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The Dominant Role of Polyadenylation in Regulating Maternal mRNA Dynamics in Dormant Oocytes and the Function of ZAR1 in this Process_LACE-seq

ABSTRACT: During the meiosis, the oocytes will keep dormant for a long time that the transcription will not be activated until zygotic genome activation (ZGA), thus the dynamic and homeostasis of maternal transcriptome deserved to be explored. In the previous researches, the maternal transcripts were reported to be drastically down-regulated by using Smart-seq2. However, we found out that the detection of Smart-seq2 can be biased by the polyA tail length of mRNAs due to the oligo-d(T) primer. In contrast, the down-regulation of maternal transcripts detected by total RNA-seq was relatively small, and the dynamic of polyA tail length were much acuter. ZAR1 is an RBP that had been reported to be important to stablize maternal mRNA. However, the differential expression of maternal transcripts in Zar1/2-/- oocytes were also different when detected by total RNA-seq and Smart-seq2, which hinted an interruption of polyadenylation. By combining total RNA-seq, LACE-seq, PAIso-seq2 and IP-MS and found out that ZAR1 may target the CDS of maternal transcripts and regulate its stability in GV stage oocytes and by interacting with other proteins to regulate the polyadenylation of mRNAs. In this research, by jointly analyzing multi-omics data, we discussed the limitation of Smart-seq2 on oocytes, reexplored the dynamic of maternal transcriptome and reported the new roles of ZAR1 on regulating maternal transriptome.

ORGANISM(S): Mus musculus

PROVIDER: GSE276330 | GEO | 2025/03/11

REPOSITORIES: GEO

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The Dominant Role of Polyadenylation in Regulating Maternal mRNA Dynamics in Dormant Oocytes and the Function of ZAR1 in this Process_total RNA-seq

Project description:During the meiosis, the oocytes will keep dormant for a long time that the transcription will not be activated until zygotic genome activation (ZGA), thus the dynamic and homeostasis of maternal transcriptome deserved to be explored. In the previous researches, the maternal transcripts were reported to be drastically down-regulated by using Smart-seq2. However, we found out that the detection of Smart-seq2 can be biased by the polyA tail length of mRNAs due to the oligo-d(T) primer. In contrast, the down-regulation of maternal transcripts detected by total RNA-seq was relatively small, and the dynamic of polyA tail length were much acuter. ZAR1 is an RBP that had been reported to be important to stablize maternal mRNA. However, the differential expression of maternal transcripts in Zar1/2-/- oocytes were also different when detected by total RNA-seq and Smart-seq2, which hinted an interruption of polyadenylation. By combining total RNA-seq, LACE-seq, PAIso-seq2 and IP-MS and found out that ZAR1 may target the CDS of maternal transcripts and regulate its stability in GV stage oocytes and by interacting with other proteins to regulate the polyadenylation of mRNAs. In this research, by jointly analyzing multi-omics data, we discussed the limitation of Smart-seq2 on oocytes, reexplored the dynamic of maternal transcriptome and reported the new roles of ZAR1 on regulating maternal transriptome.

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The Dominant Role of Polyadenylation in Regulating Maternal mRNA Dynamics in Dormant Oocytes and the Function of ZAR1 in this Process_PAIso-seq2

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ZAR1 and ZAR2 are Required for Oocyte Meiotic Maturation by Regulating the Maternal Transcriptome and mRNA Translational Activation

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.

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2022-10-25 | PXD036974 | Pride

Zygotic Arrest 1 Pathogenic Variants Disrupt Maternal mRNA Stability and Cause Oocyte Maturation Defects in Humans

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.

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Project description:In vertebrates, sexual reproduction depends on the precisely temporally controlled translation of mRNAs stockpiled in the oocyte. The RNA-binding proteins Zar1 and Zar2 have been implicated in translational control in oocytes of several vertebrate species, but how they act mechanistically is still incompletely understood. Here, we investigate the function of Zar1l, a so far uncharacterized member of the Zar protein family, in Xenopus laevis oocytes. By combining biochemical assays and mass spectrometry, we reveal that Zar1l is a constituent of a known large ribonucleoparticle containing the translation repressor 4E-T and the central polyadenylation regulator CPEB1. Employing TRIM-Away, we show that depletion of Zar1l from prophase-I arrested oocytes results in premature meiotic maturation upon hormone treatment. We provide evidence that this is based on the precocious expression of the kinase cMos, a key promotor of meiotic resumption. Based on our data, we propose a model according to which degradation of Zar1l results in dissociation of 4E-T from CPEB1, thus weakening translation inhibition imposed by the mRNA 3’UTR of cMos and probably also other M-phase promoting regulators. Thus, our detailed characterization of the function of Zar1l reveals novel mechanistic insights into the regulation of maternal mRNA translation during vertebrate meiosis.

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NAT10-mediated mRNA N4-acetylation is Essential for the Translational Regulation During Oocyte Meiotic Maturation in Mice

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.

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NAT10-mediated mRNA N4-acetylcytidine is Essential for the Translational Regulation of Oocyte Meiotic Maturation in Mice

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