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Stem Cells and Development Jul 2019The mammalian zygote is described as a totipotent cell in the literature, but this characterization is elusive ignoring the molecular underpinnings. Totipotency can... (Review)
Review
The mammalian zygote is described as a totipotent cell in the literature, but this characterization is elusive ignoring the molecular underpinnings. Totipotency can connote genetic totipotency, epigenetic totipotency, or the reprogramming capacity of a cell to epigenetic totipotency. Here, the implications of these concepts are discussed in the context of the properties of the zygote. Although genetically totipotent as any diploid somatic cell is, a zygote seems not totipotent transcriptionally, epigenetically, or functionally. Yet, a zygote may retain most of the key factors from its parental oocyte to reprogram an implanted differentiated genome or the zygote genome toward totipotency. This totipotent reprogramming process may extend to blastomeres in the two-cell-stage embryo. Thus, a revised alternative model of mammalian cellular totipotency is proposed, in which an epigenetically totipotent cell exists after the major embryonic genome activation and before the separation of the first two embryonic lineages.
Topics: Animals; Cell Differentiation; Embryo, Mammalian; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Humans; Zygote
PubMed: 31122174
DOI: 10.1089/scd.2019.0057 -
Development (Cambridge, England) Jul 2021Understanding the mechanisms of embryonic cell cycles is a central goal of developmental biology, as the regulation of the cell cycle must be closely coordinated with...
Understanding the mechanisms of embryonic cell cycles is a central goal of developmental biology, as the regulation of the cell cycle must be closely coordinated with other events during early embryogenesis. Quantitative imaging approaches have recently begun to reveal how the cell cycle oscillator is controlled in space and time, and how it is integrated with mechanical signals to drive morphogenesis. Here, we discuss how the Drosophila embryo has served as an excellent model for addressing the molecular and physical mechanisms of embryonic cell cycles, with comparisons to other model systems to highlight conserved and species-specific mechanisms. We describe how the rapid cleavage divisions characteristic of most metazoan embryos require chemical waves and cytoplasmic flows to coordinate morphogenesis across the large expanse of the embryo. We also outline how, in the late cleavage divisions, the cell cycle is inter-regulated with the activation of gene expression to ensure a reliable maternal-to-zygotic transition. Finally, we discuss how precise transcriptional regulation of the timing of mitosis ensures that tissue morphogenesis and cell proliferation are tightly controlled during gastrulation.
Topics: Animals; CDC2 Protein Kinase; Cell Cycle; Cell Cycle Checkpoints; Drosophila; Drosophila Proteins; Embryo, Mammalian; Embryo, Nonmammalian; Embryonic Development; Gene Expression Regulation, Developmental; Mitosis; Morphogenesis; Xenopus; Zygote
PubMed: 34164654
DOI: 10.1242/dev.193128 -
Cell Reports Sep 2023The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether...
The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether this generates cells similar to early embryonic stem cells. Here we identified cancer cell lines that express DUX4 and showed that DUX4 is transiently expressed in a small subset of the cells. DUX4 expression activates the DUX4-regulated ZGA transcriptional program, the subsequent 8C-like program, and markers of early embryonic lineages, while suppressing steady-state and interferon-induced MHC class I expression. Although DUX4 was expressed in a small number of cells under standard culture conditions, DNA damage or changes in growth conditions increased the fraction of cells expressing DUX4 and its downstream programs. Our demonstration that transient expression of endogenous DUX4 in cancer cells induces a metastable early embryonic stem cell program and suppresses antigen presentation has implications for cancer growth, progression, and immune evasion.
Topics: Humans; Cell Line; Genes, Homeobox; Homeodomain Proteins; Muscular Dystrophy, Facioscapulohumeral; Neoplasms; Transcription Factors; Zygote
PubMed: 37691147
DOI: 10.1016/j.celrep.2023.113114 -
Genes & Development Oct 2023Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis,...
Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis, including zygotic genome activation (ZGA) during maternal-to-zygotic transition, influence such remodeling remains unknown. Here, we have investigated the establishment of nuclear architecture, focusing on the remodeling of lamina-associated domains (LADs) during this transition. We report that LADs reorganize gradually in two-cell embryos and that blocking ZGA leads to major changes in nuclear organization, including altered chromatin and genomic features of LADs and redistribution of H3K4me3 toward the nuclear lamina. Our data indicate that the rearrangement of LADs is an integral component of the maternal-to-zygotic transition and that transcription contributes to shaping nuclear organization at the beginning of mammalian development.
