scholarly journals Transposable Element Dynamics and Regulation during Zygotic Genome Activation in Mammalian Embryos and Embryonic Stem Cell Model Systems

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Yixuan Low ◽  
Dennis Eng Kiat Tan ◽  
Zhenhua Hu ◽  
Shawn Ying Xuan Tan ◽  
Wee-Wei Tee
Keyword(s):  
Cell Model ◽  
Embryonic Stem ◽  
Model Systems ◽  
Specific Class ◽  
Mammalian Development ◽  
Zygotic Genome Activation ◽  
Somatic Tissues ◽  
Genome Activation ◽  
Zygotic Genome

Transposable elements (TEs) are mobile genetic sequences capable of duplicating and reintegrating at new regions within the genome. A growing body of evidence has demonstrated that these elements play important roles in host genome evolution, despite being traditionally viewed as parasitic elements. To prevent ectopic activation of TE transposition and transcription, they are epigenetically silenced in most somatic tissues. Intriguingly, a specific class of TEs—retrotransposons—is transiently expressed at discrete phases during mammalian development and has been linked to the establishment of totipotency during zygotic genome activation (ZGA). While mechanisms controlling TE regulation in somatic tissues have been extensively studied, the significance underlying the unique transcriptional reactivation of retrotransposons during ZGA is only beginning to be uncovered. In this review, we summarize the expression dynamics of key retrotransposons during ZGA, focusing on findings from in vivo totipotent embryos and in vitro totipotent-like embryonic stem cells (ESCs). We then dissect the functions of retrotransposons and discuss how their transcriptional activities are finetuned during early stages of mammalian development.

scholarly journals Maternal Dppa2 and Dppa4 are dispensable for zygotic genome activation but important for offspring survival

Development ◽  
2021 ◽  
Vol 148 (24) ◽  
Author(s):  
Oana Kubinyecz ◽  
Fatima Santos ◽  
Deborah Drage ◽  
Wolf Reik ◽  
Melanie A. Eckersley-Maslin
Keyword(s):  
Null Allele ◽  
Embryonic Stem ◽  
Offspring Survival ◽  
Zygotic Genome Activation ◽  
Molecular Events ◽  
Genome Activation ◽  
Mitotic Chromatin ◽  
Zygotic Genome

ABSTRACT Zygotic genome activation (ZGA) represents the initiation of transcription following fertilisation. Despite its importance, we know little of the molecular events that initiate mammalian ZGA in vivo. Recent in vitro studies in mouse embryonic stem cells have revealed developmental pluripotency associated 2 and 4 (Dppa2/4) as key regulators of ZGA-associated transcription. However, their roles in initiating ZGA in vivo remain unexplored. We reveal that Dppa2/4 proteins are present in the nucleus at all stages of preimplantation development and associate with mitotic chromatin. We generated conditional single and double maternal knockout mouse models to deplete maternal stores of Dppa2/4. Importantly, Dppa2/4 maternal knockout mice were fertile when mated with wild-type males. Immunofluorescence and transcriptome analyses of two-cell embryos revealed that, although ZGA took place, there were subtle defects in embryos that lacked maternal Dppa2/4. Strikingly, heterozygous offspring that inherited the null allele maternally had higher preweaning lethality than those that inherited the null allele paternally. Together, our results show that although Dppa2/4 are dispensable for ZGA transcription, maternal stores have an important role in offspring survival, potentially via epigenetic priming of developmental genes.

scholarly journals DPPA2 and DPPA4 are dispensable for mouse zygotic genome activation and preimplantation development

Development ◽  
2021 ◽  
Author(s):  
Zhiyuan Chen ◽  
Zhenfei Xie ◽  
Yi Zhang
Keyword(s):  
De Novo ◽  
Genetic Manipulation ◽  
Embryonic Stem ◽  
Preimplantation Development ◽  
Dependent Manner ◽  
Maternal Factors ◽  
Zygotic Genome Activation ◽  
Genome Activation ◽  
Zygotic Genome

