bims-cebooc 2025-06-08 papers

bims-cebooc

Biomed News

on Cell biology of oocytes

Issue of 2025–06–08
twenty-two papers selected by
Gabriele Zaffagnini, Universität zu Köln

Maternal iron deficiency causes male-to-female sex reversal in mouse embryos.
MPS1 promotes timely spindle bipolarization to prevent kinetochore-microtubule attachment errors in oocytes.
GATAD2B regulates spindle assembly by affecting protein deacetylation during oocyte meiotic maturation.
Maternal loss of mouse Nlrp2 alters the transcriptome and DNA methylome in GV oocytes and impairs zygotic genome activation in embryos.
Basal autophagy during meiotic prophase I is required for accurate chromosome segregation in Drosophila oocytes and declines during oocyte aging.
Landscape and regulation of mRNA translation in the early C. elegans embryo.
Characterization of H3K4me3 in mouse oocytes at the metaphase II stage.
RNA Pol I activity maintains chromatin condensation and the H3K4me3 gradient essential for oogenesis, independent of ribosome production.
Inorganic profiles of preimplantation embryos reveal a role for zinc in blastocyst development.
A conserved triple arginine motif in OMA-1 is required for RNA-binding activity and embryo viability.
The lipid droplet protein Jabba promotes actin remodeling downstream of prostaglandin signaling during Drosophila oogenesis.
Spatiotemporal and single-cell atlases to dissect regional specific cell types of the developing ovary.
Oocyte mitochondria link maternal environment to offspring phenotype.
The RNA m6A landscape during human oocyte-to-embryo transition.
A novel mutation in ZP3 causes human ovulatory dysfunction and oocyte maturation arrest.
Dynamic revelation of early development in mouse embryo via Raman spectroscopy.
A Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary.
Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice.
Transitions in the proteome and phospho-proteome during Xenopus laevis development.
Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of ZDBF2.
Loss of FUT8 impairs embryonic development by reducing cAMP production in granulosa cells.
A Comprehensive Review of Mitochondrial Complex I During Mammalian Oocyte Maturation.

Nature. 2025 Jun 04.

Maternal iron deficiency causes male-to-female sex reversal in mouse embryos.

Naoki Okashita, Ryo Maeda, Shunsuke Kuroki, Kyona Sasaki, Yoko Uno, Peter Koopman, Makoto Tachibana.

Ferrous iron (Fe2+) is essential in all eukaryotic cells for various oxidoreductase reactions, including the demethylation of DNA and proteins. Histone demethylation is required for normal epigenetic regulation of the Y-chromosomal sex-determining gene Sry in developing gonads during male sex determination1,2. Here we investigate the potential connection between iron metabolism, histone demethylation and sex determination in mammals. We found that Fe2+-producing pathways are substantially activated in mouse embryonic gonads during the sex-determining period. Chelation of iron in cultured XY gonads reduced the level of KDM3A-mediated H3K9 demethylation of Sry, mostly abolished Sry expression and caused the gonads to express ovarian markers. In vivo, conditional deletion of the gene Tfrc-which is required for iron incorporation-in fetal XY gonadal somatic cells, or acute pharmaceutical suppression of available iron in pregnant mice, resulted in male-to-female gonadal sex reversal in a proportion of offspring, highlighting the pivotal role of iron metabolism in male sex determination. Finally, long-term feeding of pregnant mice with a low-iron diet, when combined with a heterozygous variant of Kdm3a that by itself has no observable effect, suppressed Sry expression and caused male-to-female sex reversal in some of the progeny, revealing a connection between maternal dietary iron and fetal developmental outcomes.

DOI: https://doi.org/10.1038/s41586-025-09063-2
EMBO J. 2025 Jun 04.

MPS1 promotes timely spindle bipolarization to prevent kinetochore-microtubule attachment errors in oocytes.

Shuhei Yoshida, Reiko Nakagawa, Kohei Asai, Tomoya S Kitajima.

  Incorrect kinetochore-microtubule attachment leads to chromosome segregation errors. The risk of incorrect attachment is high in acentrosomal oocytes, where kinetochores are surrounded by randomly oriented microtubules until spindle bipolarization. Regulation of the temporal relationship between acentrosomal spindle bipolarization and kinetochore-microtubule attachment is unknown. Here, we show that in mouse oocytes, MPS1, a kinase more active at kinetochores with less stable microtubule attachment, promotes timely spindle bipolarization before kinetochores stably attach to microtubules. In MPS1-inhibited oocytes, spindle bipolarization is delayed and depends on microtubules stably attached to kinetochores, resulting in incorrect attachments. We propose a two-step kinetochore-based model where unstable and stable attachment states act sequentially for acentrosomal spindle assembly to reduce the risk of egg aneuploidy.

Keywords:  Kinetochore; Microtubule; Oocyte; Spindle

DOI:  https://doi.org/10.1038/s44318-025-00461-w
Anim Biosci. 2025 Jun 04.

