bims-mazytr 2025-03-02 papers

bims-mazytr

Biomed News

on Maternal‐to‐zygotic transition

Issue of 2025–03–02
nineteen papers selected by
川一刀,

Genome-coverage single-cell histone modifications for embryo lineage tracing.
Mammalian oocytes receive maternal-effect RNAs from granulosa cells.
The Mammalian Oocyte: A Central Hub for Cellular Reprogramming and Stemness.
Centrosome-assisted assembly of the Balbiani body.
Melanin deposition and key molecular features in Xenopus tropicalis oocytes.
Emerging cooperativity between Oct4 and Sox2 governs the pluripotency network in early mouse embryos.
Maternal PRDM10 activates essential genes for oocyte-to-embryo transition.
A cluster of RNA Polymerase II molecules is stably associated with an active gene.
ETV4 and ETV5 orchestrate FGF-mediated lineage specification and epiblast maturation during early mouse development.
Epigenetic control of cell identities from epiblast to gastrulation.
The temporal control and activity of maternal zsquildlike-A/hnrnpaba during zebrafish embryogenesis indicate a role in early pattern formation.
Protein degradation and growth dependent dilution substantially shape mammalian proteomes.
Totipotency and high plasticity in an embryo with a stereotyped, invariant cleavage program.
The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation.
Construction of an Atlas of transcription factor binding during mouse development identifies popular regulatory regions.
BHPF inhibits early embryonic development in mice by disrupting maternal-to-zygotic transition and mitochondrial function.
Deletion of a single CTCF motif at the boundary of a chromatin domain with three FGF genes disrupts gene expression and embryonic development.
Multi-omics analyses and machine learning prediction of oviductal responses in the presence of gametes and embryos.
Dorsoventral patterning beyond the gastrulation stage: Interpretation of early dorsoventral cues and modular development mediated by zic1/zic4.

Nature. 2025 Feb 26.

Genome-coverage single-cell histone modifications for embryo lineage tracing.

Min Liu, Yanzhu Yue, Xubin Chen, Kexin Xian, Chao Dong, Ming Shi, Haiqing Xiong, Kang Tian, Yuzhe Li, Qiangfeng Cliff Zhang, Aibin He.

Substantial epigenetic resetting during early embryo development from fertilization to blastocyst formation ensures zygotic genome activation and leads to progressive cellular heterogeneities1-3. Mapping single-cell epigenomic profiles of core histone modifications that cover each individual cell is a fundamental goal in developmental biology. Here we develop target chromatin indexing and tagmentation (TACIT), a method that enabled genome-coverage single-cell profiling of seven histone modifications across mouse early embryos. We integrated these single-cell histone modifications with single-cell RNA sequencing data to chart a single-cell resolution epigenetic landscape. Multimodal chromatin-state annotations showed that the onset of zygotic genome activation at the early two-cell stage already primes heterogeneities in totipotency. We used machine learning to identify totipotency gene regulatory networks, including stage-specific transposable elements and putative transcription factors. CRISPR activation of a combination of these identified transcription factors induced totipotency activation in mouse embryonic stem cells. Together with single-cell co-profiles of multiple histone modifications, we developed a model that predicts the earliest cell branching towards the inner cell mass and the trophectoderm in latent multimodal space and identifies regulatory elements and previously unknown lineage-specifying transcription factors. Our work provides insights into single-cell epigenetic reprogramming, multimodal regulation of cellular lineages and cell-fate priming during mouse pre-implantation development.

DOI: https://doi.org/10.1038/s41586-025-08656-1
bioRxiv. 2025 Feb 11. pii: 2025.02.10.637575. [Epub ahead of print]

Mammalian oocytes receive maternal-effect RNAs from granulosa cells.

Caroline A Doherty, Abdulfatai Tijjani, Steven C Munger, Diana J Laird.

It is currently thought that growing mammalian oocytes receive only small molecules via gap junctions from surrounding support cells, the granulosa cells. From the study of chimeric preantral oocyte and granulosa cell reaggregations, we provide evidence that growing mouse oocytes receive mRNAs from granulosa cells. Among the >1,000 granulosa-transcribed RNAs we identified in the oocyte, those that contribute to proper oocyte maturation and early embryo development were highly enriched. Predicted motifs for two RNA-binding proteins that function in RNA trafficking, FMRP and TDP43, were abundant in the UTRs of the granulosa-derived transcripts. Immunostaining demonstrated that both FMRP and TDP43 co-localize with the actin-rich granulosa cell protrusions that span the zone pellucida and connect to the oocyte, suggesting their role in importing mRNAs. Our results offer the possibility that oocyte failure may not always reflect an intrinsic oocyte deficiency but could arise from insufficient supply of maternal transcripts by granulosa cells during oocyte growth.

DOI: https://doi.org/10.1101/2025.02.10.637575
Stem Cells Cloning. 2025 ;18 15-34

The Mammalian Oocyte: A Central Hub for Cellular Reprogramming and Stemness.

Islam M Saadeldin, Seif Ehab, Mashan Essa F Alshammari, Aaser M Abdelazim, Abdullah M Assiri.

