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Current Opinion in Genetics &... Aug 2023The totipotent embryo initiates transcription during zygotic or embryonic genome activation (EGA, ZGA). ZGA occurs at the 8-cell stage in humans and its failure leads to... (Review)
Review
The totipotent embryo initiates transcription during zygotic or embryonic genome activation (EGA, ZGA). ZGA occurs at the 8-cell stage in humans and its failure leads to developmental arrest. Understanding the molecular pathways underlying ZGA and totipotency is essential to comprehend human development. Recently, human 8-cell-like cells (8CLCs) have been discovered in vitro that resemble the 8-cell embryo. 8CLCs exist among naive pluripotent stem cells and can be induced genetically or chemically. Their ZGA-like transcriptome, transposable element activation, 8-cell embryo-specific protein expression, and developmental properties make them an exceptional model system to study early embryonic cell-state transitions and human totipotency programs in vitro.
Topics: Humans; Pluripotent Stem Cells; Human Embryonic Stem Cells; Zygote; Genome, Human
PubMed: 37356343
DOI: 10.1016/j.gde.2023.102066 -
Comparative Cytogenetics 2023It is demonstrated that the initial method of fertilization in animals (Metazoa), embryophyte plants (Embryophyta), most groups of multicellular oogamous algae, oogamous... (Review)
Review
It is demonstrated that the initial method of fertilization in animals (Metazoa), embryophyte plants (Embryophyta), most groups of multicellular oogamous algae, oogamous and pseudoogamous multicellular fungi was internal fertilization (in the broad meaning) in/on the body of a maternal organism. Accordingly, during the bisexual process, the initial method of formation of a daughter multicellular organism in animals was viviparity, and in embryophyte plants and most groups of oogamous multicellular algae - the germination of a zygote in/on the body of maternal organism. The reproductive criteria of multicellularity are proposed and discussed. In this regard, the multicellularity is considered to subdivide terminologically into three variants: 1) protonemal, the most simple, characteristic of multicellular prokaryotes, most groups of multicellular algae and gametophytes of some higher plants; 2) siphonoseptal, found among multicellular fungi, some groups of green and yellow-green algae; 3) embryogenic, most complicated, known in all animals (Metazoa), all sporophytes and some gametophytes of higher plants (Embryophyta), charophyte green algae Charophyceae s.s., oogamous species of green and brown algae, some genera of red algae. In addition to the well-known division of reproduction methods into sexual and asexual, it is proposed to divide the reproduction of multicellular organisms into monocytic (the emergence of a new organism from one cell sexually or asexually) and polycytic (fragmentation, longitudinal / transverse division or budding based on many cells of the body of the mother organism), since these two ways have different evolutionary and ontogenetic origins.
PubMed: 37953852
DOI: 10.3897/compcytogen.17.109671 -
Microorganisms Jul 2023Malaria elimination may never succeed without the implementation of transmission-blocking strategies. The transmission of spp. parasites from the human host to the... (Review)
Review
Malaria elimination may never succeed without the implementation of transmission-blocking strategies. The transmission of spp. parasites from the human host to the mosquito vector depends on circulating gametocytes in the peripheral blood of the vertebrate host. Once ingested by the mosquito during blood meals, these sexual forms undergo a series of radical morphological and metabolic changes to survive and progress from the gut to the salivary glands, where they will be waiting to be injected into the vertebrate host. The design of effective transmission-blocking strategies requires a thorough understanding of all the mechanisms that drive the development of gametocytes, gametes, sexual reproduction, and subsequent differentiation within the mosquito. The drastic changes in shape and function throughout its life cycle rely on the tight regulation of stage-specific gene expression. This review outlines the mechanisms involved in sexual stage development in both the human and mosquito vector, and zygote to oocyst differentiation. Functional studies unravel mechanisms employed by to orchestrate the expression of stage-specific functional products required to succeed in its complex life cycle, thus providing us with potential targets for developing new therapeutics. These mechanisms are based on studies conducted with various species, including predominantly and the rodent malaria parasites . However, the great potential of epigenetics, genomics, transcriptomics, proteomics, and functional genetic studies to improve the understanding of malaria as a disease remains partly untapped because of limitations in studies using human malaria parasites and field isolates.
