bims-cebooc Biomed News
on Cell biology of oocytes
Issue of 2025–06–15
24 papers selected by
Gabriele Zaffagnini, Universität zu Köln
  1. Different populations of mouse egg cortical vesicles are responsible for post-fertilization zinc sparks and proteolysis of the zona pellucida.
  2. Impact of organelle architecture on oocyte developmental potential.
  3. Proteostasis in cellular dormancy: lessons from yeast to oocytes.
  4. CNTD1 is crucial for crossover formation in female meiosis and for establishing the ovarian reserve.
  5. Abundant piRNA production mediated by the Drosophila GTSF1 homolog Tpp ensures Aubergine localization and germ plasm assembly.
  6. RSPO2 Coordinates with GDF9:BMP15 Heterodimers to Promote Granulosa Cell and Oocyte Development in Mice.
  7. Biparental inheritance of germline-specific chromosomes in the sea lamprey and their roles in oocytes.
  8. Single cell transcriptomes of zebrafish germline reveal progenitor types and feminization by Foxl2l.
  9. Early signaling pathways during in vitro culture of isolated primordial follicles.
  10. CLASP1 regulates Dynein for PLK1-mediated spindle organization and cytokinesis in oocyte meiosis.
  11. WAGO-1 is a sexually dimorphic Argonaute protein required for proper germ granule structure and gametogenesis.
  12. Oviductin sets the species-specificity of the mammalian zona pellucida.
  13. DNA methylation mechanisms in the maturing and ageing oocyte.
  14. Ovarian aging: a missing diagnosis in reproductive medicine.
  15. The trade-off between reproduction and resilience.
  16. Deciphering meiotic chromatin organization by SYCP3.
  17. Bulk-level maps of pioneer factor binding dynamics during Drosophila maternal-to-zygotic transition.
  18. An intergenerational lipid memory of the social environment in C. elegans.
  19. Transcriptional Repression of reaper by Stand Still Safeguards Female Germline Development in Drosophila.
  20. Epigenetic regulation in early embryo development: from zygotic genome activation to the first lineage specification.
  21. Chip (Ldb1) is a putative cofactor of Zelda forming a functional bridge to CBP during zygotic genome activation.
  22. Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.
  23. Brain dopamine imbalance causes follicle death and underlies negative effect of high sugar diet during Drosophila oogenesis.
  24. Rewiring for movements in meiotic prophase: regulators, roles, and evolutionary pathways.
  1. iScience. 2025 Jun 20. 28(6): 112606
    Different populations of mouse egg cortical vesicles are responsible for post-fertilization zinc sparks and proteolysis of the zona pellucida.
    Omar José, Boris Baibakov, Jurrien Dean.
      Fertilization of mouse eggs by sperm triggers exocytosis of cortical granules, releasing zinc sparks as well as ovastacin that cleaves ZP2 in the zona pellucida. The mechanism by which zinc accumulates in cortical granules prior to fertilization has yet to be determined. We microinjected cRNAs encoding eight zinc transporters (ZnTs) into mouse oocytes and observed that only ZnT2 and ZnT4 accumulate in structures located in the cortex. We genetically ablated the single-copy genes encoding each of the two transporters. The absence of both transporters in ovulated eggs impaired accumulation of zinc in cortical granules and release of zinc sparks. Ovastacin and zinc are present in mostly non-overlapping populations of cortical granules. Our results provide new insights into the biology of mammalian cortical granules, but the release of zinc sparks does not affect the post-fertilization number of sperm in the perivitelline space nor increases polyspermy.
    Keywords:  Developmental biology; cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112606
  2. Curr Opin Cell Biol. 2025 Jun 11. pii: S0955-0674(25)00094-8. [Epub ahead of print]95 102556
    Impact of organelle architecture on oocyte developmental potential.
    Elvira Nikalayevich, Noemi Zollo, Marie-Hélène Verlhac.
      Oocytes are female gametes specialized in storing maternal RNAs, proteins, lipids, and metabolites essential for embryonic development after fertilization, sometimes for decades in humans. To support this extended lifespan, oocytes have evolved mechanisms to organize specialized organelles. This review highlights recent discoveries on how oocytes regulate mRNA and protein accumulation, storage, and degradation over time. Additionally, we explore advances in understanding cytoplasmic activity and remodeling, particularly the role of cortex mechanical properties in fine-tuning organelle distribution and function to ensure proper oocyte development.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102556
  3. Trends Biochem Sci. 2025 Jun 11. pii: S0968-0004(25)00108-2. [Epub ahead of print]
    Proteostasis in cellular dormancy: lessons from yeast to oocytes.
    Stephanie Rosswag de Souza, Elvan Böke, Gabriele Zaffagnini.
