scholarly journals Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse

2021 ◽  
Author(s):  
Yinan Zhao ◽  
Dan Zhang ◽  
Mengying Liu ◽  
Yingpu Tian ◽  
Jinhua Lu ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Gene Knockout ◽  
Epigenetic Modifications ◽  
Preimplantation Embryos ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Early Embryos ◽  
Gene Knockout Mouse ◽  
Core Components

Mammalian embryonic development is a complex process regulated by various epigenetic modifications. Recently, maternal histone H3 methylations were found to be inherited and reprogrammed in early embryos to regulate embryonic development. The enhancer of zest homolog 1 and 2 (Ezh1 and Ezh2) belong to the core components of Polycomb repressive complex 2 (PRC2) and are the histone methyltransferase of histone 3 lysine 27 (H3K27). How maternal Ezh1 and Ezh2 function on H3K27 methylation in in vivo preimplantation embryos and embryonic development are not clear. Here, we deleted Ezh1 or/and Ezh2 in growing oocytes using gene knockout mouse models, and found that H3K27me3 in oocytes was disappeared by loss of Ezh2 alone while H3K27me2 was absent upon deletion of both Ezh1 and Ezh2. The effects of Ezh1/2 were inherited in maternal knockout zygotes and early embryos, in which restoration of H3K27me3 was delayed until late blastocyte by loss of Ezh2 alone and H3K27me2 was reestablished until morulae by deletion of Ezh1 and Ezh2. However, the ablation of both Ezh1 and Ezh2, but not single Ezh1 or Ezh2, led to significantly decreased litter size due to growth retardation during post-implantation. Furthermore, maternal Ezh1/2 deficiency caused compromised H3K27me3 and pluripotent epiblast cells in late blastocyst, followed by defective development of epiblast. These results demonstrate that in oocytes, Ezh2 is indispensable for H3K27me3 while Ezh1 complements Ezh2 in H3K27me2. Also, maternal Ezh1/2-H3K27 methylation is inherited in descendant embryos and has a critical effect on fetus and placenta development. Thus, this work sheds light on maternal epigenetic modifications during embryonic development.

scholarly journals Genetically Altered Mouse Models: the Good, the Bad, and the Ugly

2003 ◽  
Vol 14 (3) ◽  
pp. 154-174 ◽  
Author(s):  
Tamizchelvi Thyagarajan ◽  
Satish Totey ◽  
Mary Jo S. Danton ◽  
Ashok B. Kulkarni
Keyword(s):  
Gene Targeting ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Genetically Engineered ◽  
Murine Models ◽  
Functional Roles ◽  
Targeted Gene Disruption ◽  
Gene Knockout Mouse

Targeted gene disruption in mice is a powerful tool for generating murine models for human development and disease. While the human genome program has helped to generate numerous candidate genes, few genes have been characterized for their precise in vivo functions. Gene targeting has had an enormous impact on our ability to delineate the functional roles of these genes. Many gene knockout mouse models faithfully mimic the phenotypes of the human diseases. Because some models display an unexpected or no phenotype, controversy has arisen about the value of gene-targeting strategies. We argue in favor of gene-targeting strategies, provided they are used with caution, particularly in interpreting phenotypes in craniofacial and oral biology, where many genes have pleiotropic roles. The potential pitfalls are outweighed by the unique opportunities for developing and testing different therapeutic strategies before they are introduced into the clinic. In the future, we believe that genetically engineered animal models will be indispensable for gaining important insights into the molecular mechanisms underlying development, as well as disease pathogenesis, diagnosis, prevention, and treatment.

Beneficial effects of diazepin-quinazolin-amine derivative (BIX-01294) on preimplantation development and molecular characteristics of cloned mouse embryos

2017 ◽  
Vol 29 (6) ◽  
pp. 1260 ◽  
Author(s):  
Yanfang Huang ◽  
Xiaohong Jiang ◽  
Miao Yu ◽  
Rongfu Huang ◽  
Jianfeng Yao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Specific Inhibitor ◽  
Epigenetic Modifications ◽  
Preimplantation Development ◽  
Preimplantation Embryos ◽  
Molecular Characteristics ◽  
Amine Derivative ◽  
Beneficial Effects ◽  
Small Nuclear Ribonucleoprotein