GATAD2B regulates spindle assembly by affecting protein deacetylation during oocyte meiotic maturation.

Qian Xu, Lina Yu, Yuling Lin, Aolei Guo, Yang Zhang, Zhe Zhang, Guijun Yan, Haixiang Sun, Guangyi Cao.

   Objective: Oocyte quality is critical for the stable transmission of genetic information and affects early embryonic development. But the precise mechanisms governing oocyte meiotic progression remains largely unclear. Transcription regulation through chromatin compaction and decompaction is regulated through various chromatin-remodeling complexes such as nucleosome remodeling and histone deacetylation (NuRD) complex. GATAD2B is known to be a component of the NuRD complex but whether GATAD2B regulates chromatin modification in mouse oocyte meiosis remains unclear. We hope to explore the role of GATAD2B in mouse oocyte meiosis.
Methods: In this study, we initially utilized western blot and immunofluorescence to delineate the expression and subcellular localization of GATAD2B during oocyte meiotic maturation. To further elucidate the role of GATAD2B in regulating oocyte meiotic division, we employed the method of microinjection of Gatad2b-specific siRNA to knock down the protein expression of GATAD2B. Subsequently, dynamic changes in oocyte meiotic division were captured in real-time using live-cell imaging with Geri. Additionally, spindle staining, DNA staining, spread analysis, and reanalysis of RNA-seq data were performed to investigate the mechanisms through which GATAD2B regulates oocyte meiotic division.
Results: GATAD2B was stably expressed during oocyte meiosis and was significantly increased during the MII stage. To further explore the effect of GATAD2B on oocyte meiotic maturation, we observed increased abnormal spindle, severe chromosome misalignment and MI block in GATAD2B knocked-down oocytes. Interestingly, the distribution of microtubule organizing center was abnormal and aneuploidy was significantly increased in Gatad2b-KD oocytes. In addition, some deacetylation-related genes were significantly downregulated and acetylated proteins accumulated abnormally in Gatad2b-KD oocytes.
Conclusion: These findings implicate GATAD2B as a novel regulator of histone deacetylation during oocyte maturation and provide evidence that such deacetylation is required for proper spindle assembly.

Keywords:  GATAD2B; Oocyte; deacetylation; meiosis; spindle

DOI:  https://doi.org/10.5713/ab.25.0013
Clin Epigenetics. 2025 Jun 03. 17(1): 92

Maternal loss of mouse Nlrp2 alters the transcriptome and DNA methylome in GV oocytes and impairs zygotic genome activation in embryos.

Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van den Veyver.

   BACKGROUND: NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.
RESULTS: We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the transcriptome of GV oocytes and 2-cell embryos from WT and Nlrp2-null females. The absence or reduction of NLRP2 did not alter the distinctive global DNA methylation landscape of GV oocytes, including their unique bimodal methylome patterns and methylation at the germline differentially methylated regions (gDMRs) of imprinted genes. However, altered methylation was observed in a small subset of oocyte-characteristic hyper- and hypomethylated domains and within a minor fraction of genomic regions, particularly in Nlrp2-null oocytes. Transcriptome profiling revealed substantial differences between the Nlrp2-null and WT GV oocytes, including deregulation of many crucial factors involved in oocyte transcriptome modulation and epigenetic reprogramming. Moreover, maternal absence of NLRP2 significantly altered the transcriptome of heterozygous embryos from Nlrp2-null females compared to WT embryos, whereas the transcriptome of heterozygous embryos from Nlrp2-null males was not significantly different from that of WT embryos. Maternal absence of NLRP2 also negatively impacted MZT, as evidenced by the deregulation of a large subset of zygotic genome activation (ZGA)-related genes.
CONCLUSIONS: This study demonstrates that NLRP2 is essential for shaping the transcriptome of GV oocytes and preimplantation embryos. Maternal loss of Nlrp2 negatively impacts ZGA. Our findings that the DNA methylome of Het and Nlrp2-null oocytes was subtly changed, and that gene-body DNA methylation differences did not correlate with gene expression differences, suggest that posttranscriptional changes in transcript stability, rather than altered transcription itself, are primarily responsible for the changed transcriptome of Nlrp2-null oocytes.

Keywords:  DNA methylation; Imprinted genes; Oocyte; Subcortical maternal complex

DOI:  https://doi.org/10.1186/s13148-025-01889-x
bioRxiv. 2025 May 14. pii: 2025.05.13.653863. [Epub ahead of print]

Basal autophagy during meiotic prophase I is required for accurate chromosome segregation in Drosophila oocytes and declines during oocyte aging.

Diana C Hilpert, Muhammad Abdul Haseeb, Sharon E Bickel.

Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of sister chromatid cohesion. However, the mechanisms underlying age-dependent deterioration of cohesion are not well-defined. Autophagy, a cellular degradation process critical for cellular homeostasis, is known to decline with age in various organisms and cell types. Here we quantify basal autophagy in Drosophila oocytes and use GAL4/UAS inducible knockdown to ask whether disruption of autophagy in prophase oocytes impacts the fidelity of chromosome segregation. We find that individual knockdown of autophagy proteins in Drosophila oocytes during meiotic prophase causes a significant increase in segregation errors. In addition, Atg8a knockdown in prophase oocytes leads to premature loss of arm cohesion and missegregation of recombinant homologs during meiosis I. Using an oocyte aging paradigm that we have previously described, we show that basal autophagy decreases significantly when Drosophila oocytes undergo aging. Our data support the model that a decline in autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors.

DOI: https://doi.org/10.1101/2025.05.13.653863
Cell Rep. 2025 May 30. pii: S2211-1247(25)00549-2. [Epub ahead of print]44(6): 115778

Landscape and regulation of mRNA translation in the early C. elegans embryo.

Yash Shukla, Vighnesh Ghatpande, Cindy F Hu, Daniel J Dickinson, Can Cenik.

  Animal embryos rely on regulated translation of maternally deposited mRNAs to drive early development. Using low-input ribosome profiling combined with RNA sequencing on precisely staged embryos, we measure mRNA translation during the first four cell cycles of C. elegans development. We uncover stage-specific patterns of developmentally coordinated translational regulation. Our results confirm that mRNA localization correlates with translational efficiency, though initial translational repression in germline precursors occurs before P-granule association. Our analysis suggests that the RNA-binding protein OMA-1 represses the translation of its target mRNAs in a stage-specific manner while indirectly promoting the translational efficiency of other transcripts. These findings illuminate how post-transcriptional mechanisms shape the embryonic proteome to direct cell differentiation, with implications for understanding similar regulation across species where maternal factors guide early development.

Keywords:  C. elegans; CP: Developmental biology; CP: Molecular biology; OMA-1; P granules; Ribo-ITP; cell fate determination; embryogenesis; mRNA translation; maternal transcripts; post-transcriptional control; ribosome profiling; translational regulation

DOI:  https://doi.org/10.1016/j.celrep.2025.115778
J Biol Chem. 2025 May 29. pii: S0021-9258(25)02158-1. [Epub ahead of print] 110308

Characterization of H3K4me3 in mouse oocytes at the metaphase II stage.

Atsushi Takasu, Toshiaki Hino, Osamu Takenouchi, Yasuki Miyagawa, Zhihua Liang, Shota Tanaka, Tomoya Mimura, Chisato Ida, Yuki Matsuo, Yuna Lee, Haruka Ikegami, Miho Ohsugi, Shogo Matoba, Atsuo Ogura, Kazuo Yamagata, Kazuya Matsumoto, Tomoya S Kitajima, Kei Miyamoto.

  Central functions of histone modifications in germ cell and embryonic development have been documented. Accumulating evidence suggests that oocytes possess unique profiles of histone modifications, among which histone H3 lysine 4 trimethylation (H3K4me3) is broadly spread on the mouse oocyte chromosomes at the metaphase II (MII) stage, unlike later embryonic stages. However, the characteristics and developmental roles of H3K4me3 on MII chromosomes are unclear. Here, we discovered that H3K4me3 was abundantly localized on some of the MII oocyte chromosomes facing the cortical side. Using multicolor FISH and CRISPR-Sirius-based labeling of chromosomes, we revealed that the X chromosome tended to be localized at the cortical side with strong H3K4me3 signals. Anchoring oocyte chromosomes to the cortex may play a role in the asymmetric H3K4me3 distribution. Furthermore, we found that the forced removal of H3K4me3 through the overexpression of a specific lysine demethylase in MII oocytes resulted in abnormal chromosome-spindle structure and impaired preimplantation development after in vitro fertilization. These findings highlight the developmental function of H3K4me3 in transcriptionally-silent MII oocytes.

Keywords:  Chromosome; H3K4me3; Mouse; Oocyte; Pre-implantation development

DOI:  https://doi.org/10.1016/j.jbc.2025.110308
bioRxiv. 2025 May 12. pii: 2025.05.07.652530. [Epub ahead of print]

RNA Pol I activity maintains chromatin condensation and the H3K4me3 gradient essential for oogenesis, independent of ribosome production.

Raquel Mejia-Trujillo, Qiuxia Zhao, Ayesha Rahman, Elif Sarinay Cenik.

