bims-mazytr Biomed News
on Maternal‐to‐zygotic transition
Issue of 2025–05–04
ten papers selected by
川一刀
  1. Super RNA Pol II domains enhance minor ZGA through 3D interaction to ensure the integrity of major transcriptional waves in late-ZGA mammals.
  2. Moving toward totipotency: the molecular and cellular features of totipotent and naive pluripotent stem cells.
  3. Maternal transcription factor OTX2 directly induces SETD1A and promotes embryonic genome activation in human pre-implantation embryos.
  4. Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
  5. Towards an integrated view and understanding of embryonic signalling during murine gastrulation.
  6. Signaling switches: Metabolism regulates gastruloid self-organization.
  7. Analysis of Na+ concentration patterns in trophectoderm cells of mouse blastocysts using a dual-wavelength electrolyte indicator.
  8. Fast-adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging.
  9. The role of granulosa cells in oocyte development and aging: Mechanisms and therapeutic opportunities.
  10. Does HCG and LH supplementation during ovarian stimulation improve clinical outcome? A evaluation of 30 years of clinical research.
  1. Cell Genom. 2025 Apr 29. pii: S2666-979X(25)00112-0. [Epub ahead of print] 100856
    Super RNA Pol II domains enhance minor ZGA through 3D interaction to ensure the integrity of major transcriptional waves in late-ZGA mammals.
    Jingcheng Zhang, Hengkuan Li, Linmi Li, Jie Wu, Linjie Song, Xin Liu, Zhangyuan Pan, Chuan Zhou, Wenying Li, Zixiao Liu, Mei Jiao, Mingyang Hu, Zhenyu Dong, Hexu Zhang, Binqiang Shi, Yong Wang, Debao Wang, Benjamin Carter, Shuhong Zhao, Gang Ren, Yunxia Zhao, Yong Zhang.
      Zygotic genome activation (ZGA) occurs at distinct stages across mammals, with mice initiating ZGA at the 2-cell stage and bovines and humans activating the process in the 4- to 8-cell stages. RNA polymerase II (RNA Pol II) gradually initiates ZGA in mice, but regulation in late-ZGA species remains unclear. Here, RNA Pol II profiling in bovine embryos identified strong intergenic clusters that boost minor ZGA gene expression via chromatin interactions and are named super RNA Pol II domains (SPDs). CRISPRi perturbation of SPDs in bovine embryos decreases the expression of minor ZGA genes, whereas the knockdown of these genes disrupts major ZGA and embryogenesis. Rapid enhancement of minor ZGA genes also occurs in human embryos. Alternatively, mouse and porcine oocytes precociously express these minor ZGA genes without SPDs. Thus, SPDs appear to be an adaptation in bovine embryos, promoting minor ZGA gene expression to comparable levels as early-ZGA species, illuminating species-specific regulation of ZGA timing.
    Keywords:  3D interaction; RNA Pol II; SPDs; ZGA pace; interspecies comparison; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.xgen.2025.100856
  2. Hum Reprod Update. 2025 Apr 29. pii: dmaf006. [Epub ahead of print]
    Moving toward totipotency: the molecular and cellular features of totipotent and naive pluripotent stem cells.
    Lingyue Hua, Yuyang Peng, Liying Yan, Peng Yuan, Jie Qiao.
       BACKGROUND: Dissecting the key molecular mechanism of embryonic development provides novel insights into embryogenesis and potential intervention strategies for clinical practices. However, the ability to study the molecular mechanisms of early embryo development in humans, such as zygotic genome activation and lineage segregation, is meaningfully constrained by methodological limitations and ethical concerns. Totipotent stem cells have an extended developmental potential to differentiate into embryonic and extraembryonic tissues, providing a suitable model for studying early embryo development. Recently, a series of ground-breaking results on stem cells have identified totipotent-like cells or induced pluripotent stem cells into totipotent-like cells.
    OBJECTIVE AND RATIONALE: This review followed the PRISMA guidelines, surveys the current works of literature on totipotent, naive, and formative pluripotent stem cells, introduces the molecular and biological characteristics of those stem cells, and gives advice for future research.
    SEARCH METHODS: The search method employed the terms 'totipotent' OR 'naive pluripotent stem cell' OR 'formative pluripotent stem cell' for unfiltered search on PubMed, Web of Science, and Cochrane Library. Papers included were those with information on totipotent stem cells, naive pluripotent stem cells, or formative pluripotent stem cells until June 2024 and were published in the English language. Articles that have no relevance to stem cells, or totipotent, naive pluripotent, or formative pluripotent cells were excluded.