      Cellular dormancy is characterized by a prolonged, reversible cell cycle arrest and absence of growth. Dormancy allows organisms to endure unfavorable environmental conditions and to maintain long-lived quiescent progenitor cells essential for tissue homeostasis and reproduction. Protein homeostasis (proteostasis) is central to the maintenance of intracellular integrity in all cell types, particularly in long-lived, non-dividing cells. Here we review adaptations to support proteostasis in dormant cells and highlight common themes of cellular dormancy across organisms, from yeast to adult quiescent stem cells. We also feature vertebrate oocytes as an emerging model of proteostasis during dormancy. Together, these comparisons reveal common and unique strategies to sustain proteostasis during dormancy, offering insights into how cells preserve function and viability over long quiescence periods.
    Keywords:  mTOR; protein aggregates; protein degradation; quiescence; ribosome biogenesis; translation
    DOI:  https://doi.org/10.1016/j.tibs.2025.05.004
  4. J Cell Biol. 2025 Aug 04. pii: e202401021. [Epub ahead of print]224(8):
    CNTD1 is crucial for crossover formation in female meiosis and for establishing the ovarian reserve.
    Anna J Wood, Rania M Ahmed, Leah E Simon, Rachel A Bradley, Stephen Gray, Ian D Wolff, Paula E Cohen.
      In meiotic prophase I, hundreds of DNA double-strand breaks are formed and subsequently repaired as noncrossovers or crossovers (COs). COs are essential for accurate chromosome segregation during the first meiotic division, and errors in this process result in aneuploidy, birth defects, or infertility. Such errors are more pronounced in females compared with males, indicating that CO regulation and surveillance are sexually dimorphic. We demonstrate here dual roles of cyclin N-terminal domain containing 1 (CNTD1) in ensuring appropriate CO between homologous chromosomes in oocytes and in establishing the pool of follicles in the postnatal ovary. CNTD1-deficient oocytes fail to form COs and exhibit a severely depleted follicle pool shortly after birth, which is temporally distinct from previously reported CO mutants. Further investigation indicates that follicle loss is CHK2-dependent, resulting from inappropriate retention of HORMAD1 and the absence of SKP1. These findings indicate that CNTD1 plays novel roles in CO designation and establishment of the follicular reserve in female mammals.
    DOI:  https://doi.org/10.1083/jcb.202401021
  5. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2419375122
    Abundant piRNA production mediated by the Drosophila GTSF1 homolog Tpp ensures Aubergine localization and germ plasm assembly.
    Hirono Kina, Natsuko Izumi, Kazuko Hanyu-Nakamura, Takashi Yoshitani, Mariko Yamane, Hitoshi Niwa, Yukihide Tomari, Akira Nakamura.
      Germ cells transmit genetic information to offspring and maintain the genome of the species. In many animals including Drosophila, germ cell formation relies on maternal determinants in the germ plasm. Several proteins present in the germ plasm of oocytes also localize to the perinuclear nuage in nurse cells, where they contribute to the production of PIWI-interacting RNAs (piRNAs). These piRNAs guide the silencing of transposons, thereby protecting the germline genome from invading mobile elements. Aubergine (Aub) is a germ plasm/nuage protein and a piRNA-directed endonuclease that inactivates transposons. Aub is also essential for germ plasm assembly. The Aub-bound piRNAs in the germ plasm are inherited by the progeny germline and serve as templates for piRNA biogenesis in the next generation. Thus, piRNA production in the nurse cell nuage is thought to be coordinated with germ plasm assembly in the oocyte. However, the underlying mechanism remains unclear. Here, we report that a maternal factor, named tiny pole plasm (tpp), mediates this coordination. Tpp is a GTSF1 family PIWI cofactor. In tpp- ovaries, the production of piRNAs, particularly Aub-bound piRNAs, is defective, resulting in reduced Aub localization to the germ plasm and impaired germ cell formation. Notably, the levels of piRNA production required for proper Aub localization are much higher than those required for transposon silencing. We propose that producing abundant piRNAs beyond what is required for transposon silencing in the ovary promotes germ plasm assembly, thereby enabling the progeny germline to properly silence transposons for species survival.
    Keywords:  Drosophila; germ cells; germ plasm; piRNA; transposon
    DOI:  https://doi.org/10.1073/pnas.2419375122
  6. Adv Sci (Weinh). 2025 Jun 10. e01973
    RSPO2 Coordinates with GDF9:BMP15 Heterodimers to Promote Granulosa Cell and Oocyte Development in Mice.
    Yingmei Wang, Hongjiang Li, Liji You, Shuhui Wang, Jinglei Bie, Ziyang Su, Lanying Shi, You-Qiang Su.