Topics: Animals; Mice; RNA Polymerase II; Transcription, Genetic; Embryonic Development; Zygote; Mammals; Gene Expression Regulation, Developmental; Chromatin
PubMed: 37914351
DOI: 10.1101/gad.350799.123 -
Genome Research Feb 2022The zygote, a totipotent stem cell, is crucial to the life cycle of sexually reproducing organisms. It is produced by the fusion of two differentiated cells-the egg and...
The zygote, a totipotent stem cell, is crucial to the life cycle of sexually reproducing organisms. It is produced by the fusion of two differentiated cells-the egg and sperm, which in plants have radically different siRNA transcriptomes from each other and from multicellular embryos. Owing to technical challenges, the epigenetic changes that accompany the transition from differentiated gametes to totipotent zygote are poorly understood. Because siRNAs serve as both regulators and outputs of the epigenome, we characterized small RNA transcriptomes of zygotes from rice. Zygote small RNAs exhibit extensive maternal carryover and an apparent lack of paternal contribution, indicated by absence of sperm signature siRNAs. Zygote formation is accompanied by widespread redistribution of 24-nt siRNAs relative to gametes, such that ∼70% of the zygote siRNA loci do not overlap any egg cell siRNA loci. Newly detected siRNA loci in zygote are gene-proximal and not associated with centromeric heterochromatin, similar to canonical siRNAs, in sharp contrast to gametic siRNA loci that are gene-distal and heterochromatic. In addition, zygote but not egg siRNA loci are associated with high DNA methylation in the mature embryo. Thus, the zygote begins transitioning before the first embryonic division to an siRNA profile that is associated with future RdDM in embryogenesis. These findings indicate that, in addition to changes in gene expression, the transition to totipotency in the plant zygote is accompanied by resetting of the epigenetic reprogramming that occurred during gamete formation.
Topics: DNA Methylation; Epigenesis, Genetic; Oryza; RNA, Small Interfering; Zygote
PubMed: 34949668
DOI: 10.1101/gr.275981.121 -
Nature Cell Biology Apr 2020The importance of germline-inherited post-translational histone modifications on priming early mammalian development is just emerging. Histone H3 lysine 9 (H3K9)...
The importance of germline-inherited post-translational histone modifications on priming early mammalian development is just emerging. Histone H3 lysine 9 (H3K9) trimethylation is associated with heterochromatin and gene repression during cell-fate change, whereas histone H3 lysine 4 (H3K4) trimethylation marks active gene promoters. Mature oocytes are transcriptionally quiescent and possess remarkably broad domains of H3K4me3 (bdH3K4me3). It is unknown which factors contribute to the maintenance of the bdH3K4me3 landscape. Lysine-specific demethylase 4A (KDM4A) demethylates H3K9me3 at promoters marked by H3K4me3 in actively transcribing somatic cells. Here, we report that KDM4A-mediated H3K9me3 demethylation at bdH3K4me3 in oocytes is crucial for normal pre-implantation development and zygotic genome activation after fertilization. The loss of KDM4A in oocytes causes aberrant H3K9me3 spreading over bdH3K4me3, resulting in insufficient transcriptional activation of genes, endogenous retroviral elements and chimeric transcripts initiated from long terminal repeats during zygotic genome activation. The catalytic activity of KDM4A is essential for normal epigenetic reprogramming and pre-implantation development. Hence, KDM4A plays a crucial role in preserving the maternal epigenome integrity required for proper zygotic genome activation and transfer of developmental control to the embryo.