    OUTCOMES: There were 152 records included in this review. These publications were divided into four groups according to the species of the cells included in the studies: 67 human stem cell studies, 70 mouse stem cell studies, 9 porcine stem cell studies, and 6 cynomolgus stem cell studies. Naive pluripotent stem cell models have been established in other species such as porcine and cynomolgus. Human and mouse totipotent stem cells, e.g. human 8-cell-like cells, human totipotent blastomere-like cells, and mouse 2-cell-like cells, have been successfully established and exhibit high developmental potency for both embryonic and extraembryonic contributions. However, the observed discrepancies between these cells and real embryos in terms of epigenetics and transcription suggest that further research is warranted. Our results systematically reviewed the established methods, molecular characteristics, and developmental potency of different naive, formative pluripotent, and totipotent stem cells. Furthermore, we provide a parallel comparison between animal and human models, and offer recommendations for future applications to advance early embryo research and assisted reproduction technologies.
    WIDER IMPLICATIONS: Totipotent cell models provide a valuable resource to understand the underlying mechanisms of embryo development and forge new paths toward future treatment of infertility and regenerative medicine. However, current in vitro cell models exhibit epigenetic and transcriptional differences from in vivo embryos, and many cell models are unstable across passages, thus imperfectly recapitulating embryonic development. In this regard, standardizing and expanding current research on totipotent stem cell models are essential to enhance our capability to resemble and decipher embryogenesis.
    Keywords:  ZGA; embryo development; lineage segregation; naive pluripotency; stem cells; totipotency
    DOI:  https://doi.org/10.1093/humupd/dmaf006
  3. Sci China Life Sci. 2025 Apr 22.
    Maternal transcription factor OTX2 directly induces SETD1A and promotes embryonic genome activation in human pre-implantation embryos.
    Tianlei Zhang, Ziyan Peng, Fei Meng, Zhuo Li, Junru Chen, Qinwei Zhou, Lizhi Leng, Hao Bo, Guangxiu Lu, Yun Deng, Feng Gu, Ge Lin.
      Early embryonic development is controlled by maternal factors originating from mature oocytes. The zygotic genome is activated from a transcriptionally quiescent state through a process called embryonic genome activation (EGA), which involves the depletion and clearance of maternal factors. However, the mechanism by which maternal factors regulate EGA and embryonic development, particularly in humans, remains elusive. In this study, using tri-pronuclear (3PN) embryos and human embryonic stem cells (hESCs), we demonstrated that the maternal transcription factor Orthodenticle Homeobox 2 (OTX2), a paired-like homeobox gene, promotes EGA in human pre-implantation embryos. Knockdown of OTX2 through Trim-Away technology blocked embryonic development and minor EGA gene expression. Overexpression of OTX2 (OTX2OE) in hESCs increased transcript products, primarily at the 2-cell embryo stage genes, including genes encoding methyltransferase of histone H3K4. OTX2OE increased the level of H3K4me3 and increased the open chromatin region that co-occurs with the H3K4me3 region at the 4-cell stage in hESCs. Based on these findings in hESCs, we further verified that OTX2 directly induced the expression of SETD1A by binding to its promoter, leading to increased H3K4me3 levels in both hESCs and 3PN embryos. These findings suggest that the maternal transcription factor OTX2 regulates EGA and early embryogenesis via epigenetic mechanisms.
    Keywords:   SETD1A ; OTX2; embryonic genome activation; maternal transcription factor
    DOI:  https://doi.org/10.1007/s11427-024-2875-3
  4. Res Sq. 2025 Apr 09. pii: rs.3.rs-6330979. [Epub ahead of print]
    Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
    David Sherwood, Siddharthan Balachandar Thendral, Sasha Bacot, Katherine Morton, Qiuyi Chi, Isabel Kenny-Ganzert, Joel Meyer.
      The quality of mitochondria inherited from the oocyte determines embryonic viability, metabolic health throughout progeny lifetime, and future generation endurance. High levels of endogenous reactive oxygen species and exogenous toxicants are threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in developed oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here we discover that in C. elegans, the onset of oocyte-to-zygote transition (OZT) developmentally triggers a rapid mitophagy event. We show that mitophagy at OZT (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway, and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Impaired MOZT leads to increased deleterious mtDNA inheritance and decreases embryonic survival. Inherited mtDNA damage accumulates across generations, leading to the extinction of descendent populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity.
