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Richard M. Schultz - One of the best experts on this subject based on the ideXlab platform.

  • minor zygotic gene activation is essential for mouse Preimplantation Development
    Proceedings of the National Academy of Sciences of the United States of America, 2018
    Co-Authors: Kenichiro Abe, Richard M. Schultz, Satoshi Funaya, Dai Tsukioka, Machika Kawamura, Yutaka Suzuki, Masataka G Suzuki, Fugaku Aoki
    Abstract:

    In mice, transcription initiates at the mid-one-cell stage and transcriptional activity dramatically increases during the two-cell stage, a process called zygotic gene activation (ZGA). Associated with ZGA is a marked change in the pattern of gene expression that occurs after the second round of DNA replication. To distinguish ZGA before and after the second-round DNA replication, the former and latter are called minor and major ZGA, respectively. Although major ZGA are required for Development beyond the two-cell stage, the function of minor ZGA is not well understood. Transiently inhibiting minor ZGA with 5, 6-dichloro-1-β-d-ribofuranosyl-benzimidazole (DRB) resulted in the majority of embryos arresting at the two-cell stage and retention of the H3K4me3 mark that normally decreases. After release from DRB, at which time major ZGA normally occurred, transcription initiated with characteristics of minor ZGA but not major ZGA, although degradation of maternal mRNA normally occurred. Thus, ZGA occurs sequentially starting with minor ZGA that is critical for the maternal-to-zygotic transition.

  • histone deacetylase 1 hdac1 regulates histone acetylation Development and gene expression in Preimplantation mouse embryos
    Developmental Biology, 2008
    Co-Authors: Richard M. Schultz
    Abstract:

    Abstract Superimposed on activation of the embryonic genome in Preimplantation mouse embryos is the formation of a chromatin-mediated transcriptionally repressive state that arises in the late two-cell embryo and becomes more pronounced with Development. In this study, we investigated expression and function of Class I histone deacetylases (HDAC) HDAC1, HDAC2, and HDAC3 during Preimplantation Development. HDAC1 is likely a major deacetylase in Preimplantation embryos and its expression inversely correlates with changes in the acetylation state of histone H4K5 during Preimplantation Development. RNAi-mediated reduction of HDAC1 leads to hyperacetylation of histone H4 and a Developmental delay even though expression of HDAC2 and HDAC3 is significantly induced in Hdac1-suppresssed embryos; increased expression of p21Cip1/Waf may contribute to the observed Developmental delay. RNAi-mediated reduction of HDAC2 has no noticeable effect on Preimplantation Development, suggesting that individual HDACs have distinct functions during Preimplantation Development. Although RNAi-mediated targeting of Hdac3 mRNA was very efficient, maternal HDAC3 protein was stable during Preimplantation Development, thereby preventing an examination of its role. HDAC1 knockdown does not increase the rate of global transcription in late 2-cell embryos, but does result in elevated levels of expression of a subset of genes; this increased expression correlates with hyperacetylation of histone H4. Results of these experiments suggest that HDAC1 is involved in the Development of a transcriptionally repressive state that initiates in 2-cell embryos.

  • selective loss of imprinting in the placenta following Preimplantation Development in culture
    Development, 2004
    Co-Authors: Mellissa R W Mann, Richard M. Schultz, Susan S Lee, Adam S Doherty, Raluca I Verona, Leisha D Nolen, Marisa S Bartolomei
    Abstract:

    Preimplantation Development is a period of dynamic epigenetic change that begins with remodeling of egg and sperm genomes, and ends with implantation. During this time, parental-specific imprinting marks are maintained to direct appropriate imprinted gene expression. We previously demonstrated that H19 imprinting could be lost during Preimplantation Development under certain culture conditions. To define the lability of genomic imprints during this dynamic period and to determine whether loss of imprinting continues at later stages of Development, imprinted gene expression and methylation were examined after in vitro Preimplantation culture. Following culture in Whitten's medium, the normally silent paternal H19 allele was aberrantly expressed and undermethylated. However, only a subset of individual cultured blastocysts (∼65%) exhibited biallelic expression, while others maintained imprinted H19 expression. Loss of H19 imprinting persisted in mid-gestation conceptuses. Placental tissues displayed activation of the normally silent allele for H19, Ascl2, Snrpn, Peg3 and Xist while in the embryo proper imprinted expression for the most part was preserved. Loss of imprinted expression was associated with a decrease in methylation at the H19 and Snrpn imprinting control regions. These results indicate that tissues of trophectoderm origin are unable to restore genomic imprints and suggest that mechanisms that safeguard imprinting might be more robust in the embryo than in the placenta.

  • gene expression in mouse oocytes and Preimplantation embryos use of suppression subtractive hybridization to identify oocyte and embryo specific genes
    Biology of Reproduction, 2003
    Co-Authors: Fanyi Zeng, Richard M. Schultz
    Abstract:

    The paucity of biological material has inhibited identifying genes that are differentially expressed during mammalian oogenesis and Preimplantation Development. We report here the linear amplification of mRNA from small numbers of mouse oocytes and Preimplantation embryos to generate amounts of sense RNA that are sufficient for suppression subtractive hybridization. The resulting oocyte-specific and 8-cell-specific cDNA libraries were partially characterized, and the known oocyte-specific ZP1, ZP2, GDF-9, BMP15, and H1oo genes were found in the oocyte-specific cDNA library but not in the 8-cell-specific library. Further characterization of the subtracted oocyte and 8cell embryo cDNA libraries should furnish a trove of information regarding temporal changes in gene expression during oogenesis and Preimplantation Development in the mouse. Developmental regulation, embryo, gametogenesis, gene regulation, oocyte Development

  • Posttranscriptional Regulation of Cyclin A1 and Cyclin A2 During Mouse Oocyte Meiotic Maturation and Preimplantation Development
    Biology of reproduction, 2001
    Co-Authors: Dai-ichiro Fuchimoto, Richard M. Schultz, Aki Mizukoshi, Senkiti Sakai, Fugaku Aoki
    Abstract:

    A shift from a meiotic cell cycle to a mitotic cell cycle occurs following fertilization. The molecular basis for this transition, however, is poorly understood. Although cyclin A1 is proposed to regulate M phase in the meiotic cell cycle, and cyclin A2 is proposed to regulate S and M phases in the mitotic cell cycle, little is known about changes in the expression levels of cyclin A1 and A2 during meiotic and mitotic cell cycles in mammalian oocytes. We report that the mRNA levels of both cyclins A1 and A2 decrease during oocyte maturation. The amount of cyclin A1 mRNA then increases between the one-cell and blastocyst stages, whereas that of cyclin A2 remains relatively constant. The amount of cyclin A1 protein declines during maturation and is not readily detected from the two-cell to the blastocyst stage. In contrast, cyclin A2 is not readily detected in the oocyte and metaphase II-arrested egg but is detected following fertilization and throughout the subsequent stages of Preimplantation Development. The appearance of cyclin A2 protein following fertilization positively correlates with an increase in the size of the mRNA. This increase, as well as the increase in the amount of cyclin A2 protein, is prevented by 39-deoxyadenosine (39-dA), an inhibitor of polyadenylation. Consistent with a role for cyclin A2 in regulating the G1/S transition, 39-dA also inhibits DNA replication in treated one-cell embryos. These results suggest that regulation of expression of cyclins A1 and A2 is under posttranscriptional regulation and that the observed changes in their expression may be involved in the transformation of a meiotic cell cycle to a mitotic cell cycle following fertilization. Developmental biology, early Development, embryo, gamete biology, meiosis

Andrew J Watson - One of the best experts on this subject based on the ideXlab platform.