      The generation of mature oocytes, a cornerstone of reproduction, relies on the coordinated interactions between oocytes and surrounding follicular somatic cells. Central to this process is the bidirectional communication between the oocyte and granulosa cells, mediated by oocyte-secreted factors (OSFs), including GDF9 and BMP15. While GDF9 and BMP15 are well-established regulators of oocyte and follicle development, the role of additional OSFs and their coordination with GDF9 and BMP15 remains largely unclear. Here, RSPO2 is identified as a key OSF that coordinates with the GDF9:BMP15 heterodimer to regulate granulosa cell development and enhance oocyte competence. RSPO2, primarily expressed in oocytes, interacts with GDF9:BMP15 to preserve transcriptomic integrity in preantral granulosa cells. This coordination is gene-specific, exhibiting either synergistic or antagonistic effects depending on the target genes, and involves crosstalk between CTNNB1- and SMAD2-dependent pathways. Conditional knockout of Rspo2 in oocytes causes severe defects in granulosa cell and oocyte development, leading to subfertility and earlier reproductive lifespan termination. Transcriptomic analysis shows that RSPO2 loss disrupts key granulosa cell genes (e.g., Amh, Ccnd2, Inhbb, Kitl) and compromises oocyte mitochondrial function, reducing developmental competence. These findings establish RSPO2 as an essential factor in the oocyte-granulosa cell regulatory loop, crucial for ovarian function and fertility.
    Keywords:  CTNNB1; GDFP:BMP15 heterodimer; OSF; RSPO2; SMAD2; female fertility; follicles; granulosa cells; oocytes; oocyte‐granulosa cell communication
    DOI:  https://doi.org/10.1002/advs.202501973
  7. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2421883122
    Biparental inheritance of germline-specific chromosomes in the sea lamprey and their roles in oocytes.
    Vladimir A Timoshevskiy, Nataliya Timoshevskaya, Kaan I Eşkut, Kasturi Rajandran, Jeramiah J Smith.
      Many eukaryotic species undergo programmed elimination of specific chromosomes during embryogenesis, typically retaining these chromosomes only in their germ cells. In some species, programmatic elimination of GRCs, or sex chromosomes, also occurs in a sex-specific manner, with specific chromosomes being transmitted or eliminated by only one sex. As such, these chromosomes provide a unique perspective on the evolution of gene functions that are advantageous to the germline and genetic tradeoffs between somatic vs germline or oocyte vs sperm biology. While GRCs have been extensively characterized in male sea lampreys (Petromyzon marinus), the status of GRCs in females has not yet been resolved, though it has been hypothesized that male-specific expression/transmission of these chromosomes might provide a solution to resolving the long-standing mystery of lamprey sex determining mechanisms. To gain insight into the roles of GRCs in female lampreys, we performed several karyological, transcriptomic, and genomic analyses, which demonstrate that GRCs are present in the female lamprey germline, transmitted by oocytes and somatically eliminated in both sexes. These analyses also show that GRCs play important roles in the maintenance and development of female germline but provide no evidence for sex-specific variation in the elimination and transmission of lamprey GRCs. These findings underscore the diversity of germline functions that are carried out by GRCs in both male and female lampreys and highlight the fact that sex-specific transmission/retention of GRCs likely follows no universal rules across the diverse lineages that have independently evolved to undergo developmentally programmed DNA elimination.
    Keywords:  DNA elimination; chromosome; germline; lamprey; oocyte
    DOI:  https://doi.org/10.1073/pnas.2421883122
  8. Elife. 2025 Jun 11. pii: e100204. [Epub ahead of print]14
    Single cell transcriptomes of zebrafish germline reveal progenitor types and feminization by Foxl2l.
    Chen-Wei Hsu, Ho Hao, Ching-Hsin Yang, Yan-Wei Wang, Ker-Chau Li, Bon-Chu Chung.
      Zebrafish is an important organism for genetic studies, but its early germ cell types and the mechanism of sex differentiation have not been fully characterized. Here, we profiled single-cell transcriptomes and charted a developmental trajectory going from germline stem cells, through early, committed, and late progenitors, to pre-meiotic and meiotic cells. We showed that transcription factor Foxl2l expressed in the progenitor directed progenitor differentiation toward oocytes. CRISPR-Cas9-mediated mutation of foxl2l produced 100% male fish with normal fertility. Another single-cell profiling of foxl2l-/- germ cells revealed the arrest of germ cell development at the stage of progenitor commitment. Concomitantly, nanos2 transcript (germline stem cell marker) was elevated together with an increase of nanos2+ germ cells in foxl2l mutants, indicating the acquisition of a novel stem cell state. Thus, we have identified developmental stages of germ cells in juvenile zebrafish and demonstrated that zebrafish Foxl2l drives progenitor germ cells toward feminization and prevents them from expressing nanos2.
    Keywords:  developmental biology; zebrafish
    DOI:  https://doi.org/10.7554/eLife.100204
  9. Mol Hum Reprod. 2025 Jun 09. pii: gaaf026. [Epub ahead of print]
    Early signaling pathways during in vitro culture of isolated primordial follicles.
    Pritha Dey, Noemi Monferini, Ludovica Donadini, Filippo Zambelli, Maria Belen Rabaglino, Valentina Lodde, Federica Franciosi, Alberto Maria Luciano.