Topics: Animals; Embryo Implantation; Embryo, Mammalian; Female; Fertilization; Heterochromatin; Histone Demethylases; Histones; Male; Metaphase; Methylation; Mice; Mice, Knockout; Oocytes; Promoter Regions, Genetic; Protein Processing, Post-Translational; Transcription, Genetic; Zygote
PubMed: 32231309
DOI: 10.1038/s41556-020-0494-z -
Frontiers in Plant Science 2020Flowering plant zygotes possess complete developmental potency, and the mixture of male and female genetic and cytosolic materials in the zygote is a trigger to initiate... (Review)
Review
Flowering plant zygotes possess complete developmental potency, and the mixture of male and female genetic and cytosolic materials in the zygote is a trigger to initiate embryo development. Plasmogamy, the fusion of the gamete cytoplasms, facilitates the cellular dynamics of the zygote. In the last decade, mutant analyses, live cell imaging-based observations, and direct observations of fertilized egg cells by fusion of isolated gametes have accelerated our understanding of the post-plasmogamic events in flowering plants including cell wall formation, gamete nuclear migration and fusion, and zygotic cell elongation and asymmetric division. Especially, it has become more evident that paternal parent-of-origin effects, via sperm cytoplasm contents, not only control canonical early zygotic development, but also activate a biparental signaling pathway critical for cell fate determination after the first cell division. Here, we summarize the plasmogamic paternal contributions via the entry of sperm contents during/after fertilization in flowering plants.
PubMed: 32636867
DOI: 10.3389/fpls.2020.00871 -
Fertility and Sterility Jan 2021
Topics: Blastocyst; Female; Fertilization; Humans; Infant, Newborn; Pregnancy; Retrospective Studies; Sperm Injections, Intracytoplasmic; Zygote
PubMed: 33250186
DOI: 10.1016/j.fertnstert.2020.11.009 -
Development (Cambridge, England) Oct 2022The complex process by which a single-celled zygote develops into a viable embryo is nothing short of a miraculous wonder of the natural world. Elucidating how this...
The complex process by which a single-celled zygote develops into a viable embryo is nothing short of a miraculous wonder of the natural world. Elucidating how this process is orchestrated in humans has long eluded the grasp of scientists due to ethical and practical limitations. Thankfully, pluripotent stem cells that resemble early developmental cell types possess the ability to mimic specific embryonic events. As such, murine and human stem cells have been leveraged by scientists to create in vitro models that aim to recapitulate different stages of early mammalian development. Here, we examine the wide variety of stem cell-based embryo models that have been developed to recapitulate and study embryonic events, from pre-implantation development through to early organogenesis. We discuss the applications of these models, key considerations regarding their importance within the field, and how such models are expected to grow and evolve to achieve exciting new milestones in the future.
Topics: Humans; Mice; Animals; Embryo, Mammalian; Embryonic Development; Pluripotent Stem Cells; Organogenesis; Zygote; Mammals
PubMed: 36255368
DOI: 10.1242/dev.201015 -
Cellular and Molecular Life Sciences :... Jan 2022Putative RNA-binding proteins (RBPs), zygote arrested-1 (ZAR1), and ZAR2 (also known as ZAR1L), have been identified as maternal factors that mainly function in... (Review)
Review
Putative RNA-binding proteins (RBPs), zygote arrested-1 (ZAR1), and ZAR2 (also known as ZAR1L), have been identified as maternal factors that mainly function in oogenesis and embryogenesis. Despite divergence in their spatio-temporal expression among species, the CxxC structure of the C-terminus of ZAR proteins is highly conserved and is reported to be the functional domain for the activity of the RBPs of ZAR proteins. In oocytes from Xenopus laevis and zebrafish, ZAR proteins have been reported to bind to maternal transcripts and inhibit translation in immature growing oocytes, whereas in fully grown mouse oocytes, they promote the translation during meiotic maturation. Thus, ZAR1 and ZAR2 may be required for the maternal-to-zygotic transition by stabilizing the maternal transcriptome in oocytes with partial functional redundancy. In addition, recent studies have suggested non-ovarian expression and function of ZAR proteins, particularly their involvement in tumorigenesis. ZAR proteins are potentially associated with tumor suppressors and can serve as epigenetically inactivated cancer biomarkers. In this review, studies on Zar1/2 are systematically summarized, and some issues that require discussion and further investigation are introduced as perspectives.
Topics: Animals; Egg Proteins; Female; Fertility; Humans; Oogenesis; Tumor Suppressor Proteins
PubMed: 35072788
DOI: 10.1007/s00018-022-04141-4