  • Preimplantation embryo programming transcription epigenetics and culture environment
    Reproduction, 2008
    Co-Authors: Veronique Duranthon, Andrew J Watson, P Lonergan
    Abstract:

    Preimplantation Development directs the formation of an implantation- or attachment-competent embryo so that metabolic interactions with the uterus can occur, pregnancy can be initiated, and fetal Development can be sustained. The Preimplantation embryo exhibits a form of autonomous Development fueled by products provided by the oocyte and also from activation of the embryo's genome. Despite this autonomy, the Preimplantation embryo is highly influenced by factors in the external environment and in extreme situations, such as those presented by embryo culture or nuclear transfer, the ability of the embryo to adapt to the changing environmental conditions or chromatin to become reprogrammed can exceed its own adaptive capacity, resulting in aberrant embryonic Development. Nuclear transfer or embryo culture-induced influences not only affect implantation and establishment of pregnancy but also can extend to fetal and postnatal Development and affect susceptibility to disease in later life. It is therefore critical to define the basic program controlling Preimplantation Development, and also to utilize nuclear transfer and embryo culture models so that we may design healthier environments for Preimplantation embryos to thrive in and also minimize the potential for negative consequences during pregnancy and post-gestational life. In addition, it is necessary to couple gene expression analysis with the investigation of gene function so that effects on gene expression can be fully understood. The purpose of this short review is to highlight our knowledge of the mechanisms controlling Preimplantation Development and report how those mechanisms may be influenced by nuclear transfer and embryo culture.

  • Mouse Preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation
    BMC Developmental Biology, 2007
    Co-Authors: Barry Fong, Patricia H Watson, Andrew J Watson
    Abstract:

    Mechanisms that confer an ability to respond positively to environmental osmolarity are fundamental to ensuring embryo survival during the Preimplantation period. Activation of p38 mitogen-activated protein kinase (MAPK) occurs following exposure to hyperosmotic treatment. Recently, a novel scaffolding protein called Osmosensing Scaffold for MEKK3 (OSM) was linked to p38 MAPK activation in response to sorbitol-induced hypertonicity. The human ortholog of OSM is cerebral cavernous malformation 2 (CCM2). The present study was conducted to investigate whether CCM2 is expressed during mouse Preimplantation Development and to determine whether this scaffolding protein is associated with p38 MAPK activation following exposure of Preimplantation embryos to hyperosmotic environments. Our results indicate that Ccm2 along with upstream p38 MAPK pathway constituents (Map3k3, Map2k3, Map2k6, and Map2k4) are expressed throughout mouse Preimplantation Development. CCM2, MAP3K3 and the phosphorylated forms of MAP2K3/MAP2K6 and MAP2K4 were also detected throughout Preimplantation Development. Embryo culture in hyperosmotic media increased p38 MAPK activity in conjunction with elevated CCM2 levels. These results define the expression of upstream activators of p38 MAPK during Preimplantation Development and indicate that embryo responses to hyperosmotic environments include elevation of CCM2 and activation of p38 MAPK.

  • p38 mapk signaling during murine Preimplantation Development
    Developmental Biology, 2004
    Co-Authors: David R C Natale, Andrew J M Paliga, Frank Beier, Sudhir J A Dsouza, Andrew J Watson
    Abstract:

    Mitogen-activated protein kinase (MAPK) pathways mediate some important cellular processes and are likely to also regulate Preimplantation Development. The role of p38 MAP kinase signaling during murine Preimplantation Development was investigated in the present study. p38 MAPK, p38-regulated or -activated kinase (PRAK; MK5), map kinase-activated protein kinase 2 (MK2), and heat shock protein 25 (hsp25) mRNAs and proteins were detected throughout Preimplantation Development. Two-cell stage embryos cultured in the presence of SB220025 and SB203580 (specific inhibitors of p38 MAPK alpha/beta), progressed to the eight-cell stage with the same frequency as controls; however, treated embryos halted their Development at the 8- to 16-cell stage. In addition, embryos treated with p38 MAPK inhibitors displayed a complete loss of MK2 and hsp25 phosphorylation and also a complete loss of filamentous actin as indicated by the absence of rhodamine-phalloidin staining. In these inhibitor-treated groups, the embryos were composed of a mixture of compacting and noncompacting cells, and the embryos were one to two cell divisions behind controls. Treated embryos remained viable as the Developmental blockade was rescued by removing embryos from the drug treatment and placing them in drug-free medium until they progressed to the blastocyst stage. This study demonstrates that p38 MAPK activity is required to support Development through the murine Preimplantation interval.