    DOI:  https://doi.org/10.21203/rs.3.rs-6330979/v1
  5. Cells Dev. 2025 Apr 30. pii: S2667-2901(25)00035-X. [Epub ahead of print] 204028
    Towards an integrated view and understanding of embryonic signalling during murine gastrulation.
    Rhanna R Haantjes, Jeske Strik, Joëlle de Visser, Marten Postma, Renée van Amerongen, Antonius L van Boxtel.
      At the onset of mammalian gastrulation, secreted signalling molecules belonging to the Bmp, Wnt, Nodal and Fgf signalling pathways induce and pattern the primitive streak, marking the start for the cellular rearrangements that generate the body plan. Our current understanding of how signalling specifies and organises the germ layers in three dimensions, was mainly derived from genetic experimentation using mouse embryos performed over many decades. However, the exact spatiotemporal sequence of events is still poorly understood, both because of a lack of tractable models that allow for real time visualisation of signalling and differentiation and because of the molecular and cellular complexity of these early developmental events. In recent years, a new wave of in vitro embryo models has begun to shed light on the dynamics of signalling during primitive streak formation. Here we discuss the similarities and differences between a widely adopted mouse embryo model, termed gastruloids, and real embryos from a signalling perspective. We focus on the gene regulatory networks that underlie signalling pathway interactions and outline some of the challenges ahead. Finally, we provide a perspective on how embryo models may be used to advance our understanding of signalling dynamics through computational modelling.
    Keywords:  Computational modelling; ES cells; Embryo; Gastrulation; Gastruloid; Mouse; Signalling
    DOI:  https://doi.org/10.1016/j.cdev.2025.204028
  6. Cell Stem Cell. 2025 May 01. pii: S1934-5909(25)00140-7. [Epub ahead of print]32(5): 673-675
    Signaling switches: Metabolism regulates gastruloid self-organization.
    María J Rodríguez Colman, Katharina F Sonnen.
      Metabolic regulation of embryonic development is increasingly recognized. Villaronga-Luque et al.1 and Stopornwongkul et al.2 show that metabolic activity influences gastruloid formation from mouse embryonic stem cells, revealing that the balance between glycolysis and oxidative phosphorylation regulates cell fate decisions during gastruloid self-organization.
    DOI:  https://doi.org/10.1016/j.stem.2025.04.005
  7. PLoS One. 2025 ;20(4): e0322286
    Analysis of Na+ concentration patterns in trophectoderm cells of mouse blastocysts using a dual-wavelength electrolyte indicator.
    Ayaka Fujishima, Kazumasa Takahashi, Mayumi Goto, Akiko Fujishima, Takeo Hirakawa, Takuya Iwasawa, Hiromitsu Shirasawa, Yukiyo Kumazawa, Yukihiro Terada.
      The developmental process of the mammalian blastocyst involves the intricate interplay of cellular and molecular mechanisms, including electrolyte dynamics within the trophectoderm (TE). We hypothesized that sodium (Na+) is actively transported from the TE into the blastocyst cavity, driving water influx and promoting blastocyst expansion. In this study, we investigated the dynamics of Na+ concentration in the TE of mouse embryos using sodium-binding benzofuran isophthalate (SBFI), a dual-wavelength Na+-sensitive fluorescent indicator. Observations revealed three distinct patterns of Na+ dynamics, each correlating with variations in blastocyst cross-sectional area and developmental outcomes. Embryos exhibiting an initial decrease followed by stabilization of Na+ concentration (Group A) demonstrated the highest rates of hatching, suggesting a relationship between Na+ flux and successful embryonic development. In contrast, embryos with transient increases (Group B) displayed reduced hatching rates and developmental progression. Further, the inhibition of Na+/K+-ATPase activity disrupted Na+ flux and blastocyst cavity expansion, emphasizing its critical role in blastocyst formation. This study highlights the potential of dual-wavelength imaging for elucidating electrolyte dynamics in preimplantation embryos and its implications for optimizing embryo culture systems in reproductive medicine.
    DOI:  https://doi.org/10.1371/journal.pone.0322286
  8. Nat Methods. 2025 Apr 29.
    Fast-adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging.
