Tang, Walfred W C / Kobayashi, Toshihiro / Irie, Naoko / Dietmann, Sabine / Surani, M Azim

    Nature reviews. Genetics

    2016  Band 17, Heft 10, Seite(n) 585–600

    Abstract: Primordial germ cells (PGCs), the precursors of sperm and eggs, are established in perigastrulation-stage embryos in mammals. Signals from extra-embryonic tissues induce a unique gene regulatory network in germline-competent cells for PGC specification. ... ...

    Abstract Primordial germ cells (PGCs), the precursors of sperm and eggs, are established in perigastrulation-stage embryos in mammals. Signals from extra-embryonic tissues induce a unique gene regulatory network in germline-competent cells for PGC specification. This network also initiates comprehensive epigenome resetting, including global DNA demethylation and chromatin reorganization. Mouse germline development has been studied extensively, but the extent to which such knowledge applies to humans was unclear. Here, we review the latest advances in human PGC specification and epigenetic reprogramming. The overall developmental dynamics of human and mouse germline cells appear to be similar, but there are crucial mechanistic differences in PGC specification, reflecting divergence in the regulation of pluripotency and early development.
    Mesh-Begriff(e) Animals ; DNA Methylation ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Germ Cells ; Humans ; Mice ; Signal Transduction
    Sprache Englisch
    Erscheinungsdatum 2016-08-30
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2035157-4
    ISSN 1471-0064 ; 1471-0056
    ISSN (online) 1471-0064
    ISSN 1471-0056
    DOI 10.1038/nrg.2016.88
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Pluripotency and X chromosome dynamics revealed in pig pre-gastrulating embryos by single cell analysis.

    Ramos-Ibeas, Priscila / Sang, Fei / Zhu, Qifan / Tang, Walfred W C / Withey, Sarah / Klisch, Doris / Wood, Liam / Loose, Matt / Surani, M Azim / Alberio, Ramiro

    Nature communications

    2019  Band 10, Heft 1, Seite(n) 500

    Abstract: High-resolution molecular programmes delineating the cellular foundations of mammalian embryogenesis have emerged recently. Similar analysis of human embryos is limited to pre-implantation stages, since early post-implantation embryos are largely ... ...

    Abstract High-resolution molecular programmes delineating the cellular foundations of mammalian embryogenesis have emerged recently. Similar analysis of human embryos is limited to pre-implantation stages, since early post-implantation embryos are largely inaccessible. Notwithstanding, we previously suggested conserved principles of pig and human early development. For further insight on pluripotent states and lineage delineation, we analysed pig embryos at single cell resolution. Here we show progressive segregation of inner cell mass and trophectoderm in early blastocysts, and of epiblast and hypoblast in late blastocysts. We show that following an emergent short naive pluripotent signature in early embryos, there is a protracted appearance of a primed signature in advanced embryonic stages. Dosage compensation with respect to the X-chromosome in females is attained via X-inactivation in late epiblasts. Detailed human-pig comparison is a basis towards comprehending early human development and a foundation for further studies of human pluripotent stem cell differentiation in pig interspecies chimeras.
    Mesh-Begriff(e) Animals ; Cell Differentiation/physiology ; Female ; Gastrulation/physiology ; Gene Expression Regulation, Developmental ; Germ Layers/metabolism ; Humans ; Single-Cell Analysis/methods ; Swine ; X Chromosome/metabolism ; X Chromosome Inactivation/physiology
    Sprache Englisch
    Erscheinungsdatum 2019-01-30
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-08387-8
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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