Oogenesis requires extensive and dynamic chromatin remodeling that primes gene promoters for later transcriptional activation during embryonic development. Here, we uncover a pivotal, non-canonical role for RNA Polymerase I (Pol I) in driving these chromatin state transitions during Caenorhabditis elegans oogenesis. Using the auxin-inducible degron system to selectively deplete either a Pol I-specific catalytic subunit or a ribosome assembly factor, we disentangle the consequences of impaired nucleolar integrity from reductions in ribosome biogenesis. Strikingly, although disrupting ribosome assembly caused minimal effects on oocyte production, loss of nucleolar structure via Pol I depletion led to severe meiotic chromosome abnormalities, widespread changes in chromatin accessibility, and a dampening of the typical distal-proximal H3K4me3 gradient required for oogenesis, resulting in fewer but significantly larger oocytes. Despite their promoters becoming more accessible, oogenesis genes did not show large changes in steady-state mRNA, consistent with transcriptional repression prior to fertilization. Instead, Pol I depletion prematurely remodeled oogenic chromatin, through a misdirection of H3K4me3 deposition towards promoters normally primed for zygotic genome activation. These findings reveal an epigenetic gating function for nucleolar integrity in oocyte maturation: Pol I preserves three-dimensional chromatin organization and maintains proper spatiotemporal regulation of histone modifications, independent of ribosome production. Given the evolutionary conservation of nucleolar dynamics and histone modifications during gametogenesis, our work suggests that nucleolar stress, whether from environmental factors, aging, or genetic disorders, could broadly compromise fertility by disrupting oogenic chromatin priming.

DOI: https://doi.org/10.1101/2025.05.07.652530
bioRxiv. 2025 May 18. pii: 2025.05.14.654061. [Epub ahead of print]

Inorganic profiles of preimplantation embryos reveal a role for zinc in blastocyst development.

Julia L Balough, Thomas V O'Halloran, Francesca E Duncan, Teresa K Woodruff.

Elements such as iron, copper and zinc play essential roles in the mammalian oocyte, egg, and embryo, however among these metals, zinc plays unique regulatory roles. Temporal fluctuations in zinc concentrations drive reproductive milestones such as meiotic resumption, egg activation, and initiation of the mitotic cell cycle. Roles for zinc in late preimplantation embryo development, have not been well characterized. Using a quantitative element approach we report the inorganic profiles of mouse embryos progressing through the late blastocyst stage. We find that blastocysts, like oocytes and eggs, and distinct to somatic cells, maintain higher levels of zinc than copper and iron. All three of these essential metals are more abundant in the inner cell mass, which contains the population of pluripotent stem cells that give rise to the fetus, relative to the trophectoderm which gives rise to the placenta and extraembryonic tissues. To test whether zinc abundance was associated with mitotic progress and cell fate lineage, we perturbed zinc homeostasis during blastocyst formation by artificially raising intracellular zinc concentrations with zinc pyrithione. This treatment during the morula-to-blastocyst transition when cell fate lineages emerge resulted in an elevation of zinc in the ICM. This treatment did not impact cell number, but did increase expression of the pluripotency and epiblast marker, Nanog , and decreased expression of the primitive endoderm marker, Gata4 . These results demonstrate that the inorganic profiles of the late preimplantation embryo retain elemental hallmarks of earlier developmental stages and perturbation of zinc levels alters pluripotency gene expression in the blastocyst.

DOI: https://doi.org/10.1101/2025.05.14.654061
bioRxiv. 2025 May 12. pii: 2025.05.09.653132. [Epub ahead of print]

A conserved triple arginine motif in OMA-1 is required for RNA-binding activity and embryo viability.

Asli Ertekin, Sharon T Noronha, Christable Darko, Francesca Massi, Sean P Ryder.

Sexually reproducing organisms make haploid gametes-oocytes and spermatocytes-that combine during fertilization to make an embryo. While both gametes contain similar DNA content, oocytes contain the bulk of the cytoplasm including maternally supplied mRNAs and proteins required prior to zygotic gene activation. RNA-binding proteins are key regulators of these maternal transcripts. In Caenorhabditis elegans , the tandem zinc finger proteins OMA-1 and OMA-2 are required for fertilization. Here, we show that OMA-1 RNA-binding activity requires a short basic region immediately up-stream from the canonical tandem zinc finger domain. Mutation of this region in animals produces a phenotype distinct from a genetic null. Oocytes can be fertilized, but fail to form an intact chitin egg-shell, frequently break in utero, and arrest prior to morphogenesis. Our results identify a critical region outside of the canonical RNA-binding domain required for both RNA-binding activity as well as revealing a new role for OMA-1 during the oocyte-to-embryo transition.

DOI: https://doi.org/10.1101/2025.05.09.653132
bioRxiv. 2025 May 13. pii: 2025.05.09.653087. [Epub ahead of print]

The lipid droplet protein Jabba promotes actin remodeling downstream of prostaglandin signaling during Drosophila oogenesis.

Jonathon M Thomalla, Michelle S Giedt, Roger P White, Israel J Wipf, Alicia Shipley, Michael A Welte, Tina L Tootle.

