ZAR1/2-regulated Histone Modifications are Required for Zygotic Activation and Age-associated Oocyte Quality Maintenance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1149704 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30295420_1.fastq.gz | Fastqsanger.gz | |||
| SRR30295420_2.fastq.gz | Fastqsanger.gz | |||
| SRR30295421_1.fastq.gz | Fastqsanger.gz | |||
| SRR30295421_2.fastq.gz | Fastqsanger.gz | |||
| SRR30295422_1.fastq.gz | Fastqsanger.gz |
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Project description:The developmental competence and epigenetic progression of oocytes gradually become dysregulated with increasing maternal age. However, the mechanisms underlying age-related epigenetic regulation in oocytes remain poorly understood. Zygote arrest proteins 1 and 2 (ZAR1/2) are two maternal factors with redundant roles in maintaining oocyte quality. Here, we found that Zar1/2-deleted oocytes exhibited reduced levels of multiple histone modifications and of the corresponding histone modifiers, along with over-condensed chromatin, leading to disordered histone modification, compromised zygotic genome activation and deficient embryo development following fertilisation. Cytoplasmic ZAR1/2 participated in intranuclear epigenetic maturation by binding to the transcripts that encoding histone modifiers in oocytes, and regulating their stability and translational activity. Moreover, oocytes from older mice exhibited similar histone-modification deficiency to Zar1/2-deleted oocytes. In contrast, forced ZAR1/2 expression in aged mouse oocytes partially restored histone modifications. ZAR1/2 mRNA and protein levels were lower in oocytes from older mice and in those from older women, suggesting ZAR1/2 as regulators of aging-associated epigenetic disorganizations. This study presents a new nucleo-ooplasmic interaction mechanism that is vital for oocyte epigenetic maturation and declining of developmental potentials with female aging. Further, it provides the potential gene targets for diagnosis and clinical intervention in age-associated deficiency in oocyte and embryo development.
2025-03-05 | GSE275156 | GEO
Project description:The developmental competence and epigenetic progression of oocytes gradually become dysregulated with increasing maternal age. However, the mechanisms underlying age-related epigenetic regulation in oocytes remain poorly understood. Zygote arrest proteins 1 and 2 (ZAR1/2) are two maternal factors with partially redundant roles in maintaining oocyte quality, mainly known by regulating mRNA stability. In addition to this known function, it is found that ZAR1/2 is required for oocyte epigenetic maturation and zygotic reprogramming. Zar1/2-deleted oocytes exhibited reduced levels of multiple histone modifications and of the expression of corresponding histone modifiers, along with over-condensed chromatin, leading to compromised minor zygotic genome activation and deficient embryo development following fertilization. Cytoplasmic ZAR1/2 participated in intranuclear epigenetic maturation by binding the transcripts encoding histone modifiers and regulating their stability and translational activity. Moreover, oocytes from aged mice exhibited similar histone-modification deficiencies as the Zar1/2-deleted oocytes. ZAR1/2 mRNA and protein levels are downregulated in oocytes from mice and women with advanced ages, suggesting ZAR1/2 as regulators of epigenetic changes with reproductive aging. This study presents a new nucleo-cytoplasmic interaction mechanism that is involved in preventing oocyte epigenetic aging. Further, ZAR1/2 represents potential gene targets for diagnosis and clinical interventions in age-associated deficiencies in oocyte and embryo development.
| S-EPMC11848533 | biostudies-literature
Project description:Zar1 was the first mammalian maternal-effect gene to be identified. Embryos derived from Zar1-null female mice are blocked before zygotic genome activation; however, the underlying mechanism remains unclear. By knocking out Zar1 and its homolog Zar2 in mice, we revealed a novel function of these genes in oocyte meiotic maturation. Zar1/2-deleted oocytes displayed delayed meiotic resumption and polar body-1 emission and a higher incidence of abnormal meiotic spindle formation and chromosome aneuploidy. The grown oocytes of Zar1/2-null mice contained fewer total mRNAs and displayed a reduced level of protein synthesis. Key maturation-associated changes failed to occur in the Zar1/2-null oocytes, including the translational activation of maternal mRNAs encoding the cell cycle proteins cyclin B1 and WEE2, as well as maternal-to-zygotic transition (MZT) licensing factor BTG4. Consequently, maternal mRNA decay was impaired and MZT was abolished. ZAR1/2 bound mRNAs to regulate the translational activity of their 3ʹ-UTRs and interacted with other oocyte proteins, including mRNA-stabilizing protein MSY2 and cytoplasmic lattice components. These results countered the traditional view that ZAR1 only functions after fertilization and highlight a previously unrecognized role of ZAR1/2 in regulating the maternal transcriptome and translational activation in maturing oocytes.
2019-09-25 | GSE135787 | GEO
Project description:Zygotic arrest 1 (ZAR1) is one of the earliest identified maternal-effect genes that function during the maternal-to-zygotic transition (MZT) in mice. However, the role of human ZAR1 was unclear. This study investigated the association of ZAR1 gene variants and infertility in women, focusing on their impact on oocyte and early embryonic development. In five individuals with unexplained female infertility, defects in oocyte maturation and early embryonic arrest were observed during in vitro fertilization treatment. Whole-exon sequencing identified either homozygous or compound heterozygous variants of ZAR1 in the patients. Functional analysis revealed that the V118A mutation disrupted the localization of ZAR1 to the mitochondria-associated ribonucleoprotein domain (MARDO) structure, a key mRNA storage site in oocytes. In contrast, R397Q and S121* mutations impaired ZAR1’s RNA-binding capability. These variants disrupt MARDO formation and function, thereby negatively affecting oocyte maturation and early embryonic development. Additionally, transcriptome analysis of oocytes and embryos from ZAR1 variant carriers showed downregulation of maternal mRNAs and altered translation profiles, indicating a disrupted MZT. This study highlights the critical roles of ZAR1 and MARDO in human reproduction and provides insights into the molecular mechanisms underlying some forms of female infertility.