Wolf Reik - One of the best experts on this subject based on the ideXlab platform.

  • single cell transcriptome analysis of human marmoset and mouse embryos reveals common and divergent features of Preimplantation Development
    Development, 2018
    Co-Authors: Thorsten Boroviak, Wolf Reik, Giuliano Giuseppe Stirparo, Sabine Dietmann, Irene Hernandoherraez, Hisham Mohammed, Austin Smith, Erika Sasaki, Jennifer Nichols, Paul Bertone
    Abstract:

    The mouse embryo is the canonical model for mammalian Preimplantation Development. Recent advances in single cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single cell RNA-seq. Zygotic genome activation correlates with the presence of polycomb repressive complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species, stage and lineage specific. The pluripotency network in the primate epiblast lacks certain regulators that are operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and non-human primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of Preimplantation Development, and underscores the molecular adaptability of early mammalian embryogenesis.

  • single cell transcriptome analysis of human marmoset and mouse embryos reveals common and divergent features of Preimplantation Development
    bioRxiv, 2018
    Co-Authors: Thorsten Boroviak, Wolf Reik, Giuliano Giuseppe Stirparo, Sabine Dietmann, Irene Hernandoherraez, Hisham Mohammed, Austin Smith, Erika Sasaki, Jennifer Nichols, Paul Bertone
    Abstract:

    The mouse embryo is the canonical model for mammalian Preimplantation Development. Recent advances in single-cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single-cell RNA-seq. Zygotic genome activation correlates with the presence of Polycomb Repressive Complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species-, stage- and lineage-specific. The pluripotency network in the primate epiblast lacks certain regulators operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and nonhuman primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of Preimplantation Development and underscores the molecular adaptability of early mammalian embryogenesis.

  • dynamics of the epigenetic landscape during the maternal to zygotic transition
    Nature Reviews Molecular Cell Biology, 2018
    Co-Authors: Melanie A Eckersleymaslin, Celia Aldacatalinas, Wolf Reik
    Abstract:

    A remarkable epigenetic remodelling process occurs shortly after fertilization, which restores totipotency to the zygote. This involves global DNA demethylation, chromatin remodelling, genome spatial reorganization and substantial transcriptional changes. Key to these changes is the transition from the maternal environment of the oocyte to an embryonic-driven Developmental expression programme, a process termed the maternal-to-zygotic transition (MZT). Zygotic genome activation occurs predominantly at the two-cell stage in mice and the eight-cell stage in humans, yet the dynamics of its control are still mostly obscure. In recent years, partly due to single-cell and low-cell number epigenomic studies, our understanding of the epigenetic and chromatin landscape of Preimplantation Development has improved considerably. In this Review, we discuss the latest advances in the study of the MZT, focusing on DNA methylation, histone post-translational modifications, local chromatin structure and higher-order genome organization. We also discuss key mechanistic studies that investigate the mode of action of chromatin regulators, transcription factors and non-coding RNAs during Preimplantation Development. Finally, we highlight areas requiring additional research, as well as new technological advances that could assist in eventually completing our understanding of the MZT.