Growing evidence supports that lipid droplets (LDs) are critical for producing high-quality oocytes. However, the functions of LDs during oocyte development remain largely unknown. Using Drosophila oogenesis as a model, we previously discovered the LD-associated Adipose Triglyceride Lipase (ATGL) promotes actin remodeling necessary for oocyte development by providing the substrate for producing lipid signals termed prostaglandins (PGs). Here we find that Jabba, a LD-associated protein best known for its role in anchoring other proteins to LDs, also promotes PG-dependent actin remodeling. Overexpression of Jabba results in thickened cortical actin and excessive actin bundles, whereas loss of Jabba results in cortical actin breakdown and severely defective actin bundle formation. We find that Jabba regulates actin remodeling independently of ATGL but in conjunction with PG signaling. These data support that there are two PG signaling pathways that promote actin remodeling: one PG pathway that is dependent on ATGL and the other requires Jabba. Overexpression of Jabba rescues the actin defects when PG signaling is lost. Together these data lead to the model that PGs produced independently of ATGL positively regulate Jabba to promote actin remodeling necessary for follicle morphogenesis and the production of a fertilization competent oocyte.
Significance statement: Across organisms, lipid droplets accumulate during oocyte development and are implicated in fertility. The functions of lipid droplets during oogenesis are poorly understood.The authors use the genetic tools and well-characterized process of Drosophila oogenesis to reveal that Jabba, a lipid droplet anchoring protein, is a new downstream effector of prostaglandin signaling and promotes actin remodeling necessary for producing a fertilization competent oocyte.The results extend prior studies connecting lipid droplet proteins, prostaglandins, and actin remodeling, providing insight into how these critical conserved factors contribute to high-quality oocytes.

DOI: https://doi.org/10.1101/2025.05.09.653087
Commun Biol. 2025 Jun 03. 8(1): 849

Spatiotemporal and single-cell atlases to dissect regional specific cell types of the developing ovary.

Zheng-Hui Zhao, Tie-Gang Meng, Xue-Ying Chen, Fei Gao, Heide Schatten, Xiang-Hong Ou, Qing-Yuan Sun.

Characterization of cellular heterogeneity and molecular diversity greatly enhances our understanding of the ovary differentiation process. However, regional specification remains largely unexplored during ovary development. Here, we combine spatial transcriptomics and single-cell RNA sequencing to build a spatiotemporal developmental atlas of ovaries from the fetal stage through adulthood. We construct the developmental trajectory of female germ cells and identify key genes essential for primordial follicle assembly. Specifically, we characterize the regional heterogeneity of granulosa cell subtypes contributing to the folliculogenesis, and analyze the molecular distinctions between healthy and atretic follicles. Notably, we discover that Onecut2-positive luteal cells exhibit a specific spatial distribution. Furthermore, lineage tracing reveals that these Onecut2-positive luteal cells originate from Foxl2-positive granulosa cells and Cyp17a1-positive theca cells. Collectively, this study provides a comprehensive delineation of ovary development and regional specificity of ovarian cell types.

DOI: https://doi.org/10.1038/s42003-025-08277-4
bioRxiv. 2025 May 16. pii: 2025.05.13.653493. [Epub ahead of print]

Oocyte mitochondria link maternal environment to offspring phenotype.

Jason F Cooper, Kim Nguyen, Darrick Gates, Emily Wolfrum, Colt Capan, Hyoungjoo Lee, Devia Williams, Chidozie Okoye, Kelsie Nauta, Ximena Sanchez-Avila, Ryan T Kelly, Ryan Sheldon, Andrew P Wojtovich, Nicholas O Burton.

During oogenesis and maturation oocytes undergo a recently discovered mitochondrial electron transport chain (ETC) remodeling in flies 1 , frogs 1 , and humans 2 . This conserved oocyte ETC remodeling is regulated by maternal insulin signaling, but its role in biology remains unclear. In the model animal Caenorhabditis elegans , we previously found that insulin signaling to oocytes regulates offspring's ability to adapt to future osmotic stress by altering offspring metabolism. However, the molecular mechanisms that function in oocytes to mediate this intergenerational stress response are similarly unknown. Here, we developed a low-input oocyte proteomics workflow and combined it with our C. elegans intergenerational stress response model to find that both a mother's environment and maternal insulin signaling regulate the abundance of ETC proteins in oocytes - particularly the abundance of proteins involved in the transfer of electrons from QH 2 to cytochrome C by ETC Complex III. Using genetic perturbations of ETC function we further found that promoting ETC Complex III function in oocytes was both necessary and sufficient to link a mother's environment to adaptive changes in offspring metabolism. Lastly, we found that the effects of Complex III dysfunction in oocytes on offspring were mediated via an AMP-kinase (AAK-2) dependent mechanism and that AAK-2 functions in offspring to promote ATP preservation and glycerol metabolism in response to stress. Collectively, our data suggest that the role of oocyte ETC remodeling in biology includes linking maternal environments to changes in offspring metabolism that promote offspring survival in the environment experienced by their mother.

DOI: https://doi.org/10.1101/2025.05.13.653493
EMBO J. 2025 Jun 04.