      The ability to grow undifferentiated oocytes in vitro from primordial follicles would increase the availability of fully grown oocytes in fertility preservation programs and other downstream applications. To date, the development of living offspring in vitro from the primordial follicle reserve has only been achieved in mice, proving the principle of the potential value of follicle culture as a source of competent oocytes. In certain pathophysiological conditions, such as polycystic ovarian syndrome, premature ovarian failure, or ovarian and blood cancer, where the ovarian tissue cannot be reintroduced into the patient, it is essential to isolate these follicles from the surrounding tissue and culture them in vitro. However, the culture systems that produce mature oocytes from isolated primordial follicles are still under investigation. Upon isolation from the ovarian microenvironment, a critical limiting factor is follicle death after a short period of culture. Previous studies suggest that glycine, a key component of glutathione (GSH), plays a protective role against the programmed cell death mechanism, ferroptosis, in in vitro matured porcine oocytes via the System Xc-/GSH/glutathione peroxidase 4 (GPX4) axis. Employing a previously developed high-yielding primordial follicle mechanical isolation strategy and a defined culture system, we used RNA-seq to advance the knowledge of the main transcriptional events and molecular factors determining follicle fate in a 2D culture system. Our transcriptome analyses identified genes involved in ferroptosis that may bring about primordial follicle death. To suppress ferroptosis, glycine supplementation maintained the viability of primordial follicles at approximately 85% for 16 hours. Future improvements to the culture system should inhibit programmed cell death mechanisms and ensure the physiological compliance of the genes regulating primordial follicle activation and transition to the primary stage, along with effective supplementation media to develop isolated primordial follicles in vitro.
    Keywords:   In vitro Culture; Bovine; Ferroptosis; Folliculogenesis; Glycine; Mechanical Isolation; Ovarian Reserve; Primordial Follicle; Programmed cell death; RNA-seq
    DOI:  https://doi.org/10.1093/molehr/gaaf026
  10. J Cell Sci. 2025 Jun 12. pii: jcs.264015. [Epub ahead of print]
    CLASP1 regulates Dynein for PLK1-mediated spindle organization and cytokinesis in oocyte meiosis.
    Meng-Meng Shan, Ping-Shuang Lu, Yuan-Jing Zou, Kun-Huan Zhang, Jing-Cai Liu, Jia-Qian Ju, Shao-Chen Sun.
      The meiotic spindle organization and cytokinesis are important for mammalian oocyte maturation. CLIP-associating protein (CLASP) 1 is a member of microtubule plus-end binding proteins, which is reported to regulate cytokinesis in mitosis; however, the functions of CLASP1 in meiosis are still unclear. In this study, we reported that CLASP1 played critical roles both at metaphase and telophase in mouse oocyte meiosis. Our results indicated that CLASP1 was essential for oocyte maturation and its depletion caused the spindle organization and microtubule-kinetochore attachment defects at metaphase Ⅰ, while this might be due to its association with PLK1/p-MAPK. Besides, deacetylases HDAC6/ SIRT1 were found to be decreased which further affected tubulin acetylation level and microtubule stability after CLASP1 depletion. We also showed that CLASP1 could associate with PLK1/PRC1-based central spindle formation and cytokinesis at telophase Ⅰ. Moreover, Dynein was recognized to interact closely with CLASP1 and may function as a downstream motor protein involved in the orderly transport of PLK1. Taken together, we demonstrated that CLASP1 may play multiple roles in Dynein-based PLK1 for spindle organization and cytokinesis in mouse oocyte meiosis.
    Keywords:  Cytokinesis; Meiosis; Oocyte; Spindle; Tubulin acetylation
    DOI:  https://doi.org/10.1242/jcs.264015
  11. bioRxiv. 2025 Jun 01. pii: 2025.05.29.656876. [Epub ahead of print]
    WAGO-1 is a sexually dimorphic Argonaute protein required for proper germ granule structure and gametogenesis.
    Acadia L DiNardo, Nicole A Kurhanewicz, Hannah R Wilson, Veronica Berg, Diana E Libuda.
      Germ cell proliferation and proper genome inheritance are critical for maintaining fertility through generations. To promote proper germ cell development, small RNA pathways employ Argonaute proteins (AGOs) to modulate gene expression and protect against deleterious genomic elements while not silencing against self. Here we identify sexual dimorphisms in localization and function of protein structural features of the Argonaute WAGO-1 that affects sex-specific gene regulation during C. elegans germ cell development. During meiotic prophase I progression, we find that germ granule structural proteins and the PIWI AGO, PRG-1, display dynamic and distinct localization patterns between egg and sperm development which coincide with differential WAGO-1 localization and biophysical properties. Sexually dimorphic functions of specific WAGO-1 protein structural domains underpin these differences. Disruption or modification to the N-terminus intrinsically disordered region (IDR) of WAGO-1 leads to loss of PGL-1 phase separation only during spermatogenesis. Further, we find that these germ granule disruptions are likely due to prolonged association of the IDR with the RNA-binding pocket of WAGO-1. In addition, deletion of the MID and part of the PIWI domains causes male-specific sterility and disruption to WAGO-1 localization with PGL-1 during oogenesis. Finally, we demonstrate that these disruptions to WAGO-1 protein structure dynamically change the mRNA and sRNA landscape of adult males and hermaphrodites, in which the AGOs ALG-3/4 and VSRA-1 are misregulated. Together, these data suggest that WAGO-1 differentially regulates genes during oogenesis versus spermatogenesis, and that these differences in gene regulation may be due to the sex-specific configuration and biophysical properties of WAGO-1 within the germ granule.