  • methylation levels of maternal and paternal genomes during Preimplantation Development
    Development, 1991
    Co-Authors: S K Howlett, Wolf Reik
    Abstract:

    The methylation status of three highly repeated sequences was studied in sperm, eggs and Preimplantation embryos with different combinations of parental chromosomes. High levels of methylation of the IAP and MUP sequence families were found in sperm and in eggs, whereas the L1 repeat was found to be highly methylated in sperm but only about 42% methylated in eggs. To assess how the two parental genomes behaved during Preimplantation Development, normal, fertilised embryos were compared with parthenogenetic embryos where the chromosomes are exclusively of maternal origin. It was observed that the high levels of methylation at the IAP and MUP sequences were retained through early Development, with the first signs of demethylation at the IAP sequences apparent on both parental chromosomes in the blastocyst. Methylation at the sperm-derived L1 sequences dropped to about the same level as that of the egg-derived sequences by the late 2-cell stage, both then remain at this intermediate level until around the time of cavitation when levels fell to about 10% in the blastocyst. High levels of DNA methylase were detected in germinal vesicle and metaphase II oocytes; these high levels were maintained in fertilised and parthenogenetic embryos through into the morula and then declined to be undetectable in the blastocyst. Our comparison of maternal and paternal genomes suggests that methylation levels at repeat sequences are remarkably similar at the time of fertilisation or, as in the case of the L1 sequences, they become so during the first few cell cycles. Hence, there do not appear to be global methylation differences between the genomes that are retained through Preimplantation Development.(ABSTRACT TRUNCATED AT 250 WORDS)

Robert F Casper - One of the best experts on this subject based on the ideXlab platform.

  • alterations in mitochondrial membrane potential during Preimplantation stages of mouse and human embryo Development
    Molecular Human Reproduction, 2004
    Co-Authors: B M Acton, Andrea Jurisicova, Igor Jurisica, Robert F Casper
    Abstract:

    Mitochondria are cellular organelles regulating metabolism and cell death pathways. This study examined changes in mitochondrial membrane potential (DYm) throughout the stages of Preimplantation Development in mouse embryos conceived either in vivo or in vitro and human embryos donated to research from IVF. Embryos stained with the DYm-sensitive dye (JC-1) were quantified for the ratio of high- to low-polarized mitochondria using a deconvolution microscope. Overall, mouse zygotes and early embryos contain a subset of high-polarized mitochondria with a progressive increase in the ratio of DYm observed with increasing cleavage. A transient increase in the ratio of high to low DYm was observed in in vivo fertilized 2-cell stage embryos, coincident with embryonic genome activation in the mouse, but not in 2-cell embryos obtained through IVF. We further observed that arrested mouse 2-cell embryos possessed an increased ratio of DYm compared with non-arrested embryos. In human 8-cell embryos we observed an increased ratio of high- to low-polarized mitochondria with increasing degrees of embryo fragmentation. We concluded that the pattern of mitochondrial membrane potential progressively changes throughout Preimplantation Development, and that an aberrant shift in DYm could contribute to, or is associated with, decreased Developmental potential.

  • alterations in mitochondrial membrane potential during Preimplantation stages of mouse and human embryo Development
    Molecular Human Reproduction, 2004
    Co-Authors: B M Acton, Andrea Jurisicova, Igor Jurisica, Robert F Casper
    Abstract:

    Mitochondria are cellular organelles regulating metabolism and cell death pathways. This study examined changes in mitochondrial membrane potential (deltapsim) throughout the stages of Preimplantation Development in mouse embryos conceived either in vivo or in vitro and human embryos donated to research from IVF. Embryos stained with the deltapsim-sensitive dye (JC-1) were quantified for the ratio of high- to low-polarized mitochondria using a deconvolution microscope. Overall, mouse zygotes and early embryos contain a subset of high-polarized mitochondria with a progressive increase in the ratio of deltapsim observed with increasing cleavage. A transient increase in the ratio of high to low deltapsim was observed in in vivo fertilized 2-cell stage embryos, coincident with embryonic genome activation in the mouse, but not in 2-cell embryos obtained through IVF. We further observed that arrested mouse 2-cell embryos possessed an increased ratio of deltapsim compared with non-arrested embryos. In human 8-cell embryos we observed an increased ratio of high- to low-polarized mitochondria with increasing degrees of embryo fragmentation. We concluded that the pattern of mitochondrial membrane potential progressively changes throughout Preimplantation Development, and that an aberrant shift in deltapsim could contribute to, or is associated with, decreased Developmental potential.