The RNA m6A landscape during human oocyte-to-embryo transition.

Yanjiao Li, Yunhao Wang, Aylin Cengiz, Kang-Xuan Jin, Blanca Corral Castroviejo, Xiaolin Lin, Marie Indahl, Rujuan Zuo, Trine Skuland, Madeleine Fosslie, Maria Biba, Xuechen Wu, Peter Fedorcsak, Magnar Bjørås, Adam Filipczyk, John Arne Dahl, Gareth D Greggains, Kin Fai Au, Arne Klungland.

  RNA N6-methyladenosine (m6A, m6A) modification is a critical regulator for a range of physiological processes. However, the dynamic m6A profiles within human preimplantation embryos remain uncharacterized. Here, we present the first RNA m6A landscape of single human oocytes and early embryos. Comparative analyses with mouse data reveal an intriguing divergence during the window of zygotic genome activation. m6A-modified genes are involved in regulation of gene transcription, while unmodified genes are mainly associated with basic metabolic processes. Maternal decay mRNAs exhibit a propensity for m6A modifications, and these genes are targeted by miRNAs. m6A modified genes that are constantly expressed across all stages demonstrate higher translation efficiency. Moreover, we observe frequent m6A enrichment on stage-specifically expressed retrotransposons, particularly within young subfamilies. m6A inhibitor leads to m6A erasure on massive retrotransposons. In summary, this study provides a resource to broaden our understanding about the regulatory roles of m6A during early human embryo development.

Keywords:  Human Early Embryos; Retrotransposons; Zygotic Genome Activation; m6A

DOI:  https://doi.org/10.1038/s44318-025-00474-5
J Ovarian Res. 2025 Jun 02. 18(1): 117

A novel mutation in ZP3 causes human ovulatory dysfunction and oocyte maturation arrest.

Yingxue Liu, Guanghui Yuan, Yameng Hui, Xiaoxiao Wang, Jiashan Li, Jiao Zhuang, Huaiqian Dou, Linfang Han, Duan Li, Cuifang Hao.

   BACKGROUND: Ovulatory dysfunction and oocyte maturation arrest are among the common causes of female infertility, but the genetic etiology of these phenotypes is not well understood. The ZP3 gene is responsible for coding the oocyte zona pellucida (ZP), and ZP3 mutation clinically manifests as abnormal zona pellucida or empty follicle syndrome. Nevertheless, its role in the process of ovulation and maturation of oocytes has rarely been reported.
CASE PRESENTATION: In our study, we performed whole-exome sequencing in a 26-year-old proband with ovulatory dysfunction and oocyte maturation arrest, and we identified a novel heterozygous mutation in ZP3 (NM_001110354.1: c. 662 C > T, p.Pro221Leu), which is located within the ZP domain. The effects of the mutation were investigated through in vitro studies in HeLa cells, which revealed that the mutation resulted in a significant decrease in ZP3 protein levels. Additionally, the maturity of oocytes obtained from the patient with ZP3 mutation was significantly improved through the dual trigger treatment protocol, and the proband ultimately had a successful live birth.
CONCLUSIONS: Our findings expanded the pathogenetic spectrum of the ZP3 gene, which provided insights for treating patients with ovulatory dysfunction and oocyte maturation arrest related to ZP3 mutations.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:   ZP3 mutation; Dual trigger; Oocyte maturation arrest; Ovulatory dysfunction; Whole-exome sequencing

DOI:  https://doi.org/10.1186/s13048-025-01706-2
Spectrochim Acta A Mol Biomol Spectrosc. 2025 Dec 05. pii: S1386-1425(25)00781-4. [Epub ahead of print]342 126475

Dynamic revelation of early development in mouse embryo via Raman spectroscopy.

Chenwei He, Shan Huang, Runxin Yi, Jun Zhang, Nan Yan, Lingyin Kong, Kaidi Yu, Qingkai Guo, FangFang Dong, Bo Liang, Shuai Zhou, Junqiang Zhang.

  Non-invasive embryo quality assessment techniques in clinical practice remain in early developmental phase, highlighting the critical need to expand technical methods and improve evaluation accuracy.This study applies Raman spectroscopy to characterize glucose and lipid metabolic profiles during the early development of mouse embryos, aiming to explore the possibility of both as biomarkers for non-invasive assessment of embryo quality. Through semi-quantitative analysis, this research demonstrate that the average glucose metabolism remains relatively stable from Day 0 to 3 post conception (D0-3), followed by a significant increase in consumption around D3, and robust metabolic activity during D4-D5. The study also confirms the pivotal role of glucose metabolism in facilitating blastocyst formation. Additionally, Raman imaging was employed to visualize distribution of structural components and the dynamic lipid metabolism changes across 1-cell, 2-cell, and 4-cell stages, providing novel insights into quantitative lipidomic analysis of early embryos.