    DOI:  https://doi.org/10.1101/2025.05.29.656876
  12. Elife. 2025 Jun 09. pii: RP101338. [Epub ahead of print]13
    Oviductin sets the species-specificity of the mammalian zona pellucida.
    Daniel de la Fuente, Maria Maroto, Yulia N Cajas, Karina Canon-Beltran, Raul Fernandez-Gonzalez, Ana Munoz-Maceda, Juana M Sanchez-Puig, Rafael Blasco, Paula Cots-Rodríguez, Manuel Avilés, Dimitrios Rizos, Alfonso Gutierrez-Adan.
      The zona pellucida (ZP) is vital for species-specific fertilization as this barrier mediates sperm-oocyte binding. Here, we determined whether sperm from distant mammalian orders (Carnivora, Primates, and Rodentia) could penetrate bovine oocytes by examining the role of bovine oviductal fluid and species-specific oviductal glycoprotein (OVGP1 or oviductin) from bovine, murine, or human sources in modulating the species-specificity of bovine and murine oocytes. Sperm from all the species were found to penetrate intact bovine ovarian oocytes to form hybrid embryos. However, contact with oviductal fluid or bovine, murine, or human OVGP1, conferred the ZP species-specificity, allowing only the penetration of the corresponding sperm regardless of the ZP's origin. Glycolytic and microstructural analyses revealed that OVGP1 covers the pores present in the ZP and that OVGP1 glycosylation determines sperm specificity. This suggests specific fertilization capacity is acquired in the oviduct through the ZP's incorporation of specific oviductin.
    Keywords:  OVGP1; bovine; developmental biology; fertilization; human; mouse; zona pellucida
    DOI:  https://doi.org/10.7554/eLife.101338
  13. Epigenetics Chromatin. 2025 Jun 11. 18(1): 34
    DNA methylation mechanisms in the maturing and ageing oocyte.
    Carla Caniçais, Sara Vasconcelos, Fátima Santos, Sofia Dória, C Joana Marques.
      Oocyte maturation involves both nuclear and cytoplasmic processes that are critical for the acquisition of oocyte competence. Granulosa cells, surrounding the oocyte, play a pivotal role in the maturation process, with mechanisms such as cAMP signaling significantly influencing oocyte development. Epigenetic mechanisms - including DNA methylation and its oxidative derivatives, histone post-translational modifications and chromatin remodeling - interfere with the accessibility of transcription factors to regulatory regions of the genome, such as promoter regions of genes, hence generally regulating gene expression profiles; however, in oocytes, transcription is largely independent of DNA methylation patterns. Here we highlight epigenetic reprogramming events occurring during oocyte development and ageing, focusing on the establishment of gamete-specific epigenetic marks, including DNA modifications at imprinted regions, and age-related epigenetic changes. We focus on the mechanisms of DNA methylation and demethylation during mouse and human oocyte maturation, alongside an exploration of how ageing impacts the oocyte epigenome and its implications for reproductive success. By providing a comprehensive analysis of the role of epigenetics in oocyte development and maturation, this review addresses the importance of comprehending these processes to enhance in vitro fertilization treatments and improve reproductive outcomes.
    Keywords:  Ageing; DNA methylation; Epigenetics; Genomic imprinting; Oocyte
    DOI:  https://doi.org/10.1186/s13072-025-00600-x
  14. Nat Med. 2025 Jun 06.
    Ovarian aging: a missing diagnosis in reproductive medicine.
    Lydia Hughes, Francesca E Duncan, Elnur Babayev.
      
    DOI:  https://doi.org/10.1038/s41591-025-03733-4
  15. Trends Endocrinol Metab. 2025 Jun 10. pii: S1043-2760(25)00102-X. [Epub ahead of print]
    The trade-off between reproduction and resilience.
    Liankui Zhou, Ying Liu.
      The mitochondrial unfolded protein response (UPRmt) is a transcriptional program that alleviates mitochondrial dysfunction by facilitating the recovery of the mitochondrial network. In Caenorhabditis elegans, reproductive maturity leads to suppression of the UPRmt, suggesting a trade-off between maintenance of stress resilience and fertility. Here, we examine emerging evidence suggesting that the reproduction-associated suppression of UPRmt is a representative example of the physiological costs of reproduction. We focus on the germline-to-soma intertissue signaling mechanisms recently identified in C. elegans, which modulate systemic physiological responses during reproduction. These findings not only illuminate the trade-offs between stress resistance and reproductive capacity but also underscore the broader implications of intertissue communication in coordinating resource allocation.
