bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–12–21
ten papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Pre-marking chromatin with H3K4 methylation is required for accurate zygotic genome activation and development.
  2. The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.
  3. The 3D genome during germline development and meiosis.
  4. Hedgehog and Drosophila germ cell migration.
  5. High resolution multi-scale profiling of embryonic germ cell-like cell derivation reveals pluripotent state transitions in humans.
  6. Tatdn2 is required for DNA repair to safeguard genome stability in primordial germ cells.
  7. MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential.
  8. ZAR1 pathogenic variants disrupt maternal mRNA storage and cause oocyte maturation defects in humans.
  9. Senescence-Linked Fibrosis in the Aging Human Ovary Revealed by p16-Based Histological Profiling and Spatial Transcriptomics.
  10. Multi-omics atlas of ovarian cellular and molecular responses to diabetes.
  1. Nat Commun. 2025 Dec 19.
    Pre-marking chromatin with H3K4 methylation is required for accurate zygotic genome activation and development.
    Meghana S Oak, Marco Stock, Ana Janeva, Matthias Mezes, Antony M Hynes-Allen, Tobias Straub, Ignasi Forné, Andreas Ettinger, Stephan Hamperl, Axel Imhof, Jelle van den Ameele, Antonio Scialdone, Eva Hörmanseder.
      In vertebrate embryos, gene expression is first initiated at zygotic genome activation (ZGA). Maternally expressed transcription factors are essential for this process. However, it is unknown whether active chromatin modifications established in gametes are present in early embryos and contribute to ZGA and embryonic development. Here, we show that in Xenopus laevis, H3K4me3 occurs at common genomic loci in gametes, in transcriptionally quiescent pre-ZGA embryos, and in transcriptionally active ZGA embryos. These loci exhibit high H3K4me3 intensities and breadth, DNA hypomethylation, and elevated CpG content. We show that H3K4 methylation pre-marking is required for successful ZGA and development, including expression of the key ZGA transcription factor Pou5f3.2. We demonstrate that the H3K4 methyltransferase Cxxc1 ensures establishment of H3K4me3 and proper ZGA. These findings reveal a role for H3K4 methylation in defining active chromatin states in Xenopus laevis embryos and highlight its importance for accurate ZGA and embryonic development.
    DOI:  https://doi.org/10.1038/s41467-025-67692-7
  2. bioRxiv. 2025 Nov 28. pii: 2025.11.26.690476. [Epub ahead of print]
    The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.
    Haik V Varderesian, Juliet N Utaegbulam, Hannah E Brown, Beverly Ramirez, Melina Velcani, Sean P Ryder.
      During fertilization, haploid gametes combine to form a zygote. The male (sperm) and female (oocyte) gametes contribute a similar amount of DNA, but the oocyte contributes nearly all the cytoplasm. Oocytes are loaded with maternal mRNAs thought to be essential for embryonic patterning after fertilization. A conserved suite of RNA-binding proteins (RBPs) regulates the spatiotemporal translation and stability of maternal mRNAs. POS-1 is a CCCH-type tandem zinc finger RBP expressed in fertilized Caenorhabditis elegans zygotes from maternally supplied mRNA. POS-1 accumulates in the posterior of the embryo where it promotes posterior cell fate. Here, we show that the pos-1 3' untranslated region (UTR) is essential for POS-1 patterning and contributes to maximal reproductive fecundity. We engineered a pos-1 mutant where most of the endogenous pos-1 3'UTR was removed using CRISPR genome editing. Our results show that the 3'UTR represses POS-1 expression in the maternal germline but increases POS-1 protein levels in embryos after fertilization. In a wild-type background, POS-1 repression via the 3'UTR has little impact on fertility. In a sensitized background, the deletion mutant has a complex pleiotropic phenotype where most adult homozygous progeny lack either one or both gonad arms. Most phenotypes become more penetrant at elevated temperature. Together, our results support an emerging model where the 3'UTRs of maternal transcripts, rather than being essential, contribute to reproductive robustness during stress.