Keywords:  Glucose metabolism; Lipid metabolism; Non-invasive embryo quality assessment; Raman Spectroscopy

DOI:  https://doi.org/10.1016/j.saa.2025.126475
Aging Cell. 2025 Jun 01. e70111

A Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary.

Pooja Raj Devrukhkar, Mark A Watson, Bikem Soygur, Fei Wu, Joanna Bons, Hannah Anvari, Tomiris Atazhanova, Nicolas Martin, Tommy Tran, Kevin Schneider, Jacob P Rose, Daniel Winer, Elisheva Shanes, Mary Ellen G Pavone, Judith Campisi, David Furman, Simon Melov, Birgit Schilling, Francesca E Duncan.

  A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary. We thus established a doxorubicin-induced model of cellular senescence to establish a "senotype" (gene/protein signature of a senescence cell state) for ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 h, followed by culture for up to 10 days in a doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins: Lumican, SOD2, MYH9, and Periostin were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging, inform biomarker development to identify, and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.

Keywords:  cellular senescence; explant tissues; ovarian aging; reproductive aging; senescence‐associated secretory phenotype SASP

DOI:  https://doi.org/10.1111/acel.70111
bioRxiv. 2025 May 23. pii: 2025.05.19.654918. [Epub ahead of print]

Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice.

Nehemiah S Alvarez, Pavla Brachova.

Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries. Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, mitochondrial genes were disproportionately affected. We highlight Ndufs4 , a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a truncated isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased ROS production. Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.
In brief: Reproductive aging is associated with changes in alternative splicing patterns in the mouse ovary. Our study identifies alterations in exon usage that may have altered protein function and important roles in ovarian physiology as well as in reproductive aging.

DOI: https://doi.org/10.1101/2025.05.19.654918
Dev Biol. 2025 Jun 02. pii: S0012-1606(25)00145-9. [Epub ahead of print]

Transitions in the proteome and phospho-proteome during Xenopus laevis development.

Elizabeth Van Itallie, Matthew Sonnett, Marian Kalocsay, Martin Wühr, Leonid Peshkin, Marc W Kirschner.

Vertebrate development from an egg to a complex multi-cell organism is accompanied by multiple phases of genome-scale changes in the repertoire of proteins and their post-translational modifications. While much has been learned at the RNA level, we know less about changes at the protein level. In this paper, we present a deep analysis of changes of ∼15,000 proteins and ∼11,500 phospho-sites at 11 developmental time points in Xenopus laevis embryos ranging from the stage VI oocyte to juvenile tadpole. We find that the most dramatic changes to the proteome occur during the transition to functional organ systems, which occurs as the embryo becomes a tadpole. At that time, the absolute amount of non-yolk protein increases two-fold, and there is a shift in the balance of expression from proteins regulating gene expression to receptors, ligands, and proteins involved in cell-cell and cell-environment interactions. Between the early and late tadpole, the median increase for membrane and secreted proteins is substantially higher than that of nuclear proteins. To begin to appreciate changes at the post-translational level, we have measured quantitative phospho-proteomic data across the same developmental stages. In contrast to the significant protein changes that are concentrated at the end of the time series, the most significant phosphorylation changes are concentrated in the very early stages of development. A clear exception are phosphorylations of proteins involved in gene expression: these increase just after fertilization, with patterns that are highly correlated with the underlying protein changes. To facilitate the interpretation of this unique phospho-proteome data set, we created a pipeline for identifying homologous human phosphorylations from the measured Xenopus phospho-proteome. Collectively, our data reveal multiple coordinated transitions in protein and phosphorylation profiles, reflecting distinct developmental strategies and providing an extensive resource to further explore developmental biology at the proteomic and phospho-proteomic levels.

DOI: https://doi.org/10.1016/j.ydbio.2025.05.022
Elife. 2025 Jun 02. pii: RP94502. [Epub ahead of print]13

Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of ZDBF2.

Hisato Kobayashi, Tatsushi Igaki, Soichiro Kumamoto, Keisuke Tanaka, Tomoya Takashima, So I Nagaoka, Shunsuke Suzuki, Masaaki Hayashi, Marilyn B Renfree, Manabu Kawahara, Shun Saito, Toshihiro Kobayashi, Hiroshi Nagashima, Hitomi Matsunari, Kazuaki Nakano, Ayuko Uchikura, Hiroshi Kiyonari, Mari Kaneko, Hiroo Imai, Kazuhiko Nakabayashi, Matthew Lorincz, Kazuki Kurimoto.