Hiroyuki Sasaki - One of the best experts on this subject based on the ideXlab platform.

  • Histone H3K9 Methyltransferase G9a in Oocytes Is Essential for Preimplantation Development but Dispensable for CG Methylation Protection
    Elsevier, 2019
    Co-Authors: Wan Kin Au Yeung, Julie Brind’amour, Yu Hatano, Kazuo Yamagata, Robert Feil, Matthew C. Lorincz, Makoto Tachibana, Yoichi Shinkai, Hiroyuki Sasaki
    Abstract:

    Summary: Mammalian histone methyltransferase G9a (also called EHMT2) deposits H3K9me2 on chromatin and is essential for postimplantation Development. However, its role in oogenesis and Preimplantation Development remains poorly understood. We show that H3K9me2-enriched chromatin domains in mouse oocytes are generally depleted of CG methylation, contrasting with their association in embryonic stem and somatic cells. Oocyte-specific disruption of G9a results in reduced H3K9me2 enrichment and impaired reorganization of heterochromatin in oocytes, but only a modest reduction in CG methylation is detected. Furthermore, in both oocytes and 2-cell embryos, G9a depletion has limited impact on the expression of genes and retrotransposons. Although their CG methylation is minimally affected, Preimplantation embryos derived from such oocytes show abnormal chromosome segregation and frequent Developmental arrest. Our findings illuminate the functional importance of G9a independent of CG methylation in Preimplantation Development and call into question the proposed role for H3K9me2 in CG methylation protection in zygotes. : Au Yeung et al. report that H3K9 methyltransferase G9a in mouse oocytes is essential for Preimplantation Development. Contrary to the previous model, however, maternal G9a is dispensable for CG methylation protection in zygotes and is instead important for chromatin reorganization in oocytes and proper chromosome segregation in Preimplantation embryos. Keywords: oocyte, Preimplantation embryo, histone modification, DNA methylation, G9a, H3K9me2, chromatin organization, chromosome segregatio

  • Histone H3K9 Methyltransferase G9a in Oocytes Is Essential for Preimplantation Development but Dispensable for CG Methylation Protection.
    Cell Reports, 2019
    Co-Authors: Wan Kin Au Yeung, Julie Brind’amour, Yu Hatano, Kazuo Yamagata, Robert Feil, Matthew C. Lorincz, Makoto Tachibana, Yoichi Shinkai, Hiroyuki Sasaki
    Abstract:

    Mammalian histone methyltransferase G9a (also called EHMT2) deposits H3K9me2 on chromatin and is essential for postimplantation Development. However, its role in oogenesis and Preimplantation Development remains poorly understood. We show that H3K9me2-enriched chromatin domains in mouse oocytes are generally depleted of CG methylation, contrasting with their association in embryonic stem and somatic cells. Oocyte-specific disruption of G9a results in reduced H3K9me2 enrichment and impaired reorganization of heterochromatin in oocytes, but only a modest reduction in CG methylation is detected. Furthermore, in both oocytes and 2-cell embryos, G9a depletion has limited impact on the expression of genes and retrotransposons. Although their CG methylation is minimally affected, Preimplantation embryos derived from such oocytes show abnormal chromosome segregation and frequent Developmental arrest. Our findings illuminate the functional importance of G9a independent of CG methylation in Preimplantation Development and call into question the proposed role for H3K9me2 in CG methylation protection in zygotes.