    DOI:  https://doi.org/10.1101/2025.11.26.690476
  3. Trends Genet. 2025 Dec 16. pii: S0168-9525(25)00286-0. [Epub ahead of print]
    The 3D genome during germline development and meiosis.
    Yuka Kitamura, Satoshi H Namekawa.
      Germ cell development involves extensive remodeling of the 3D genome architecture, which is tightly coupled to transcriptional programs, meiotic chromosome dynamics, and re-establishment of totipotency in the next generation. Recent advances in chromosome conformation capture methods have uncovered stage-specific alterations in chromosome organization during spermatogenesis and oogenesis, including germline-specific 3D genome features. These distinctive nuclear configurations orchestrate gene expression programs essential for each developmental stage and meiosis, contribute to epigenetic inheritance, and shape genome evolution. In this review, we synthesize recent progress in understanding 3D genome organization in male and female germlines, and highlight emerging principles, unresolved questions, and innovative approaches that will advance our understanding of germline biology and the principles of genome architecture.
    Keywords:  3D genome; epigenetic priming; germ cells; germline; meiosis; oogenesis; spermatogenesis
    DOI:  https://doi.org/10.1016/j.tig.2025.11.004
  4. Development. 2025 Dec 15. pii: dev205291. [Epub ahead of print]152(24):
    Hedgehog and Drosophila germ cell migration.
    Girish Deshpande, Ji Hoon Kim, Caitlin D Hanlon, Paul Schedl, Deborah J Andrew.
      The functional gonads, essential for the continuity of a species, have both somatic and germline components. Newly formed germ cells are quiescent and are often physically isolated from the rest of the soma, protecting them from the signals that control somatic specification and differentiation. Nonetheless, the sequestered germ cells must ultimately navigate through the embryo to meet up with the somatic gonadal components. Forward genetic screens conducted in Drosophila have uncovered several crucial factors that generate both attractive and repulsive signals controlling germ cell movement. Efforts to reveal how the range of molecular players coordinate their activities to ensure that navigation is a robust and reproducible process have led to exciting, albeit sometimes contentious, discoveries. Herein, we summarize evidence for Hedgehog functioning in a single pathway from the signal source to signal reception to the downstream cytoskeletal events controlling the directed movement of germ cells to the site of gonad formation.
    Keywords:   Drosophila ; Germ cells; Hedgehog; Primordial germ cells; Somatic gonadal precursors
    DOI:  https://doi.org/10.1242/dev.205291
  5. Stem Cell Reports. 2025 Dec 18. pii: S2213-6711(25)00350-9. [Epub ahead of print] 102746
    High resolution multi-scale profiling of embryonic germ cell-like cell derivation reveals pluripotent state transitions in humans.
    Sarah Stucchi, Lessly P Sepulveda-Rincon, Camille Dion, Gaja Matassa, Alessia Valenti, Cristina Cheroni, Alessandro Vitriolo, Filippo Prazzoli, George Young, Marco Tullio Rigoli, Riccardo Nagni, Martina Ciprietti, Benedetta Muda, Zoe Heckhausen, Petra Hajkova, Nicolò Caporale, Giuseppe Testa, Harry G Leitch.
      Primordial germ cells (PGCs) are the embryonic precursors of the gametes. In rodents, PGCs readily form self-renewing embryonic germ cell (EGC) lines in vitro. Although human PGCs undergo a similar conversion during germ cell tumorigenesis, no comparable in vitro system has yet been established in humans. Here we report that hPGC-like cells (hPGCLCs) undergo conversion to human EGC-like cells (hEGCLCs) using the inductive signals previously identified in mice. This feeder-free culture system allows efficient derivation of hEGCLCs that are transcriptionally similar to human induced pluripotent stem cells and can give rise to hPGCLCs once more demonstrating the interconvertibility of pluripotent states. This is also evident at the chromatin level, as the initial DNA demethylation that occurs in hPGCLCs is reversed in hEGCLCs. This new in vitro model provides a highly tractable system to study human pluripotent and early developmental transitions, including those driving germ cell tumorigenesis and epigenetic inheritance.