PubMed: 37630530
DOI: 10.3390/microorganisms11081966 -
Theriogenology Jan 2024The mammalian zygote, formed after a sperm fertilizes an egg, undergoes several rounds of mitosis and morphogenesis to form the blastocyst. During the peri-implantation... (Review)
Review
The mammalian zygote, formed after a sperm fertilizes an egg, undergoes several rounds of mitosis and morphogenesis to form the blastocyst. During the peri-implantation period, the blastocyst hatches out of the zona pellucida (ZP) and invades the receptive uterine endometrium. This process promotes maternal-fetal dialogue at the physiological and molecular level, thereby initiating the implantation process. Blastocyst hatching is a consequence of elevated osmotic pressure due to active Na/K ion transporter in the blastocyst cavity, as well as proteases produced by trophectoderm (TE) that hydrolyze the ZP. This review summarizes the process underpinning blastocyst hatching, such as the hatching schedule, the location of TEs during initial hatching out of the ZP, the molecules involved in blastocyst hatching, and how these processes affect implantation events. Additionally, we focus on identifying crucial molecules that may influence the quality of implantation and predict the outcome of embryo implantation. Further understanding the mechanism of these molecules may help us to improve the efficiency of Assisted reproductive technology (ART) in livestock breeding. This review provides insight into embryonic development, specifically during the short-term process of blastocyst hatching and its effects on the following implantation.
Topics: Pregnancy; Female; Male; Animals; Semen; Embryo Implantation; Embryonic Development; Parturition; Blastocyst; Zona Pellucida; Mammals
PubMed: 37857152
DOI: 10.1016/j.theriogenology.2023.10.011 -
EMBO Molecular Medicine Jun 2023Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)-binding...
Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)-binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock-in (KI) female mice were infertile. RNA-sequencing analysis showed abnormal activation of the Mos-MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility.
Topics: Female; Humans; Mice; Animals; Infertility, Female; Oocytes; Homozygote; RNA, Messenger
PubMed: 37052235
DOI: 10.15252/emmm.202217177 -
Neurobiology of Disease Oct 2023De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug... (Review)
Review
De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug resistant epilepsy (DRE) associated with malformations of cortical development, in particular, focal cortical dysplasias (FCD). Somatic variants in at least 16 genes have been linked to FCD type II, all encoding components of the mechanistic target of rapamycin (mTOR) pathway. FCD type II is characterized histopathologically by cytomegalic dysmorphic neurons and balloon cells. In contrast, the molecular pathogenesis of FCD I subtypes is less well understood, and histological features are characterized by alterations in columnar or laminar organization without cytomegalic dysmorphic neurons or balloon cells. In 2018, we reported somatic mutations in Solute Carrier Family 35 member A2 (SLC35A2) linked to DRE underlying FCD type I and subsequently to a new histopathological phenotype: excess oligodendrocytes and heterotopic neurons in subcortical white matter known as MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia). These discoveries opened the door to studies linking somatic mutations to FCD. In this review, we discuss the biology of SLC35A2 somatic mutations in epilepsy in FCD and MOGHE, and insights into SLC35A2 epilepsy pathogenesis, describing progress to date and critical areas for investigation.
Topics: Humans; Drug Resistant Epilepsy; Focal Cortical Dysplasia; Epilepsy; Malformations of Cortical Development, Group I; Malformations of Cortical Development
PubMed: 37739137
DOI: 10.1016/j.nbd.2023.106299 -
Genes & Development Jul 2023Nucleosome positioning can alter the accessibility of DNA-binding proteins to their cognate DNA elements, and thus its precise control is essential for cell identity and...
Nucleosome positioning can alter the accessibility of DNA-binding proteins to their cognate DNA elements, and thus its precise control is essential for cell identity and function. Mammalian preimplantation embryos undergo temporal changes in gene expression and cell potency, suggesting the involvement of dynamic epigenetic control during this developmental phase. However, the dynamics of nucleosome organization during early development are poorly understood. In this study, using a low-input MNase-seq method, we show that nucleosome positioning is globally obscure in zygotes but becomes well defined during subsequent development. Down-regulation of the chromatin assembly in embryonic stem cells can partially reverse nucleosome organization into a zygote-like pattern, suggesting a possible link between the chromatin assembly pathway and fuzzy nucleosomes in zygotes. We also reveal that YY1, a zinc finger-containing transcription factor expressed upon zygotic genome activation, regulates the de novo formation of well-positioned nucleosome arrays at the regulatory elements through identifying YY1-binding sites in eight-cell embryos. The YY1-binding regions acquire H3K27ac enrichment around the eight-cell and morula stages, and YY1 depletion impairs the morula-to-blastocyst transition. Thus, our study delineates the remodeling of nucleosome organization and its underlying mechanism during early mouse development.
Topics: Animals; Mice; Chromatin; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Gene Expression Regulation; Mammals; Nucleosomes; Transcription Factors
PubMed: 37532472
DOI: 10.1101/gad.350376.122 -
Life Science Alliance Aug 2023Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a protein essential for the maintenance of DNA methylation in somatic cells. However, UHRF1 is predominantly...