  The imprinted gene ZDBF2 is regulated through a unique mechanism involving a transient paternal transcript in early embryos, rather than persistent gametic DNA methylation. In humans and mice, this transcript-CMKLR2-AS (also known as GPR1-AS) or the long isoform of Zdbf2 (Liz/Zdbf2linc/Platr12)-arises from the unmethylated paternal allele and initiates secondary epigenetic marks that maintain ZDBF2 expression. Here, we investigate the evolutionary origin of this mechanism, and show that the first exon of human GPR1-AS overlaps with a MER21C long terminal repeat (LTR), a retrotransposon subfamily specific to Boreoeutherian mammals. Comparative analyses revealed that this MER21C insertion occurred in the common ancestor of Euarchontoglires, including primates, rodents, and rabbits. Although not annotated, the first exon of mouse Liz displays conserved features with the MER21C-overlapping exon in humans. In rabbit and nonhuman primate placentas, GPR1-AS orthologs with LTR-embedded first exons were also identified. In contrast, in non-Euarchontoglire mammals such as cow and tammar wallaby, ZDBF2 is biallelically expressed, suggesting absence of imprinting. These findings suggest that ZDBF2 imprinting emerged in Euarchontoglires via MER21C insertion. Together with our prior work on LTR-driven imprinting in oocytes, our findings demonstrate that post-fertilization activation of retrotransposons can also drive lineage-specific acquisition of imprinting.

Keywords:  LTR retrotransposon; RNA-seq; chromosomes; evolutionary biology; gene expression; genomic imprinting; human; mammalian evolution; mouse; placenta; rhesus macaque

DOI:  https://doi.org/10.7554/eLife.94502
J Assist Reprod Genet. 2025 Jun 05.

Loss of FUT8 impairs embryonic development by reducing cAMP production in granulosa cells.

Tiantong Wang, Zhiwei Zhang, Changduo Qu, Yanbin Shi, Shaobin Chen, Wenzhe Li, Ming Li.

   PURPOSE: In cases of impaired fertility, the quality of oocytes and their subsequent embryonic development following fertilization are critical concerns in clinical practice. Core fucosylation, catalyzed by fucosyltransferase 8 (FUT8), is a common N-glycosylation modification that plays a key role in cell proliferation and signal transduction. This study examines the role of core fucosylation in follicular regulation during oocyte development.
METHODS: Patients were categorized into two groups based on their embryo formation rates. Core fucosylation levels, catalyzed by FUT8, were assessed in serum and follicular fluid (containing granulosa cells). To investigate the molecular effects of FUT8 on oocyte quality, FUT8-knockdown human granulosa cells (KGN-KD), and ovaries from Fut8 gene knockout (Fut8-/-) mice were analyzed.
RESULTS: Core fucosylation levels were lower in patients with reduced blastocyst formation rates. FUT8 depletion led to decreased cAMP production following follicle-stimulating hormone (FSH) stimulation in both KGN-KD and the ovaries of Fut8-/- mice. Additionally, the expression of FIGLA (folliculogenesis-specific basic helix-loop-helix transcription factor) and other genes associated with embryonic development was downregulated in the ovaries of Fut8-/- mice. Oocytes from Fut8-/- mice exhibited abnormal zona pellucida formation and impaired embryonic development.
CONCLUSION: These findings indicate that FUT8 ablation may disrupt embryonic development post-fertilization by reducing FSH receptor (FSHR) signaling and downregulating FIGLA expression. The results suggest that core fucosylation is essential for female reproduction and oocyte quality.

Keywords:  Core fucosylation; Embryonic development; FSH signaling; FUT8; Female fertility; Granulosa cells; Oocyte quality

DOI:  https://doi.org/10.1007/s10815-025-03536-z
Genesis. 2025 Jun;63(3): e70017

A Comprehensive Review of Mitochondrial Complex I During Mammalian Oocyte Maturation.

Nazlican Bozdemir, Ceren Cakir, Ulas Topcu, Fatma Uysal.

  This review provides a comprehensive overview of Complex I during mammalian oocyte maturation. Complex I (NADH:ubiquinone oxidoreductase) is a crucial member of the electron transport chain and serves two principal functions during oxidative phosphorylation: NADH oxidation and proton pumping. It is located at the inner mitochondrial membrane and consists of 14 core and 31 accessory subunits that are necessary for its function and assembly. Moreover, Complex I is the primary site of reactive oxygen species (ROS) production among the different tissues. In light of the literature, it has been demonstrated that ROS and oxidative stress are significantly important among the various factors that can affect oocyte maturation. Factors such as malnutrition, alcohol use, obesity, PCOS, aging, and smoking are some of the common causes of infertility. Each one of them causes disruption in the equilibrium of the body's redox system and related with oxidative stress. During oocyte maturation, excessive ROS levels are associated with chromosomal errors and developmental insufficiency. In addition, excess oxidative stress adversely affects embryo growth and development and may cause fetal embryopathies with damage to macromolecules in the cytoskeleton. At this particular juncture, Complex I plays a key role in determining ROS production and the success of the oocyte maturation. This review evaluates mitochondrial Complex I's function, structure, and its crucial role during oocyte maturation.

Keywords:  ROS; complex I; mitochondria; oocyte maturation; oogenesis; oxidative stress

DOI:  https://doi.org/10.1002/dvg.70017