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Frontiers in Genetics 2023Most epigenetic information is reprogrammed during gametogenesis and early development. However, some epigenetic information persists and can be inherited, a phenomenon...
Most epigenetic information is reprogrammed during gametogenesis and early development. However, some epigenetic information persists and can be inherited, a phenomenon that is common in plants. On the other hand, there are increasing examples of epigenetic inheritance in metazoans, especially for small non-coding RNAs. The presence of regulatory important RNAs in oocytes is undisputed, whereas the corresponding RNA payload in spermatozoa and its regulatory influence in the zygote and early embryogenesis is largely enigmatic. For humans, we herein describe small YRNA fragments (YsRNA) as a paternal contribution to the zygote. First, we trace the biogenesis of these YsRNAs from the source YRNAs with respect to the 5' and 3' modifications. Both the length and modifications make these YsRNAs reminiscent of canonical piRNAs that are not derived from piRNA clusters. Second, from the early stages of spermatogenesis to maturation in the epididymis, we observe distinct YsRNA profile dynamics in the male germline. We detected YsRNAs exclusively in mature sperm heads, the precursor of the male pronucleus in the zygote, suggesting an important role of the epididymis as a site for transmitting and modification of epigenetic information in the form of YsRNA between soma and germline in humans. Since this YsRNA-based epigenetic mechanism is effective across generations, we wondered whether this phenomenon of epigenetic inheritance has an adaptive value. Full-length YRNAs bind to Ro60, an RNA chaperone that additionally binds to non-coding RNAs. We described the profiles of non-coding RNAs bound to Ro60 in the human sperm head and detected specific binding profiles of RNA to Ro60 but no YRNA bound to Ro60. We hypothesize that the sperm head Ro60 system is functional. An adaptive phenotype mediated by the presence of a large amount of YsRNA in the sperm head, and thus as a paternal contribution in the zygote, might be related to an association of YsRNA with YRNA that prevents the adoption of a YRNA secondary structure capable of binding to Ro60. We hypothesize that preventing YRNAs from acting as Ro60-associated gatekeepers for misfolded RNAs in the zygote and early development may enhance RNA chaperoning and, thus, represent the adaptive molecular phenotype.
PubMed: 38162679
DOI: 10.3389/fgene.2023.1294389 -
IScience Oct 2023Double homeobox (DUX) genes are unique to eutherian mammals, expressed transiently during zygotic genome activation (ZGA) and involved in facioscapulohumeral muscular...
Double homeobox (DUX) genes are unique to eutherian mammals, expressed transiently during zygotic genome activation (ZGA) and involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer when misexpressed. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 cytotoxicity is not shared with DUXA or DUXB, but surprisingly is shared with platypus sDUX, which binds DNA as a homodimer and activates numerous ZGA genes and long terminal repeat (LTR) elements. DUXA, although transcriptionally inactive, has DNA binding overlap with DUX4, and DUXA-VP64 activates DUX4 targets and is cytotoxic. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is a DUX4 target gene, this competition potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises antagonistic members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.
PubMed: 37744032
DOI: 10.1016/j.isci.2023.107823 -
Nature Communications Dec 2023Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome...
Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.
Topics: Child; Humans; Wilms Tumor; Genotype; DNA Methylation; DNA; Kidney Neoplasms; Epigenesis, Genetic; Genomic Imprinting
PubMed: 38110397
DOI: 10.1038/s41467-023-43730-0 -
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 -
ELife Jul 2023Sex-specific splicing is an essential process that regulates sex determination and drives sexual dimorphism. Yet, how early in development widespread sex-specific...
Sex-specific splicing is an essential process that regulates sex determination and drives sexual dimorphism. Yet, how early in development widespread sex-specific transcript diversity occurs was unknown because it had yet to be studied at the genome-wide level. We use the powerful model to show that widespread sex-specific transcript diversity occurs early in development, concurrent with zygotic genome activation. We also present a new pipeline called time2Splice to quantify changes in alternative splicing over time. Furthermore, we determine that one of the consequences of losing an essential maternally deposited pioneer factor called CLAMP (chromatin-linked adapter for MSL proteins) is altered sex-specific splicing of genes involved in diverse biological processes that drive development. Overall, we show that sex-specific differences in transcript diversity exist even at the earliest stages of development..
Topics: Animals; Male; Female; Drosophila; Drosophila melanogaster; Drosophila Proteins; Embryonic Development; Genome; Alternative Splicing
PubMed: 37466240
DOI: 10.7554/eLife.87865 -
Cell Reports Sep 2023The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether...
The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether this generates cells similar to early embryonic stem cells. Here we identified cancer cell lines that express DUX4 and showed that DUX4 is transiently expressed in a small subset of the cells. DUX4 expression activates the DUX4-regulated ZGA transcriptional program, the subsequent 8C-like program, and markers of early embryonic lineages, while suppressing steady-state and interferon-induced MHC class I expression. Although DUX4 was expressed in a small number of cells under standard culture conditions, DNA damage or changes in growth conditions increased the fraction of cells expressing DUX4 and its downstream programs. Our demonstration that transient expression of endogenous DUX4 in cancer cells induces a metastable early embryonic stem cell program and suppresses antigen presentation has implications for cancer growth, progression, and immune evasion.
Topics: Humans; Cell Line; Genes, Homeobox; Homeodomain Proteins; Muscular Dystrophy, Facioscapulohumeral; Neoplasms; Transcription Factors; Zygote
PubMed: 37691147
DOI: 10.1016/j.celrep.2023.113114 -
Genes & Development Oct 2023Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis,...
Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis, including zygotic genome activation (ZGA) during maternal-to-zygotic transition, influence such remodeling remains unknown. Here, we have investigated the establishment of nuclear architecture, focusing on the remodeling of lamina-associated domains (LADs) during this transition. We report that LADs reorganize gradually in two-cell embryos and that blocking ZGA leads to major changes in nuclear organization, including altered chromatin and genomic features of LADs and redistribution of H3K4me3 toward the nuclear lamina. Our data indicate that the rearrangement of LADs is an integral component of the maternal-to-zygotic transition and that transcription contributes to shaping nuclear organization at the beginning of mammalian development.
Topics: Animals; Mice; RNA Polymerase II; Transcription, Genetic; Embryonic Development; Zygote; Mammals; Gene Expression Regulation, Developmental; Chromatin
PubMed: 37914351
DOI: 10.1101/gad.350799.123 -
International Journal of Molecular... Jun 2023is a worldwide ornamental flower and an emerging oil crop. Zyotic embryogenesis is a critical process during seed development, and it can provide a basis for improving...
is a worldwide ornamental flower and an emerging oil crop. Zyotic embryogenesis is a critical process during seed development, and it can provide a basis for improving the efficiency of somatic embryogenesis (SE). In this study, transcriptome sequencing of embryo development was performed to investigate gene expression profiling in and identified Differentially expressed genes (DEGs) related to transcription factors, plant hormones, and antioxidant enzymes. The results indicated that IAA (Indole-3-acetic acid), GA (Gibberellin), BR (Brassinosteroid) and ETH (Ethylene) were beneficial to early embryonic morphogenesis, while CTK (Cytokinin) and ABA (Abscisic Acid) promoted embryo morphogenesis and maturation. The antioxidant enzymes' activity was the highest in early embryos and an important participant in embryo formation. The high expression of the genes encoding fatty acid desaturase was beneficial to fast oil accumulation. Representative DEGs were selected and validated using qRT-PCR. Protein-protein interaction network (PPI) was predicted, and six central node proteins, including AUX1, PIN1, ARF6, LAX3, ABCB19, PIF3, and PIF4, were screened. Our results provided new insights into the formation of embryo development and even somatic embryo development in tree peonies.
Topics: Humans; Transcriptome; Paeonia; Antioxidants; Gene Expression Profiling; Embryonic Development; Gene Expression Regulation, Plant; NIMA-Interacting Peptidylprolyl Isomerase
PubMed: 37445891
DOI: 10.3390/ijms241310715 -
Mechanisms of nuclear pore complex disassembly by the mitotic Polo-like kinase 1 (PLK-1) in embryos.Science Advances Jul 2023The nuclear envelope, which protects and organizes the genome, is dismantled during mitosis. In the zygote, nuclear envelope breakdown (NEBD) of the parental pronuclei...
The nuclear envelope, which protects and organizes the genome, is dismantled during mitosis. In the zygote, nuclear envelope breakdown (NEBD) of the parental pronuclei is spatially and temporally regulated during mitosis to promote the unification of the maternal and paternal genomes. Nuclear pore complex (NPC) disassembly is a decisive step of NEBD, essential for nuclear permeabilization. By combining live imaging, biochemistry, and phosphoproteomics, we show that NPC disassembly is a stepwise process that involves Polo-like kinase 1 (PLK-1)-dependent and -independent steps. PLK-1 targets multiple NPC subcomplexes, including the cytoplasmic filaments, central channel, and inner ring. PLK-1 is recruited to and phosphorylates intrinsically disordered regions (IDRs) of several multivalent linker nucleoporins. Notably, although the phosphosites are not conserved between human and nucleoporins, they are located in IDRs in both species. Our results suggest that targeting IDRs of multivalent linker nucleoporins is an evolutionarily conserved driver of NPC disassembly during mitosis.
Topics: Animals; Humans; Nuclear Pore; Caenorhabditis elegans; Nuclear Pore Complex Proteins; Caenorhabditis elegans Proteins; Polo-Like Kinase 1
PubMed: 37467327
DOI: 10.1126/sciadv.adf7826 -
International Journal of Molecular... Jul 2023Zinc finger and SCAN domain-containing 4 (), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells,...
Zinc finger and SCAN domain-containing 4 (), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells, including maintaining genomic stability and defying cellular senescence. However, the effect of in porcine parthenogenetic embryos remains unclear. To investigate the function of and the underlying mechanism in porcine embryo development, was knocked down via dsRNA injection in the one-cell stage. was highly expressed in the four- and five- to eight-cell stages in porcine embryos. The percentage of four-cell stage embryos, five- to eight-cell stage embryos, and blastocysts was lower in the knockdown group than in the control group. Notably, depletion of induced the protein expression of and 5-Methylcytosine (5mC, a methylated form of the DNA base cytosine) in the four-cell stage. The H3K27ac level and ZGA genes expression decreased following knockdown. Furthermore, knockdown led to DNA damage and shortened telomere compared with the control. Additionally, -dsRNA was injected to reduce DNA hypermethylation in knockdown embryos. knockdown rescued telomere shortening and developmental defects caused by knockdown. In conclusion, is involved in the regulation of transcriptional activity and is essential for maintaining telomere length by regulating expression in porcine ZGA.
Topics: Animals; Mice; Swine; Transcription Factors; Telomere; Telomere Shortening; DNA-Binding Proteins; Zygote; Embryonic Development; Gene Expression Regulation, Developmental
PubMed: 37569497
DOI: 10.3390/ijms241512121