2025-03-01 | GSE261831 | GEO
Project description:We generated maternal and paternal mouse models with Yap1-deletion, and elucidated the function of maternal YAP in zygotic genome activation. RNA sequencing with 2 WT oocyte samples at GV stage, 2 YAP-/- oocyte samples at GV stage, 1 WT embryo samples at 4cell stage, 1 YAP-/- embryo samples at at 4-cell stage.
2016-02-28 | E-GEOD-74344 | biostudies-arrayexpress
Project description:Maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment of oocyte transits to the zygotic genome driven expression program, and terminally differentiated oocyte and sperm are reprogrammed to totipotency. It is initiated by maternal mRNAs and proteins during the period of zygotic genome quiescence after fertilization, followed by a gradual switch to zygotic genome activation and accompanied by clearance of maternal RNAs and proteins. A key question for embryonic development is how MZT process is regulated. Here we used a low-input proteomic analysis to measure the proteomic dynamics during early development of mouse maternal-to-zygotic transition.
2023-03-27 | PXD041023 | Pride
Project description:Mammalian oocyte maturation is driven by strictly translational regulation of maternal mRNAs stored in the cytoplasm. However, the function and mechanism of post-transcriptional chemical modifications especially the newly identified N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) in this process are previously unknown. In this study, we developed a low-input ac4C sequencing technology—ac4C LACE-seq and mapped 8241 ac4C peaks at the whole transcriptome level using 50 mouse oocytes at the germinal vesicle (GV) stage. We profiled the mRNA landscapes of NAT10-interactions and ac4C modifications. The NAT10-interacted and ac4C modified transcripts displayed association with high translation efficiency in oocytes. Oocyte-specific Nat10 knockout wiped out ac4C signals in oocytes and caused severe defects in meiotic maturation and female infertility. ac4C LACE-seq results indicated that Nat10 deletion led to a failure of ac4C deposition on mRNAs encoding key maternal factors such as MAY2, ZAR1, BTG4 and cyclin B1 that regulate transcriptome stability and maternal-to-zygotic transition. Nat10-deleted oocytes had decreased mRNA translation efficiencies during meiotic maturation, partially due to the direct inhibition ac4C sites on specific transcripts. In sum, we developed low-input, high-sensitivity mRNA ac4C profiling approach and highlighted the important physiological function of ac4C in precise regulation of the oocyte meiotic maturation by enhancing translation efficiency.
2024-02-18 | GSE254288 | GEO
Project description:Mammalian oocyte maturation is driven by strictly translational regulation of maternal mRNAs stored in the cytoplasm. However, the function and mechanism of post-transcriptional chemical modifications especially the newly identified N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) in this process are previously unknown. In this study, we developed a low-input ac4C sequencing technology - ac4C LACE-seq and mapped 8241 ac4C peaks at the whole transcriptome level using 50 mouse oocytes at the germinal vesicle (GV) stage. We profiled the mRNA landscapes of NAT10-interactions and ac4C modifications. The NAT10-interacted and ac4C modified transcripts displayed association with high translation efficiency in oocytes. Oocyte-specific Nat10 knockout wiped out ac4C signals in oocytes and caused severe defects in meiotic maturation and female infertility. ac4C LACE-seq results indicated that Nat10 deletion led to a failure of ac4C deposition on mRNAs encoding key maternal factors such as MAY2, ZAR1, BTG4 and cyclin B1 that regulate transcriptome stability and maternal-to-zygotic transition. Nat10-deleted oocytes had decreased mRNA translation efficiencies during meiotic maturation, partially due to the direct inhibition ac4C sites on specific transcripts. In sum, we developed low-input, high-sensitivity mRNA ac4C profiling approach and highlighted the important physiological function of ac4C in precise regulation of the oocyte meiotic maturation by enhancing translation efficiency.
2024-08-26 | GSE253976 | GEO
Project description:Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and is intimately related to changes of chromatin structure and histone modifications. Mono-ubiquitination of histone H2A at lysine-119 (H2AK119ub1), an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by polycomb repressive complex 1 (PRC1) and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated by chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes, enriched at the transcriptional start sequences (TSSs) of maternal genes, but was promptly removed after meiotic resumption, particularly at the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase of H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, andor meiotic maturation. However, oocytes lacking USP16 were unable to undergo zygotic genome activation or gain developmental competence after fertilization, due to high levels of H2AK119ub1 deposition on the zygotic genomes. Taken together, this study indicates that H2AK119ub1 is erased during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.
2022-06-05 | GSE154412 | GEO
Project description:Maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment of oocyte transits to the zygotic genome driven expression program, and terminally differentiated oocyte and sperm are reprogrammed to totipotency. Metaphase II (MII) oocytes and zygotes (one-cell embryo) serve as the mature oocyte and the initiation of pre-implantation embryo development respectively, and characterizing their molecular landscapes at protein levels plays an important role in uncovering MZT and zygotic genome activation (ZGA )in mammals. Here we used an ultrasensitive proteomic approach to depict an in-depth landscape for the very early stage of mouse MZT.
2023-05-23 | PXD041399 | Pride