    Keywords:  DNA methylation; embryonic germ cells; epigenetic reprogramming; germ cell tumor; multi-omics; pluripotency; primordial germ cells; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102746
  6. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1289. [Epub ahead of print]53(22):
    Tatdn2 is required for DNA repair to safeguard genome stability in primordial germ cells.
    Hanqiao Shang, Puxuan Jiang, Zehui Wang, Zhaojun Shan, Yuze Chen, Ting Zhang, Yingshu Li, Qiang Tu.
      Maintaining genome integrity in germ cells is crucial for fertility and species survival. However, the DNA repair mechanisms that sustain genome integrity in primordial germ cells (PGCs), which cope with high levels of replication stress, remain largely unknown. While the TatD family of proteins, evolutionarily conserved nucleases, has been found to play roles in various DNA-related processes, their in vivo functions in vertebrates have yet to be fully elucidated. TATDN2 has recently been implicated in resolving R-loops and participating in the replication stress response in BRCA1-deficient cancer cells. Here we found that tatdn2 exhibits conserved expression in mitotic and early meiotic germ cells across teleosts and mammals. Using medaka fish as a model, we then showed that loss of tatdn2 leads to all-phenotypically male adults and infertility due to PGC depletion during mitotic proliferation. We further demonstrated that knockout of tatdn2 increases R-loop accumulation and DNA damage, subsequently triggering apoptosis in PGCs. These findings indicate that tatdn2 plays a critical role in DNA damage repair associated with R-loop resolution in mitotic PGCs. Our study provides novel insights into the physiological function of TATDN2 and the mechanisms of genome maintenance in PGCs.
    DOI:  https://doi.org/10.1093/nar/gkaf1289
  7. J Genet Genomics. 2025 Dec 17. pii: S1673-8527(25)00343-1. [Epub ahead of print]
    MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential.
    Yiyang Wang, Yu Qi, Keyan Xu, Shuyan Tang, Luyi Tan, Bingying Xu, Ying Wang, Shuxian Zhang, Yang Zou, Yuan Gao, Chunmei Zhang, Xin Liang, Xue Jiao, Shidou Zhao, Han Zhao, Shixuan Wang, Yingying Qin, Ting Guo, Zi-Jiang Chen.
      Meiotic DNA double-strand break (DSB) formation is pivotal for oocyte development, regulating both ovarian reserve and oocyte developmental potential. Mutations in DSB formation genes have been associated with premature ovarian insufficiency (POI) and adverse pregnancy outcomes in women. Whole exome sequencing in 1530 POI patients across two Chinese cohorts identifies loss-of-function variants in the DSB formation gene, MEI4, enriched in POI. These MEI4 variants impair DSB formation in vitro and reveal a previously unrecognized function of the MEI4 C-terminus in stabilizing the MEI4-REC114 subcomplex on the chromosome axes. Additionally, Mei4Arg356*/Arg356* mice display severe defects in DSB formation, leading to massive apoptosis in oocytes triggered by the HORMAD1-dependent synapsis checkpoint in late prophase I. The few mutant oocytes surviving past the checkpoint exhibit low developmental potential, characterized by complete early embryonic arrest due to aneuploidy. Notably, heterozygous Mei4+/Arg356* mice show intermediate follicle depletion and embryonic development arrest consistent with the phenotype of heterozygous POI and preimplantation embryonic arrest, suggesting a haploinsufficiency effect. This study defines the impacts of MEI4 mutation on oocyte quantity and quality, which can guide genetic diagnosis and intervention in patients with POI and early embryonic arrest, especially those with mutations in meiotic DSB formation genes.
    Keywords:  DNA double-strand break formation; Female reproductive disorders; MEI4; Meiosis; Preimplantation embryonic arrest; Premature ovarian insufficiency
    DOI:  https://doi.org/10.1016/j.jgg.2025.12.005
  8. Cell Mol Life Sci. 2025 Dec 20.
    ZAR1 pathogenic variants disrupt maternal mRNA storage and cause oocyte maturation defects in humans.