    Keywords:  Caenorhabditis elegans; intertissue signaling networks; mitochondrial unfolded protein response; proteostasis regulation; reproduction-associated trade-offs
    DOI:  https://doi.org/10.1016/j.tem.2025.05.003
  16. Nucleic Acids Res. 2025 Jun 06. pii: gkaf460. [Epub ahead of print]53(11):
    Deciphering meiotic chromatin organization by SYCP3.
    Shimeng Guo, Yiran Zhang, Caifeng Fei, Xiaozhao Liu, Wei Xia, Mengcheng Luo, Gonghong Wei, Weibing Qin, Chengliang Xiong, Honggang Li, Ying Yin, Ximiao He, Li-Quan Zhou.
      Chromatin structure during meiosis is different from somatic cells due to the assembly of the synaptonemal complex between homologous chromosome axes. However, genome-wide organizing principles of this meiosis-specific multiprotein complex remain mysterious despite intensive super-resolution imaging analysis. Here, we profiled chromatin occupancy of SYCP3, the key chromatin organizer of synaptonemal complex, in mouse spermatocytes, and showed its enrichment at open chromatin regions. Moreover, SYCP3 occupancy was largely inherited from the leptotene to pachytene stage, facilitated by transcription and fibrous assembly, and was enriched at specific SINE repeats. We also identified SYCP1-occupied regions mainly as a subpopulation of SYCP3-occupied regions with high cohesin enrichment. Collectively, our results demonstrate genome-wide profiling of SYCP3 in mouse meiosis and reveal that its occupancy is a dynamic process modulated by chromatin-related events.
    DOI:  https://doi.org/10.1093/nar/gkaf460
  17. Development. 2025 Jun 13. pii: dev.204460. [Epub ahead of print]
    Bulk-level maps of pioneer factor binding dynamics during Drosophila maternal-to-zygotic transition.
    Sadia Siddika Dima, Gregory T Reeves.
      Gene regulation by transcription factors (TFs) binding cognate sequences is of paramount importance. For example, the TFs Zelda (Zld) and GAGA factor (GAF) are widely acknowledged for pioneering gene activation during zygotic genome activation (ZGA) in Drosophila. However, quantitative dose/response relationships between bulk TF concentration and DNA binding, an event tied to transcriptional activity, remain elusive. Here, we map these relationships during ZGA: a crucial step in metazoan development. To map the dose/response relationship between nuclear concentration and DNA binding, we performed raster image correlation spectroscopy, a method that can measure biophysical parameters of fluorescent molecules. We found that, although Zld concentration increases during nuclear cycles (ncs) 10 to 14, its binding in the transcriptionally active regions decreases, consistent with its function as an activator for early genes. In contrast, GAF-DNA binding is nearly linear with its concentration, which sharply increases during the major wave, implicating it in the major wave. This study provides key insights into the properties of the two factors and puts forward a quantitative approach that can be used for other TFs to study transcriptional regulation.
    Keywords:  DNA binding; GAGA factor; Pioneer factors; Raster image correlation spectroscopy; Zelda; Zygotic genome activation
    DOI:  https://doi.org/10.1242/dev.204460
  18. bioRxiv. 2025 Jun 03. pii: 2025.06.03.657568. [Epub ahead of print]
    An intergenerational lipid memory of the social environment in C. elegans.
    Thomas Wilhelm, Wei-Wen Chen, Annika Wenzel, Wenyu Tang, Marcus T Cicerone, Ben Lehner.
      Information about the environment can, in some cases, be transmitted to an organism's offspring by epigenetic inheritance. Here, we describe a novel form of epigenetics in C. elegans where information is transmitted between generations not by alterations in DNA, chromatin, or RNA, but by changes in the composition of lipids. Specifically, we delineate an environment-to-neuron-to-intestine-to-oocyte signalling axis that alters progeny thermotolerance by remodelling lipid provisioning to oocytes when animals detect social pheromones. Intergenerational information transmission via 'lipid memories' may represent an underappreciated form of epigenetics.
    DOI:  https://doi.org/10.1101/2025.06.03.657568
  19. bioRxiv. 2025 Jun 03. pii: 2025.05.17.654630. [Epub ahead of print]
    Transcriptional Repression of reaper by Stand Still Safeguards Female Germline Development in Drosophila.
    Masaya Matsui, Shinichi Kawaguchi, Toshie Kai.