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a protein essential for the maintenance of DNA methylation in somatic cells. However, UHRF1 is predominantly localized in the cytoplasm of mouse oocytes and preimplantation embryos, where it may play a role unrelated to the nuclear function. We herein report that oocyte-specific KO results in impaired chromosome segregation, abnormal cleavage division, and preimplantation lethality of derived embryos. Our nuclear transfer experiment showed that the phenotype is attributable to cytoplasmic rather than nuclear defects of the zygotes. A proteomic analysis of KO oocytes revealed the down-regulation of proteins associated with microtubules including tubulins, which occurred independently of transcriptomic changes. Intriguingly, cytoplasmic lattices were disorganized, and mitochondria, endoplasmic reticulum, and components of the subcortical maternal complex were mislocalized. Thus, maternal UHRF1 regulates the proper cytoplasmic architecture and function of oocytes and preimplantation embryos, likely through a mechanism unrelated to DNA methylation.
Topics: Animals; Mice; Proteomics; Oocytes; Cytosol; Endoplasmic Reticulum; Mitochondria; CCAAT-Enhancer-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 37225425
DOI: 10.26508/lsa.202301904 -
Epigenetics Dec 2023This study characterized variations in the methylation profile of mitochondrial DNA (mtDNA) during initial bovine embryo development and correlated the presence of...
This study characterized variations in the methylation profile of mitochondrial DNA (mtDNA) during initial bovine embryo development and correlated the presence of methylation with mtDNA transcription. Bovine oocytes were obtained from abattoir ovaries and submitted to culture procedures. Oocytes and embryos were collected at various stages (immature oocyte, IM; mature oocyte, MII; zygote, ZY; 4-cells, 4C; 16-cells, 16C and blastocysts, BL). Total DNA (including mtDNA) was used for Whole Genome Enzymatic Methyl Sequencing and for quantification of mtDNA copy number. Extracted RNA was used for quantification of mitochondrial transcripts using Droplet Digital PCR. We selected ND6, CYTB, tRNA-Phe and tRNA-Gln based on their location in the mitochondrial genome, functionality and/or previous literature associating these regions with cytosine methylation. The number of mtDNA copies per oocyte/embryo was found to be similar, while methylation levels in mtDNA varied among stages. Higher total methylation levels were found mainly at 4C and 16C. In specific gene regions, higher methylation levels were also observed at 4C and 16C (ND6, CYTB and tRNA-Phe), as well as an inverse correlation with the quantity of transcripts for these regions. This is a first description of epigenetic changes occurring in mtDNA during early embryonic development. Our results indicate that methylation might regulate the mtDNA transcription at a local level, particularly around the time of embryonic genome activation.
Topics: Pregnancy; Female; Animals; Cattle; DNA, Mitochondrial; DNA Methylation; Embryonic Development; Oocytes; Mitochondria; Blastocyst
PubMed: 37523633
DOI: 10.1080/15592294.2023.2241010 -
Nature Communications Aug 2023Somatic cell nuclear transfer (SCNT) can be used to reprogram differentiated somatic cells to a totipotent state but has poor efficiency in supporting full-term...
Somatic cell nuclear transfer (SCNT) can be used to reprogram differentiated somatic cells to a totipotent state but has poor efficiency in supporting full-term development. H3K9me3 is considered to be an epigenetic barrier to zygotic genomic activation in 2-cell SCNT embryos. However, the mechanism underlying the failure of H3K9me3 reprogramming during SCNT embryo development remains elusive. Here, we perform genome-wide profiling of H3K9me3 in cumulus cell-derived SCNT embryos. We find redundant H3K9me3 marks are closely related to defective minor zygotic genome activation. Moreover, SCNT blastocysts show severely indistinct lineage-specific H3K9me3 deposition. We identify MAX and MCRS1 as potential H3K9me3-related transcription factors and are essential for early embryogenesis. Overexpression of Max and Mcrs1 significantly benefits SCNT embryo development. Notably, MCRS1 partially rescues lineage-specific H3K9me3 allocation, and further improves the efficiency of full-term development. Importantly, our data confirm the conservation of deficient H3K9me3 differentiation in Sertoli cell-derived SCNT embryos, which may be regulated by alternative mechanisms.
Topics: Histones; Zygote; Nuclear Transfer Techniques; Embryonic Development; Blastocyst; Embryo, Mammalian; Cellular Reprogramming
PubMed: 37558707
DOI: 10.1038/s41467-023-40496-3