How maternal factors in oocytes initiate zygotic genome activation (ZGA) remains elusive in mammals, partly due to the challenge of de novo identification of key factors using scarce materials. The 2-cell (2C) embryo like cells has been widely used as an in vitro model to understand mouse ZGA and totipotency given its expression of a group of 2C embryo-specific genes and its simplicity for genetic manipulation. Recent studies indicate that DPPA2 and DPPA4 are required for establishing the 2C-like state in mouse embryonic stem cells (ESCs) in a DUX-dependent manner. These results suggest that DPPA2 and DPPA4 are essential maternal factors that regulate Dux and ZGA in embryos. By analyzing maternal knockout and maternal-zygotic knockout embryos, we unexpectedly found that DPPA2 and DPPA4 are dispensable for Dux activation, ZGA, and preimplantation development. Our study suggests that 2C-like cells do not fully recapitulate 2-cell embryos in terms of 2C-gene regulation and cautions should be taken when studying ZGA and totipotency using 2C-like cells as the model system.

scholarly journals Maternal Dppa2 and Dppa4 are dispensable for zygotic genome activation but important for offspring survival

2021 ◽  
Author(s):  
Oana Kubinyecz ◽  
Fatima Santos ◽  
Deborah Drage ◽  
Wolf Reik ◽  
Melanie A Eckersley-Maslin
Keyword(s):  
Null Allele ◽  
Embryonic Stem ◽  
Offspring Survival ◽  
Zygotic Genome Activation ◽  
Molecular Events ◽  
Genome Activation ◽  
Mitotic Chromatin ◽  
Zygotic Genome

Zygotic Genome Activation (ZGA) represents the initiation of transcription following fertilisation. Despite its importance in shifting developmental control from primarily maternal stores in the oocyte to the embryo proper, we know little of the molecular events that initiate ZGA in vivo. Recent in vitro studies in mouse embryonic stem cells (ESCs) have revealed Developmental Pluripotency Associated 2 and 4 (Dppa2/4) as key regulators of ZGA-associated transcription. However, their roles in initiating ZGA in vivo remain unexplored. We reveal Dppa2/4 proteins are present in the nucleus at all stages of preimplantation development and associate with mitotic chromatin. We generated single and double maternal knockout mouse models to deplete maternal stores of Dppa2/4. Importantly, while fertile, Dppa2/4 maternal knockout mice had reduced litter sizes, indicating decreased offspring survival. Immunofluorescence and transcriptome analyses of 2-cell embryos revealed while ZGA took place there were subtle defects in embryos lacking maternal Dppa2/4. Strikingly, heterozygous offspring that inherited the null allele maternally had higher preweaning lethality than those that inherited the null allele paternally. Together our results show that while Dppa2/4 are dispensable for ZGA transcription, maternal stores have an important role in offspring survival, potentially via epigenetic priming of developmental genes.

scholarly journals The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 453
Author(s):  
Susana M. Chuva de Sousa Lopes ◽  
Marta S. Alexdottir ◽  
Gudrun Valdimarsdottir
Keyword(s):  
Stem Cell ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Embryonic Stem ◽  
Model Systems ◽  
Special Focus ◽  
Placental Development

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

Expression of eukaryotic elongation initiation factor 1A differentially marks zygotic genome activation in biparental and parthenogenetic porcine embryos and correlates with in vitro developmental potential

2008 ◽  
Vol 20 (7) ◽  
pp. 818 ◽  
Author(s):  
Luca Magnani ◽  
Christine M. Johnson ◽  
Ryan A. Cabot
Keyword(s):  
Expression Profile ◽  
Initiation Factor ◽  
In Vitro Fertilisation ◽  
Zygotic Genome Activation ◽  
Cell Stage ◽  
Developmental Potential ◽  
Genome Activation ◽  
Parthenogenetic Embryos ◽  
Zygotic Genome

