scholarly journals Epigenetic reprogramming of the zygote in mice and men: on your marks, get set, go!

Reproduction ◽  
2016 ◽  
Vol 152 (6) ◽  
pp. R211-R222 ◽  
Author(s):  
Rupsha Fraser ◽  
Chih-Jen Lin
Keyword(s):  
Small Rnas ◽  
Cell Types ◽  
Epigenetic Reprogramming ◽  
Success Rates ◽  
Epigenetic Marks ◽  
Preimplantation Embryo Development ◽  
Molecular Events ◽  
Genome Activation ◽  
Gender Specific ◽  
Zygotic Genome

Gametogenesis (spermatogenesis and oogenesis) is accompanied by the acquisition of gender-specific epigenetic marks, such as DNA methylation, histone modifications and regulation by small RNAs, to form highly differentiated, but transcriptionally silent cell-types in preparation for fertilisation. Upon fertilisation, extensive global epigenetic reprogramming takes place to remove the previously acquired epigenetic marks and produce totipotent zygotic states. It is the aim of this review to delineate the cellular and molecular events involved in maternal, paternal and zygotic epigenetic reprogramming from the time of gametogenesis, through fertilisation, to the initiation of zygotic genome activation for preimplantation embryonic development. Recent studies have begun to uncover the indispensable functions of epigenetic players during gametogenesis, fertilisation and preimplantation embryo development, and a more comprehensive understanding of these early events will be informative for increasing pregnancy success rates, adding particular value to assisted fertility programmes.

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 Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuanyuan Li ◽  
Ning-Hua Mei ◽  
Gui-Ping Cheng ◽  
Jing Yang ◽  
Li-Quan Zhou
Keyword(s):  
Embryo Development ◽  
Preimplantation Embryo ◽  
Preimplantation Embryos ◽  
Dependent Manner ◽  
Zygotic Genome Activation ◽  
Preimplantation Embryo Development ◽  
Cell Embryo ◽  
Embryo Stage ◽  
Genome Activation ◽  
Zygotic Genome

Mitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inhibition of DRP1 activity by mitochondrial division inhibitor-1, a small molecule reported to specifically inhibit DRP1 activity, can cause severe developmental arrest of preimplantation embryos in a dose-dependent manner in mice. Meanwhile, DRP1 inhibition resulted in mitochondrial dysfunction including decreased mitochondrial activity, loss of mitochondrial membrane potential, reduced mitochondrial copy number and inadequate ATP by disrupting both expression and activity of DRP1 and mitochondrial complex assembly, leading to excessive ROS production, severe DNA damage and cell cycle arrest at 2-cell embryo stage. Furthermore, reduced transcriptional and translational activity and altered histone modifications in DRP1-inhibited embryos contributed to impeded zygotic genome activation, which prevented early embryos from efficient development beyond 2-cell embryo stage. These results show that DRP1 inhibition has potential cytotoxic effects on mammalian reproduction, and DRP1 inhibitor should be used with caution when it is applied to treat diseases. Additionally, this study improves our understanding of the crosstalk between mitochondrial metabolism and zygotic genome activation.

Expression and localization of Nlrp4g in mouse preimplantation embryo

Zygote ◽  
2014 ◽  
Vol 23 (6) ◽  
pp. 846-851 ◽  
Author(s):  
Hui Peng ◽  
Xiujiao Lin ◽  
Wenhao Li ◽  
Wenchang Zhang
Keyword(s):  
Preimplantation Embryo ◽  
Expression Patterns ◽  
Blastocyst Stage ◽  
Preimplantation Embryo Development ◽  
Gene Copies ◽  
Mouse Preimplantation Embryo ◽  
Cell Embryo ◽  
Embryo Stage ◽  
Genome Activation ◽  
Zygotic Genome

SummaryThe Nlrp gene family contains 20 members and plays a pivotal role in the innate immune and reproductive systems in the mouse. During evolution, seven Nlrp4 gene copies (named from Nlrp4a to Nlrp4g). Nlrp4a–Nlrp4g have arisen that display specific or preferential ovarian expression patterns. However, the expression pattern and localization of Nlrp4g in mouse preimplantation embryo development are unknown. Here we report that Nlrp4g was highly expressed in mature oocytes and zygotes, then downregulated and not detected after the 2-cell embryo stage. NLRP4G protein remained present through the blastocyst stage and was mainly localized in the cytoplasm. Furthermore, overexpression of Nlrp4g in zygotes did not affect normal development in terms of the rate of blastocyst formation. These results provide the first evidence that NLRP4G is a maternal factor that may play essential role during zygotic genome activation in the mouse.

scholarly journals Species and cell-type properties of classically defined human and rodent neurons and glia

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Xiao Xu ◽  
Elitsa I Stoyanova ◽  
Agata E Lemiesz ◽  
Jie Xing ◽  
Deborah C Mash ◽  
...  
Keyword(s):  
Brain Function ◽  
Cell Types ◽  
Specific Cell ◽  
Postmortem Human Brain ◽  
Molecular Events ◽  
Epigenetic Events ◽  
Postmortem Brains ◽  
Gender Specific ◽  
Robust Response