    Xiu-Quan Liao, Shuai Zhao, Chang-Long Zhang, Yan Zhu, Jun Wen, Yang Wang, Shao-Yuan Liu, Wei Su, Jiang-Tao Zhang, Qiong-Wen Lu, Fei Gong, Ge Lin, Heng-Yu Fan, Wei Zheng, Han Zhao, Qian-Qian Sha.
      
    Keywords:  Female infertility; MARDO; Oocyte; Post transcriptional regulation; RNA binding protein
    DOI:  https://doi.org/10.1007/s00018-025-06000-4
  9. bioRxiv. 2025 Dec 08. pii: 2025.12.03.692228. [Epub ahead of print]
    Senescence-Linked Fibrosis in the Aging Human Ovary Revealed by p16-Based Histological Profiling and Spatial Transcriptomics.
    Mark A Watson, Pooja Raj Devrukhkar, Natalia F Murad, Fan Wu, Moo Joong Kim, Hannah Anvari, Uyen Tran, Nicholas Martin, Tommy Tran, Giuliana Zaza, Kevin Schneider, Bikem Soygur, Elisheva D Shanes, Denis Wirtz, Mary Ellen G Pavone, Simon Melov, Pei-Hsun Wu, David Furman, Francesca E Duncan, Birgit Schilling.
      Cellular senescence is implicated as a driver of ovarian aging, but senescent cells in the human postmenopausal ovary remain poorly defined. Using spatially resolved p16 INK 4a protein expression, a canonical senescence marker, we identified and mapped senescent cells in postmenopausal ovaries. We integrated p16 immunohistochemistry, multiplexed immunofluorescence, spatial transcriptomics, and AI-guided digital pathology to map senescent microenvironments. p16-positive cells formed discrete stromal, vascular, and cyst-associated clusters that increased with age and were enriched for macrophages and myofibroblast-like cells. Wholetranscriptome profiling of 92 spatial regions uncovered a 32-gene p16-associated signature, BuckSenOvary, that distinguished p16-positive regions across cortex and medulla. BuckSenOvary is characterized by suppression of cell-cycle regulators and activation of inflammatory and extracellular-matrix remodelling genes. AI-based collagen matrix analysis confirmed that p16-positive regions exhibit more architecturally complex collagen, demonstrating that focal senescent microenvironments are fibro-inflammatory. These findings position senescent ovarian niches as therapeutic targets to preserve ovarian function.
    DOI:  https://doi.org/10.64898/2025.12.03.692228
  10. Mol Metab. 2025 Dec 13. pii: S2212-8778(25)00214-5. [Epub ahead of print] 102307
    Multi-omics atlas of ovarian cellular and molecular responses to diabetes.
    Zheng-Hui Zhao, Xue-Ying Chen, Cheng-Yan Zhuo, Xiang-Hong Ou, Qing-Yuan Sun.
      Diabetes is associated with compromised reproductive health; however, the cellular and molecular mechanisms underlying its impact on ovarian function remain largely unclear. In this study, we integrated single-cell RNA sequencing, DNA methylation profiling, and metabolomic analyses to comprehensively characterize the ovarian cellular landscape, epigenetic alterations, and metabolic reprogramming in diabetic female mice, with a focus on identifying diabetes-induced changes in ovarian cells. Our cell type-specific transcriptomic analysis revealed that dysregulated steroid hormone biosynthesis and impaired fatty acid metabolism are prominent features of diabetic ovarian dysfunction. Notably, key genes including Cyp11a1, Fshr, and Lhcgr exhibited reduced expression accompanied by increased DNA methylation levels in their gene regions within granulosa cells under diabetic conditions. Furthermore, disrupted granulosa cell differentiation was evident, leading to aberrant luteal cell formation and compromised luteal function. In parallel, metabolomic profiling revealed profound metabolic reprogramming in diabetic ovaries, with significant alterations in lipid metabolism pathways, including elevated unsaturated fatty acid and reduced glycerophospholipid metabolism. Taken together, these findings provide novel insights into the molecular pathways underlying ovarian dysfunction in the context of diabetes, thereby enhancing our understanding of folliculogenesis in metabolic disorders.
    Keywords:  DNA methylation; Diabetes; Metabolism; Ovary; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.molmet.2025.102307
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