Somatic cell nuclear transfer is frequently associated with abnormal epigenetic modifications that may lead to the developmental failure of cloned embryos. BIX-01294 (a diazepine–quinazoline–amine derivative) is a specific inhibitor of the histone methyltransferase G9a. The aim of the present study was to investigate the effects of BIX-01294 on development, dimethylation of histone H3 at lysine 9 (H3K9), DNA methylation and the expression of imprinted genes in cloned mouse preimplantation embryos. There were no significant differences in blastocyst rates of cloned embryos treated with or without 0.1 μM BIX-01294. Relative to clone embryos treated without 0.1 μM BIX-01294, exposure of embryos to BIX-01294 decreased histone H3K9 dimethylation and DNA methylation in cloned embryos to levels that were similar to those of in vivo-fertilised embryos at the 2-cell and blastocyst stages. Cloned embryos had lower expression of octamer-binding transcription factor 4 (Oct4) and small nuclear ribonucleoprotein N (Snrpn), but higher expression of imprinted maternally expressed transcript (non-protein coding) (H19) and growth factor receptor-bound protein 10 (Grb10) compared with in vivo-fertilised counterparts. The addition of 0.1 μM BIX-01294 to the activation and culture medium resulted in lower H19 expression and higher cyclin dependent kinase inhibitor 1C (Cdkn1c) and delta-like 1 homolog (Dlk1) expression, but had no effect on the expression of Oct4, Snrpn and Grb10. The loss of methylation at the Grb10 cytosine–phosphorous–guanine (CpG) islands in cloned embryos was partially corrected by BIX-01294. These results indicate that BIX-01294 treatment of cloned embryos has beneficial effects in terms of correcting abnormal epigenetic modifications, but not on preimplantation development.

NOTCH signaling pathway is required for bovine early embryonic development

2021 ◽  
Author(s):  
Shuang Li ◽  
Yan Shi ◽  
Yanna Dang ◽  
Lei Luo ◽  
Bingjie Hu ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Developmental Competence ◽  
Early Embryonic Development ◽  
Preimplantation Embryos ◽  
Early Embryos ◽  
Genes Encoding

Abstract The NOTCH signaling pathway plays an important role in regulating various biological processes, including lineage specification and apoptosis. Multiple components of the NOTCH pathway have been identified in mammalian preimplantation embryos. However, the precise role of the NOTCH pathway in early embryonic development is poorly understood, especially in large animals. Here, we show that the expression of genes encoding key transcripts of the NOTCH pathway is dynamic throughout early embryonic development. We also confirm the presence of active NOTCH1 and RBPJ. By using pharmacological and RNAi tools, we demonstrate that the NOTCH pathway is required for the proper development of bovine early embryos. This functional consequence could be partly attributed to the major transcriptional mediator-RBPJ, whose deficiency also compromised the embryo quality. Indeed, both NOTCH1 and RBPJ knockdown cause a significant increase of histone H3 serine 10 phosphorylation (pH3S10, a mitosis marker) positive blastomeres, suggesting a cell cycle arrest at mitosis. Importantly, RNA-seq analyses reveal that either NOTCH1 or RBPJ depletion triggers a reduction in H1FOO that encodes the oocyte-specific linker histone H1 variant. Interestingly, depleting H1FOO results in detrimental effects on the developmental competence of early embryos, similar with NOTCH1 inhibition. Overall, our results reveal a crucial role for NOTCH pathway in regulating bovine preimplantation development, likely by controlling cell proliferation and maintaining H1FOO expression.

scholarly journals Effect of Bacterial Endotoxins on Superovulated Mouse Embryos In Vivo: Is CSF-1 Involved in Endotoxin-Induced Pregnancy Loss?

2006 ◽  
Vol 2006 ◽  
pp. 1-9 ◽  
Author(s):  
Yogesh Kumar Jaiswal ◽  
Madan Mohan Chaturvedi ◽  
Kaushik Deb
Keyword(s):  
Embryonic Development ◽  
Pregnancy Loss ◽  
Mouse Embryos ◽  
Preimplantation Embryos ◽  
Implantation Failure ◽  
Normal Pattern ◽  
Bacterial Endotoxins ◽  
Mammalian Embryonic Development ◽  
Lps Treatment

Mammalian embryonic development is regulated by several cytokines and growth factors from embryonic or maternal origins. Since CSF-1 plays important role in embryonic development and implantation, we investigated its role in gram-negative bacterial LPS-induced implantation failure. The effect of LPS on normal (nonsuperovulated) and superovulated in vivo-produced embryos was assessed by signs of morphological degeneration. A significantly similar number of morphologically degenerated embryos recovered from both nonsuperovulated and superovulated LPS treated animals on day 2.5 of pregnancy onwards were morphologically and developmentally abnormal as compared to their respective controls (P<.001. Normal CSF-1 expression level and pattern were also altered through the preimplantation period in the mouse embryos and uterine horns after LPS treatment. This deviation from the normal pattern and level of CSF-1 expression in the preimplantation embryos and uterine tissues suggest a role for CSF-1 in LPS-induced implantation failure.

scholarly journals TheArabidopsisepigenetic regulator ICU11 as an accessory protein of Polycomb Repressive Complex 2