Determination of the molecular properties of genetically targeted cell types has led to fundamental insights into mouse brain function and dysfunction. Here, we report an efficient strategy for precise exploration of gene expression and epigenetic events in specific cell types in a range of species, including postmortem human brain. We demonstrate that classically defined, homologous neuronal and glial cell types differ between rodent and human by the expression of hundreds of orthologous, cell specific genes. Confirmation that these genes are differentially active was obtained using epigenetic mapping and immunofluorescence localization. Studies of sixteen human postmortem brains revealed gender specific transcriptional differences, cell-specific molecular responses to aging, and the induction of a shared, robust response to an unknown external event evident in three donor samples. Our data establish a comprehensive approach for analysis of molecular events associated with specific circuits and cell types in a wide variety of human conditions.

scholarly journals Regulatory principles governing the maternal-to-zygotic transition: insights from Drosophila melanogaster

Open Biology ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 180183 ◽  
Author(s):  
Danielle C. Hamm ◽  
Melissa M. Harrison
Keyword(s):  
Drosophila Melanogaster ◽  
Transcriptional Activation ◽  
Fruit Fly ◽  
Cell Types ◽  
Parallel Mechanisms ◽  
Molecular Events ◽  
Connected Set ◽  
Maternal To Zygotic Transition ◽  
Adult Organism ◽  
Zygotic Genome

The onset of metazoan development requires that two terminally differentiated germ cells, a sperm and an oocyte, become reprogrammed to the totipotent embryo, which can subsequently give rise to all the cell types of the adult organism. In nearly all animals, maternal gene products regulate the initial events of embryogenesis while the zygotic genome remains transcriptionally silent. Developmental control is then passed from mother to zygote through a process known as the maternal-to-zygotic transition (MZT). The MZT comprises an intimately connected set of molecular events that mediate degradation of maternally deposited mRNAs and transcriptional activation of the zygotic genome. This essential developmental transition is conserved among metazoans but is perhaps best understood in the fruit fly, Drosophila melanogaster . In this article, we will review our understanding of the events that drive the MZT in Drosophila embryos and highlight parallel mechanisms driving this transition in other animals.

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 Extraneous E-Cadherin Engages the Deterministic Process of Somatic Reprogramming through Modulating STAT3 and Erk1/2 Activity

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 284
Author(s):  
Yu-Hao Liu ◽  
Chien-Chang Chen ◽  
Yi-Jen Hsueh ◽  
Li-Man Hung ◽  
David Hui-Kang Ma ◽  
...  
Keyword(s):  
Stochastic Process ◽  
Molecular Mechanism ◽  
Activity Ratio ◽  
Cell Types ◽  
Deterministic Process ◽  
Modes Of Action ◽  
Molecular Events ◽  
Different Cell Types ◽  
Selection Of ◽  
E Cadherin

Although several modes of reprogramming have been reported in different cell types during iPSC induction, the molecular mechanism regarding the selection of different modes of action is still mostly unknown. The present study examined the molecular events that participate in the selection of such processes at the onset of somatic reprogramming. The activity of STAT3 versus that of Erk1/2 reversibly determines the reprogramming mode entered; a lower activity ratio favors the deterministic process and vice versa. Additionally, extraneous E-cadherin facilitates the early events of somatic reprogramming, potentially by stabilizing the LIF/gp130 and EGFR/ErbB2 complexes to promote entry into the deterministic process. Our current findings demonstrated that manipulating the pSTAT3/pErk1/2 activity ratio in the surrounding milieu can drive different modes of action toward either the deterministic or the stochastic process in the context of OSKM-mediated somatic reprogramming.

scholarly journals Chromatin Manipulation and Editing: Challenges, New Technologies and Their Use in Plants

2021 ◽  
Vol 22 (2) ◽  
pp. 512
Author(s):  
Kateryna Fal ◽  
Denisa Tomkova ◽  
Gilles Vachon ◽  
Marie-Edith Chabouté ◽  
Alexandre Berr ◽  
...  
Keyword(s):  
Cell Fate ◽  
Dna Sequence ◽  
Zinc Finger ◽  
Chromatin Structure ◽  
New Technologies ◽  
Dna Interaction ◽  
The Other ◽  
Proof Of Concept ◽  
Epigenetic Marks ◽  
Molecular Events

An ongoing challenge in functional epigenomics is to develop tools for precise manipulation of epigenetic marks. These tools would allow moving from correlation-based to causal-based findings, a necessary step to reach conclusions on mechanistic principles. In this review, we describe and discuss the advantages and limits of tools and technologies developed to impact epigenetic marks, and which could be employed to study their direct effect on nuclear and chromatin structure, on transcription, and their further genuine role in plant cell fate and development. On one hand, epigenome-wide approaches include drug inhibitors for chromatin modifiers or readers, nanobodies against histone marks or lines expressing modified histones or mutant chromatin effectors. On the other hand, locus-specific approaches consist in targeting precise regions on the chromatin, with engineered proteins able to modify epigenetic marks. Early systems use effectors in fusion with protein domains that recognize a specific DNA sequence (Zinc Finger or TALEs), while the more recent dCas9 approach operates through RNA-DNA interaction, thereby providing more flexibility and modularity for tool designs. Current developments of “second generation”, chimeric dCas9 systems, aiming at better targeting efficiency and modifier capacity have recently been tested in plants and provided promising results. Finally, recent proof-of-concept studies forecast even finer tools, such as inducible/switchable systems, that will allow temporal analyses of the molecular events that follow a change in a specific chromatin mark.

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