      Apoptosis plays a central role in shaping tissues and preserving cellular integrity across developmental stages. In the germline, its precise regulation is critical to ensure both the elimination of aberrant cells and the maintenance of reproductive capacity. However, the molecular mechanisms that control apoptotic susceptibility in germline cells remain poorly defined. Here, we identify stand still ( stil ) as a female germline-specific regulator of apoptosis in Drosophila . Loss of stil leads to near-complete depletion of germline cells at the time of eclosion, associated with upregulation of the pro-apoptotic gene reaper ( rpr ) and activation of caspase-dependent cell death. Reporter assays in S2 cells show that Stil directly represses rpr transcription through its N-terminal BED-type zinc finger domain. Despite the absence of stil , undifferentiated germline cells remain resistant to apoptosis. Analysis of publicly available chromatin data reveals that the rpr locus in these cells resides in a closed, H3K9me3-enriched chromatin state, suggesting a Stil-independent mode of transcriptional silencing. Together, our findings uncover two distinct mechanisms that protects the female germline from rpr -dependent apoptosis: Stil-mediated transcriptional repression that operates in both undifferentiated and differentiated germline cells, and an additional chromatin-based silencing mechanism that functions specifically in undifferentiated cells. This work provides new insights into the interplay between transcriptional and chromatin-based regulations that maintain germline cell identity and survival.
    DOI:  https://doi.org/10.1101/2025.05.17.654630
  20. Trends Genet. 2025 Jun 05. pii: S0168-9525(25)00112-X. [Epub ahead of print]
    Epigenetic regulation in early embryo development: from zygotic genome activation to the first lineage specification.
    Ruimin Xu, Yanhe Li, You Wu, Xiaoyu Liu, Shaorong Gao.
      Epigenetic regulation plays a pivotal role in orchestrating early embryo development, guiding the transition from a totipotent zygote to a complex multicellular organism. This review summarizes the dynamic landscape of epigenetic reprogramming during preimplantation embryo development, emphasizing the interplay between DNA methylation, histone modifications, higher-order chromatin, transposable elements (TEs), and RNA modifications in resetting the parental epigenome. We also summarize the abnormal epigenetic reprogramming observed in somatic cell nuclear transfer (SCNT) and assisted reproductive technologies (ART), as well as clinical disorders resulting from these epigenetic defects, and discuss potential therapeutic strategies and future research directions. We seek to elucidate the role of epigenetic modifications in developmental defects, offering perspectives to enhance both developmental biology studies and clinical applications of assisted reproduction.
    Keywords:  assisted reproductive technologies; early embryo; epigenetic modifications; somatic cell nuclear transfer; the first lineage specifications; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.tig.2025.05.005
  21. Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00457-5. [Epub ahead of print]
    Chip (Ldb1) is a putative cofactor of Zelda forming a functional bridge to CBP during zygotic genome activation.
    Charalampos Chrysovalantis Galouzis, Yacine Kherdjemil, Mattia Forneris, Rebecca R Viales, Raquel Marco-Ferreres, Eileen E M Furlong.
      The cofactor LIM-domain-binding protein 1 (Ldb1) is linked to many processes in gene regulation, including enhancer-promoter communication, interchromosomal interactions, and enhanceosome-cofactor-like activity. However, its functional requirement and molecular role during embryogenesis remain unclear. Here, we used optogenetics (iLEXY) to rapidly deplete Drosophila Ldb1 (Chip) from the nucleus at precise time windows. Remarkably, this pinpointed the essential window of Chip's function to just 1 h of embryogenesis, overlapping zygotic genome activation (ZGA). We show that Zelda, a pioneer factor essential for ZGA, recruits Chip to chromatin, and both factors regulate concordant changes in gene expression, suggesting that Chip is a cofactor of Zelda. Chip does not significantly impact chromatin architecture at these stages, but instead recruits CBP, and is essential for H3K27ac deposition at enhancers and promoters, and for the proper expression of co-regulated genes. These data identify Chip as a functional bridge between Zelda and the coactivator CBP to regulate gene expression in early embryogenesis.
    Keywords:  CBP; cofactors; developmental enhancers; embryogenesis; transcription factors; transcriptional regulation; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.018
  22. FASEB J. 2025 Jun 15. 39(11): e70723
    Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.
    Shangrong Zhang, Qing Liu, Siyu Wang, Xiaoyu Zhang, Dingmei Qin, Ruisong Bai, Ji Chen, Zijian Ma, Zhipeng Lin, Yuheng Bi, Huan Liu, Aoxue Sun, Zhongzhi Mo, Hongcheng Wang, Xiaoqing Wu, Yong Liu.