Zygotic genome activation (ZGA) is a major event during cleavage development. In vitro manipulation of mammalian embryos (including embryo culture) can result in developmental arrest around the time of ZGA. Eukaryotic elongation initiation factor 1A (eIF1A) has been used as a marker for ZGA in some mammalian species. We hypothesised expression of eIF1A can be used to assess ZGA in the pig; we also hypothesised that the expression profile of eIF1A can be used to assess developmental potential in vitro. The aims of the present study were to determine the expression pattern of eIF1A during porcine cleavage development and to assess its expression levels in embryos of different quality. We used a real-time reverse transcription–polymerase chain reaction assay to quantify eIF1A transcripts at different time points during cleavage development in porcine embryos produced by parthenogenetic activation (PA) and in vitro fertilisation (IVF). We found that eIF1A is activated at the two-cell stage in IVF embryos and at the four-cell stage in PA embryos. We showed that the increase in transcript levels observed in parthenogenetic embryos is dependent on de novo transcription. We found altered levels of eIF1A transcripts in parthenogenetic embryos that presented as either two- or eight-cell embryos 48 h after activation compared with four-cell embryos at the same time point. Our work supports the hypothesis that eIF1A is a marker of porcine ZGA and its expression profile can be used to assess embryo quality.

scholarly journals DPPA2 and DPPA4 are dispensable for mouse zygotic genome activation and preimplantation development

2021 ◽  
Author(s):  
Zhiyuan Chen ◽  
Zhenfei Xie ◽  
Yi Zhang
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Preimplantation Development ◽  
Dependent Manner ◽  
Maternal Factors ◽  
Zygotic Genome Activation ◽  
Cell Embryo ◽  
Genome Activation ◽  
Zygotic Genome

How maternal factors in oocytes initiate zygotic genome activation (ZGA) remains elusive. Recent studies indicate that DPPA2 and DPPA4 are required for establishing a 2-cell embryo-like (2C-like) state in mouse embryonic stem cells (ESCs) in a DUX-dependent manner. These results suggest that DPPA2 and DPPA4 are essential maternal factors that regulate Dux and ZGA in embryos. By analyzing maternal knockout and maternal-zygotic knockout embryos, we unexpectedly found that Dux activation, ZGA, and preimplantation development are normal in embryos without DPPA2 or DPPA4. Thus, unlike in ESCs/2C-like cells, DPPA2 and DPPA4 are dispensable for ZGA and preimplantation development.

scholarly journals Reciprocal zebrafish-medaka hybrids reveal maternal control of zygotic genome activation timing

2021 ◽  
Author(s):  
Krista R Gert ◽  
Luis Enrique Cabrera Quio ◽  
Maria Novatchkova ◽  
Yixuan Guo ◽  
Bradley R Cairns ◽  
...  
Keyword(s):  
Early Development ◽  
Hybrid System ◽  
Control Mechanisms ◽  
Zygotic Genome Activation ◽  
Zygotic Transcription ◽  
Versatile Tool ◽  
Paternal Control ◽  
Genome Activation ◽  
Zygotic Genome

After fertilization, the sperm and egg contribute unequally to the newly formed zygote. While the sperm contributes mainly paternal DNA, the egg provides both maternal DNA and the bulk of the future embryonic cytoplasm. Most embryonic processes (like the onset of zygotic transcription) depend on maternally-provided cytoplasmic components, and it is largely unclear whether paternal components besides the centrosome play a role in the regulation of early embryogenesis. Here we report a reciprocal zebrafish-medaka hybrid system as a powerful tool to investigate paternal vs. maternal influence during early development. By combining expression of zebrafish Bouncer on the medaka egg with artificial egg activation, we demonstrate the in vitro generation of paternal zebrafish x maternal medaka (reripes) hybrids. These hybrids complement the previously established paternal medaka x maternal zebrafish (latio) hybrids (Herberg et al., 2018). As proof of concept, we investigated maternal vs. paternal control of zygotic genome activation (ZGA) timing using this reciprocal hybrid system. RNA-seq analysis of the purebred fish species and hybrids revealed that the onset of ZGA is primarily governed by the egg. Overall, our study establishes the reciprocal zebrafish-medaka hybrid system as a versatile tool to dissect parental control mechanisms during early development.