2020 ◽  
Vol 117 (28) ◽  
pp. 16660-16666 ◽  
Author(s):  
Rebecca H. Bloomer ◽  
Claire E. Hutchison ◽  
Isabel Bäurle ◽  
James Walker ◽  
Xiaofeng Fang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nucleation Site ◽  
The Body ◽  
Accessory Protein ◽  
Polycomb Repressive Complex ◽  
Chromatin States ◽  
Polycomb Repressive Complex 2 ◽  
Core Components ◽  
Direct Target

Molecular mechanisms enabling the switching and maintenance of epigenetic states are not fully understood. Distinct histone modifications are often associated with ON/OFF epigenetic states, but how these states are stably maintained through DNA replication, yet in certain situations switch from one to another remains unclear. Here, we address this problem through identification ofArabidopsisINCURVATA11 (ICU11) as a Polycomb Repressive Complex 2 accessory protein. ICU11 robustly immunoprecipitated in vivo with PRC2 core components and the accessory proteins, EMBRYONIC FLOWER 1 (EMF1), LIKE HETEROCHROMATIN PROTEIN1 (LHP1), and TELOMERE_REPEAT_BINDING FACTORS (TRBs).ICU11encodes a 2-oxoglutarate–dependent dioxygenase, an activity associated with histone demethylation in other organisms, and mutant plants show defects in multiple aspects of theArabidopsisepigenome. To investigate its primary molecular function we identified theArabidopsis FLOWERING LOCUS C(FLC) as a direct target and foundicu11disrupted the cold-induced, Polycomb-mediated silencing underlying vernalization.icu11prevented reduction in H3K36me3 levels normally seen during the early cold phase, supporting a role for ICU11 in H3K36me3 demethylation. This was coincident with an attenuation of H3K27me3 at the internal nucleation site inFLC, and reduction in H3K27me3 levels across the body of the gene after plants were returned to the warm. Thus, ICU11 is required for the cold-induced epigenetic switching between the mutually exclusive chromatin states atFLC, from the active H3K36me3 state to the silenced H3K27me3 state. These data support the importance of physical coupling of histone modification activities to promote epigenetic switching between opposing chromatin states.

scholarly journals Roles of MicroRNAs in Establishing and Modulating Stem Cell Potential

2019 ◽  
Vol 20 (15) ◽  
pp. 3643 ◽  
Author(s):  
Zhenwu Zhang ◽  
Lili Zhuang ◽  
Chao-Po Lin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Development ◽  
Cell Fate ◽  
Noncoding Rnas ◽  
Small Interfering Rnas ◽  
Cell Potential ◽  
Early Embryos

Early embryonic development in mammals, from fertilization to implantation, can be viewed as a process in which stem cells alternate between self-renewal and differentiation. During this process, the fates of stem cells in embryos are gradually specified, from the totipotent state, through the segregation of embryonic and extraembryonic lineages, to the molecular and cellular defined progenitors. Most of those stem cells with different potencies in vivo can be propagated in vitro and recapitulate their differentiation abilities. Complex and coordinated regulations, such as epigenetic reprogramming, maternal RNA clearance, transcriptional and translational landscape changes, as well as the signal transduction, are required for the proper development of early embryos. Accumulated studies suggest that Dicer-dependent noncoding RNAs, including microRNAs (miRNAs) and endogenous small-interfering RNAs (endo-siRNAs), are involved in those regulations and therefore modulate biological properties of stem cells in vitro and in vivo. Elucidating roles of these noncoding RNAs will give us a more comprehensive picture of mammalian embryonic development and enable us to modulate stem cell potencies. In this review, we will discuss roles of miRNAs in regulating the maintenance and cell fate potential of stem cells in/from mouse and human early embryos.

scholarly journals Expression and Potential Role of microRNA-29b in Mouse Early Embryo Development

2015 ◽  
Vol 35 (3) ◽  
pp. 1178-1187 ◽  
Author(s):  
Junqiang Zhang ◽  
Ying Wang ◽  
Xiaoguang Liu ◽  
Shenglin Jiang ◽  
Chun Zhao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Embryonic Development ◽  
Dna Methyltransferase ◽  
Biological Function ◽  
Expression Patterns ◽  
Early Embryo ◽  
Early Embryonic Development ◽  
Preimplantation Embryos ◽  
Early Embryos