      Thioredoxin (TRX)-related transmembrane proteins (TMX), a subgroup of the protein disulfide isomerase (PDI) family, comprise a class of transmembrane proteins with diverse biological functions. Among these, TMX2 (PDIA12) remains one of the least characterized members. Recent studies have identified missense mutations in TMX2 associated with aberrant brain development and cerebellar malformations, highlighting its potential importance in developmental processes. Notably, Tmx2 mutant embryos exhibit developmental arrest at the E3.5 stage, suggesting a critical role in preimplantation embryogenesis. However, the precise molecular and cellular functions of Tmx2 in mammalian embryonic development remain largely unexplored. In this study, we provide novel insights into the essential role of Tmx2 during preimplantation embryonic development in mice. We demonstrate that TMX2 is specifically expressed in mouse embryos, with its subcellular localization closely associated with mitochondria during the two-cell to eight-cell stages. Knockdown of Tmx2 recapitulates the phenotypic defects observed in genetic mutants, revealing a pronounced impairment in blastomere proliferation, as confirmed by EdU incorporation assays. Furthermore, TUNEL assays indicate a significant increase in apoptotic signaling in Tmx2-deficient embryos, accompanied by elevated mRNA levels of the cell cycle inhibitors p21 and p53. Mechanistically, we show that Tmx2 knockdown disrupts mitochondrial function, leading to oxidative stress and impaired mitophagy and autophagy in developing embryos. These findings suggest that Tmx2 plays a pivotal role in maintaining mitochondrial integrity and cellular homeostasis during preimplantation embryogenesis. In summary, our study elucidates the critical role of Tmx2 in preimplantation embryonic development in mice, primarily through its regulation of mitochondrial function. These results advance our understanding of the molecular mechanisms governing preimplantation embryonic development and establish Tmx2 as a key regulator of mitochondrial dynamics and cellular survival during this critical developmental window.
    Keywords:   Tmx2 ; autophagy; embryo development; mice; mitochondrial dysfunction
    DOI:  https://doi.org/10.1096/fj.202500640R
  23. bioRxiv. 2025 Apr 29. pii: 2025.04.25.650701. [Epub ahead of print]
    Brain dopamine imbalance causes follicle death and underlies negative effect of high sugar diet during Drosophila oogenesis.
    Rodrigo Dutra Nunes, Daniela Drummond-Barbosa.
      Unhealthy diets, obesity, and low fertility are associated in Drosophila and humans. We previously showed that a high sugar diet, but not obesity, reduces Drosophila female fertility owing to increased death of newly formed germline cysts and vitellogenic follicles. Drosophila strains carrying mutations in the yellow ( y ) and white ( w ) pigmentation genes are routinely used for investigating the effects of high sugar diets, but it has remained unclear how this genetic background interacts with high sugar. Here, we show that wildtype females retain normal fertility on high sugar compared to control diets, and that mutation of y is responsible for the previously observed vitellogenic follicle death on high sugar. The known requirement of y for melanin biosynthesis from dopamine, as well as the association between high sugar consumption and reduced dopamine in mammals and decreased dopamine responses in male Drosophila , prompted us to investigate potential connections between y , high sugar, dopamine and oogenesis. We found that global impairment of dopamine metabolism leads to vitellogenic follicle degeneration while alleviating dopamine imbalance in y mutant females prevents follicle death on a high sugar diet. Finally, lack of dopamine production in the central nervous system is sufficient for vitellogenic follicle death on a high sugar diet, and severe dopamine imbalance causes follicle death regardless of diet or genetic background. Our findings are broadly relevant to our understanding of how the effects of unhealthy diets might differ depending on genetic factors and highlight a key connection between brain dopamine metabolism and ovarian follicle survival.
    ARTICLE SUMMARY: Unhealthy diets, obesity, and reduced fertility are associated in Drosophila and humans. Recently, we showed that a high sugar diet induces ovarian follicle death and reduces Drosophila fertility independently of obesity. Here, we report that follicle degeneration induced by a high sugar diet depends on genetic background in connection with brain dopamine imbalance. We also show that severe dopamine imbalance increases follicle death regardless of diet or genetic background. These findings are broadly relevant to our understanding of how the effects of unhealthy diets might differ depending on genetic factors and highlight an important connection between dopamine metabolism and oogenesis.
    DOI:  https://doi.org/10.1101/2025.04.25.650701
  24. Curr Opin Genet Dev. 2025 Jun 07. pii: S0959-437X(25)00058-9. [Epub ahead of print]93 102366
    Rewiring for movements in meiotic prophase: regulators, roles, and evolutionary pathways.
    Wenxin Xie, Manjunath Gowder, Dominic Bazzano, Morgan DeSantis, Saher S Hammoud.
      Meiotic prophase movement and chromosome bouquet formation are highly conserved processes and essential features of meiosis, yet their functional components and dependencies vary among organisms. A key feature of meiotic prophase is that chromosome regions like telomeres or centromeres become physically tethered to the inner nuclear membrane through a hierarchical and sequential arrangement of proteins. Telomeres or their analogs further interact with the cytoskeletal machinery, which provides the necessary mechanical force to execute the chromosomal movements that enable homologous pairing, synapsis, and meiotic recombination. Despite decades of research, our understanding of these processes, their interdependencies, and their precise role remains incomplete. Here, we summarize the current mechanistic understanding and describe avenues for further exploration.
    DOI:  https://doi.org/10.1016/j.gde.2025.102366
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