scholarly journals Pou5f3, SoxB1 and Nanog remodel chromatin on High Nucleosome Affinity Regions at Zygotic Genome Activation

2018 ◽  
Author(s):  
Marina Veil ◽  
Lev Yampolsky ◽  
Björn Grüning ◽  
Daria Onichtchouk
Keyword(s):  
Nucleosome Occupancy ◽  
Open Chromatin ◽  
Zygotic Genome Activation ◽  
Chromatin Dynamics ◽  
Cell Cycles ◽  
Dna Shape ◽  
Genome Activation ◽  
Zygotic Genome

AbstractThe zebrafish embryo is mostly transcriptionally quiescent during the first 10 cell cycles, until the main wave of Zygotic Genome Activation (ZGA) occurs, accompanied by fast chromatin remodeling. At ZGA, homologs of mammalian stem cell transcription factors (TFs) Pou5f3, Nanog and Sox19b bind to thousands of developmental enhancers to initiate transcription. So far, how these TFs influence chromatin dynamics at ZGA has remained unresolved. To address this question, we analyzed nucleosome positions in wild-type and Maternal-Zygotic (MZ) mutants for pou5f3 and nanog by MNase-seq. We show that Nanog, Sox19b and Pou5f3 bind to the High Nucleosome Affinity Regions (HNARs). HNARs are spanning over 600 bp, featuring high in vivo and predicted in vitro nucleosome occupancy and high predicted propeller twist DNA shape value. We suggest a two-step nucleosome destabilization-depletion model, where the same intrinsic DNA properties of HNAR promote both high nucleosome occupancy and differential binding of TFs. In the first step, already prior to ZGA, Pou5f3 and Nanog destabilize nucleosomes on HNAR centers genome-wide. In the second step, post-ZGA, Nanog, Pou5f3 and SoxB1 maintain open chromatin state on the subset of HNARs, acting synergistically. Nanog binds to the HNAR center, while the Pou5f3 stabilizes the flanks. The HNAR model will provide a useful tool for genome regulatory studies in the variety of biological systems.

scholarly journals DPPA2 and DPPA4 are necessary to establish a totipotent state in mouse embryonic stem cells

2018 ◽  
Author(s):  
Alberto De Iaco ◽  
Alexandre Coudray ◽  
Julien Duc ◽  
Didier Trono
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Early Embryo ◽  
Zygotic Genome Activation ◽  
Cell Stage ◽  
Oocyte Expression ◽  
Genome Activation ◽  
Zygotic Genome

AbstractAfter fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through so-called zygotic genome activation (ZGA), occurring in the mouse at the 2-cell stage. Amongst the first elements to be transcribed are the Dux gene, the product of which secondarily induces a wide array of ZGA genes, and a subset of evolutionary recent LINE-1 retrotransposons, which regulate chromatin accessibility in the early embryo. The maternally-inherited factors that activate Dux and LINE-1 transcription have so far remained unknown. Here we identify the paralog proteins DPPA2 and DPPA4 as responsible for this process.

scholarly journals Retinoic acid signaling is critical during the totipotency window in early mammalian development

2021 ◽  
Author(s):  
Ane Iturbide ◽  
Mayra L. Ruiz Tejeda Segura ◽  
Camille Noll ◽  
Kenji Schorpp ◽  
Ina Rothenaigner ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Regulatory Networks ◽  
Es Cells ◽  
Embryonic Stem ◽  
Mammalian Development ◽  
Cell Stage ◽  
Cell Potential ◽  
Cellular Models ◽  
Early Embryos ◽  
Genome Activation

AbstractTotipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such ‘2-cell-like-cells’ (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.

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