Background/Aims: MicroRNA-29b (miR29b) has been previously identified in early mouse embryos through miRNA microarray analysis. Recent research has indicated that miR29b participates in DNA methylation by regulating DNA methyltransferase 3a/3b (Dnmt3a/3b) expression. However, the expression pattern and biological function of miR29b in mouse preimplantation embryonic development remain unknown. Methods: In this study, we examined the expression patterns of miR29b and Dnmt3a/3b in mouse early embryos at different developmental stages. Subsequently, expression and localization of DNMT3A/3B protein was analyzed in mouse early embryos by immunofluorescence staining. The biological function of miR29b in mouse early embryos was analyzed by microinjection of commercially available miRNA-specific inhibitors and mimics. Results: Our data showed that Dnmt3a/3b mRNA expression is negatively regulated by miR29b in mouse early embryos. Immunofluorescence analysis revealed that DNMT3A/3B protein expression is predominantly localized within the nucleoplasm of embryos. Alterations to the activity of miR29b could change the DNA methylation levels in mouse preimplantation embryos and lead to a developmental blockade, from the morula to the blastocyst stage. Conclusion: These results indicated a role for the miR29b-Dnmt3a/3b-DNA methylation axis in mouse early embryonic development, and we provide evidence that miR29b is indispensable for mouse early embryonic development. This study contributes to a preliminary understanding of the role of miR29b during mouse embryonic development.

scholarly journals H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2

2020 ◽  
Author(s):  
Siddhant U. Jain ◽  
Andrew Q. Rashoff ◽  
Samuel D. Krabbenhoft ◽  
Dominik Hoelper ◽  
Truman J. Do ◽  
...  
Keyword(s):  
Cpg Islands ◽  
Methyltransferase Activity ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
K27m Mutation ◽  
Mechanistic Insight ◽  
Competitive Inhibitors ◽  
Lysine Methyltransferase

AbstractDiffuse midline gliomas and posterior fossa type-A ependymomas contain the highly recurrent histone H3 K27M mutation and the H3 K27M-mimic EZHIP, respectively. In vitro, H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3K27me3 levels, however residual peaks of H3K27me3 remain at CpG islands through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2 in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved molecular mechanism. Our results highlight the mechanistic similarities between EZHIP and H3 K27M in vivo and provide mechanistic insight for the retention of residual H3K27me3 in tumors driven by these oncogenes.

Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment

2004 ◽  
Vol 32 (2) ◽  
pp. 393-396 ◽  
Author(s):  
P. Workman
Keyword(s):  
Cancer Treatment ◽  
Gene Knockout ◽  
Genomic Analysis ◽  
Gene Knockout Mouse ◽  
Show Evidence ◽  
In Vivo Animal Models ◽  
Phosphoinositide 3 Kinase ◽  
Kinase Pathway

There is extensive evidence from the molecular and genomic analysis of human cancers that the PI 3-kinase (phosphoinositide 3-kinase)–Akt/PKB (protein kinase B) pathway is deregulated in malignant progression. Furthermore, the causal involvement of PI 3-kinase is supported by gene-knockout mouse models. Prototype inhibitors show evidence of anticancer activity in vitro and in vivo animal models. The recent development of isoform-selective inhibitors shows considerable promise for cancer treatment.

scholarly journals Reproductive biology, embryonic development and matrotrophy in the phylactolaemate bryozoan Plumatella casmiana

2021 ◽  
Author(s):  
Julian Bibermair ◽  
Andrew N. Ostrovsky ◽  
Andreas Wanninger ◽  
Thomas Schwaha
Keyword(s):  
Embryonic Development ◽  
Embryo Sac ◽  
The Body ◽  
Transcellular Transport ◽  
Cell Contacts ◽  
Transmission Electron ◽  
Distal Side ◽  
Early Embryos ◽  
Mesoderm Formation ◽  
Cytoplasmic Processes

AbstractBryozoa is a phylum of aquatic, colonial suspension-feeders within the Lophotrochozoa. In the Phylactolaemata embryonic development occurs in an internal brood sac on the body wall accompanied by extraembryonic nutrition. Owing to previous contradictive descriptions, many aspects of their sexual reproduction require restudy. Consequently, this study analyses embryogenesis of the freshwater bryozoan Plumatella casmiana by serial sections, 3D reconstruction and transmission electron microscopy. Early embryos cleave and soon develop into blastulae with a small central cavity. The mesoderm forms by delamination starting from the distal side towards the proximal end. In later embryos two polypides form on the posterior side that ultimately will be covered by a ciliated mantle in the larva. Embryos increase in size during development and form temporary cell contacts to the embryo sac. Mesodermal cells of the embryo sac show signs of transcellular transport indicating that embryos are nourished by transferring nutrients from the maternal coelom towards the brood cavity. This study clarifies several details such as mesoderm formation and the onset of bud development. Embryos are connected to their respective embryo sacs by a variety of temporary cytoplasmic processes formed by both tissues during embryogenesis, including a ‘placental’ ring zone. Although ultrastructural data of these cell contacts are not entirely conclusive about their function, we suggest that embryos absorb nutrients via the entire surface. The close opposition of embryos to the embryo sac implies placentation as matrotrophic mode in phylactolaemate bryozoans, with embryo sacs acting as placental analogues.

Sign in / Sign up

Export Citation Format

Share Document