    Chang Qiao, Ziwei Li, Zongfa Wang, Yuhuan Lin, Chong Liu, Siwei Zhang, Yong Liu, Yun Feng, Xiaoyu Yang, Wenfeng Fu, Xue Dong, Jiabao Guo, Wencong Xu, Xinyu Wang, Tao Jiang, Quan Meng, Qinghua Wang, Qionghai Dai, Dong Li.
      Lattice light-sheet microscopy provides a crucial observation window into intra- and intercellular physiology of living specimens but at the diffraction-limited resolution or anisotropic super-resolution with structured illumination. Here we present meta-learning-empowered reflective lattice light-sheet virtual structured illumination microscopy (Meta-rLLS-VSIM), which upgrades lattice light-sheet microscopy to a near-isotropic super resolution of ~120 nm laterally and ~160 nm axially without modifications of the core optical system or loss of other live-cell imaging metrics. Moreover, we devised an adaptive online training approach by synergizing the front-end imaging system and back-end meta-learning framework, which alleviated the demand for training data by tenfold and reduced the total time for data acquisition and model training down to tens of seconds. We demonstrate the versatile functionalities of Meta-rLLS-VSIM by imaging a variety of bioprocesses with ultrahigh spatiotemporal resolution for hundreds of multicolor volumes, delineating the nanoscale distributions, dynamics and interaction patterns of multiple organelles in embryos and eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41592-025-02678-3
  9. Semin Cell Dev Biol. 2025 Apr 28. pii: S1084-9521(25)00024-2. [Epub ahead of print]171 103614
    The role of granulosa cells in oocyte development and aging: Mechanisms and therapeutic opportunities.
    HaiYang Wang.
      Granulosa cells (GCs) are essential for oocyte maturation, providing metabolic support, hormonal signaling, and structural integrity critical to successful follicular development. However, advancing age disrupts these functions, driven by factors such as increased oxidative stress, mitochondrial dysfunction, and transcriptomic and proteomic alterations. These age-related changes in GCs contribute to compromised oocyte quality, diminished follicular support, and a decline in fertility, particularly in women of advanced maternal age. This review highlights recent progress in understanding the pivotal roles of GCs in maintaining oocyte health, with a focus on the mechanisms underlying their aging-related dysfunction. Furthermore, we explore promising therapeutic strategies, including antioxidant therapies, metabolic modulators, and GC-based rejuvenation techniques, aimed at mitigating the impacts of reproductive aging. By consolidating and analyzing existing research, this review provides valuable perspectives on fertility preservation and factors shaping reproductive outcomes in women of advanced maternal age.
    Keywords:  Follicular Microenvironment; Granulosa Cells; Oocyte Development; Reproductive Aging; Therapeutic Interventions
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103614
  10. Reprod Biomed Online. 2024 Dec 23. pii: S1472-6483(24)00971-4. [Epub ahead of print]50(6): 104782
    Does HCG and LH supplementation during ovarian stimulation improve clinical outcome? A evaluation of 30 years of clinical research.
    Bernadette Mannaerts, Claus Yding Andersen, Colin M Howles.
      This review evaluates the effect of HCG and LH supplementation during ovarian stimulation. Controlled trials were divided into four groups comparing the treatment effect of recombinant FSH (r-FSH) with urinary FSH (u-FSH), with human menopausal gonadotrophin (HMG), with r-FSH + recombinant LH (r-LH) and with rFSH + recombinant HCG (r-HCG). First r-FSH seemed to be more potent than u-FSH in downregulated women, which translated into more follicles and oocytes. In line, numerous trials comparing HMG (containing u-FSH + u-HCG) with r-FSH demonstrated that HMG recruited fewer follicles, thus providing fewer oocytes but resulted in slightly higher pregnancy rates after a first fresh embryo transfer. The latter may be explained by the higher potency of r-FSH resulting in more and higher premature progesterone rises. Prospective trials addressing r-FSH + r-LH compared with r-FSH could not demonstrate any difference in pregnancy rates in normal or poor responders. A placebo-controlled trial of r-HCG added to a fixed daily r-FSH dose revealed that r-HCG inhibited the growth of intermediate follicles, resulting in fewer oocytes, fewer embryos and lower pregnancy rates. In conclusion, the beneficial effect of HCG and LH supplementation on clinical outcome has never been definitely proven for any of the combined gonadotrophin products.
    Keywords:  HCG; HMG; LH; inhibition multi-follicular growth
    DOI:  https://doi.org/10.1016/j.rbmo.2024.104782
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