  The mammalian oocyte is pivotal in reproductive biology, acting as a central hub for cellular reprogramming and stemness. It uniquely contributes half of the zygotic nuclear genome and the entirety of the mitochondrial genome, ensuring individual development and health. Oocyte-mediated reprogramming, exemplified by nuclear transfer, resets somatic cell identity to achieve pluripotency and has transformative potential in regenerative medicine. This process is critical for understanding cellular differentiation, improving assisted reproductive technologies, and advancing cloning and stem cell research. During fertilization, the maternal-zygotic transition shifts developmental control from maternal factors to zygotic genome activation, establishing totipotency. Oocytes also harbor reprogramming factors that guide nuclear remodeling, epigenetic modifications, and metabolic reprogramming, enabling early embryogenesis. Structures like mitochondria, lipid droplets, and cytoplasmic lattices contribute to energy production, molecular regulation, and cellular organization. Recent insights into oocyte components, such as ooplasmic nanovesicles and endolysosomal vesicular assemblies (ELVAS), highlight their roles in maintaining cellular homeostasis, protein synthesis, and reprogramming efficiency. By unraveling the reprogramming mechanisms inherent in oocytes, we advance our understanding of cloning, cell differentiation, and stem cell therapy, highlighting their valuable significance in developmental biology and regenerative medicine.

Keywords:  epigenetics; genome activation; oocytes; reprogramming

DOI:  https://doi.org/10.2147/SCCAA.S513982
bioRxiv. 2025 Feb 12. pii: 2025.02.11.637656. [Epub ahead of print]

Centrosome-assisted assembly of the Balbiani body.

Divyanshi

The Balbiani body (Bb), which was discovered about 170 years ago, is a membraneless organelle in the oocyte in most species. In organisms like Xenopus and Zebrafish, Bb accumulates mitochondria, endoplasmic reticulum (ER), and germline determinants and regulates the proper localization of germline determinants. The Bb forms around the centrosome in the oocyte during early oogenesis. The mechanism behind its assembly has gained attention only very recently. Here, we report that overexpression of the germ plasm matrix protein Xvelo leads to the formation of a 'Bb-like' structure in somatic cells. The 'Bb-like' structure assembles around the centrosome and selectively recruits mitochondria, ER, and germline determinants. Taking advantage of this system, we investigated the roles of centrosome components on the assembly of Xvelo. Our results reveal that multiple components of the centrosome, including Sas6, Cenexin, and DZIP1, interact with Xvelo and promote its assembly, with Sas6 exhibiting the most prominent activity. Importantly, knocking down Sas6, Cenexin, and DZIP1 individually or in combination resulted in reduced Xvelo aggregates. Taken together, our work suggests that the centrosome may function as a nucleation center to promote the initiation of Xvelo assembly, resulting in the formation of the Bb around the centrosome.

DOI: https://doi.org/10.1101/2025.02.11.637656
BMC Biol. 2025 Feb 27. 23(1): 62

Melanin deposition and key molecular features in Xenopus tropicalis oocytes.

Hongyang Yi, Weizheng Liang, Sumei Yang, Han Liu, Jiayu Deng, Shuhong Han, Xiaohui Feng, Wenjie Cheng, Yonglong Chen, Jing Hang, Hongzhou Lu, Rensen Ran.

   BACKGROUND: Melanin pigmentation in oocytes is a critical feature for both the esthetic and developmental aspects of oocytes, influencing their polarity and overall development. Despite substantial knowledge of melanogenesis in melanocytes and retinal pigment epithelium cells, the molecular mechanisms underlying oocyte melanogenesis remain largely unknown.
RESULTS: Here, we compare the oocytes of wild-type, tyr-/- and mitf-/- Xenopus tropicalis and found that mitf-/- oocytes exhibit normal melanin deposition at the animal pole, whereas tyr-/- oocytes show no melanin deposition at this site. Transmission electron microscopy confirmed that melanogenesis in mitf-/- oocytes proceeds normally, similar to wild-type oocytes. Transcriptomic analysis revealed that mitf-/- oocytes still express melanogenesis-related genes, enabling them to complete melanogenesis. Additionally, in Xenopus tropicalis oocytes, the expression of the MiT subfamily factor tfe3 is relatively high, while tfeb, mitf, and tfec levels are extremely low. The expression pattern of tfe3 is similar to that of tyr and other melanogenesis-related genes. Thus, melanogenesis in Xenopus tropicalis oocytes is independent of Mitf and may be regulated by other MiT subfamily factors such as Tfe3, which control the expression of genes like tyr, dct, and tyrp1. Furthermore, transcriptomic data revealed that changes in the expression of genes related to mitochondrial cloud formation represent the most significant molecular changes during oocyte development.
CONCLUSIONS: Overall, these findings suggest that further elucidation of Tyr-dependent and Mitf-independent mechanisms of melanin deposition at the animal pole will enhance our understanding of melanogenesis and Oogenesis.

Keywords:   Xenopus tropicalis ; Melanogenesis; Mitochondrial cloud; Oogenesis

DOI:  https://doi.org/10.1186/s12915-025-02168-0
Elife. 2025 Feb 27. pii: RP100735. [Epub ahead of print]13

Emerging cooperativity between Oct4 and Sox2 governs the pluripotency network in early mouse embryos.

Yanlin Hou, Zhengwen Nie, Qi Jiang, Sergiy Velychko, Sandra Heising, Ivan Bedzhov, Guangming Wu, Kenjiro Adachi, Hans R Scholer.

  During the first lineage segregation, mammalian embryos generate the inner cell mass (ICM) and trophectoderm (TE). ICM gives rise to the epiblast (EPI) that forms all cell types of the body, an ability referred to as pluripotency. The molecular mechanisms that induce pluripotency in embryos remain incompletely elucidated. Using knockout (KO) mouse models in conjunction with low-input ATAC-seq and RNA-seq, we found that Oct4 and Sox2 gradually come into play in the early ICM, coinciding with the initiation of Sox2 expression. Oct4 and Sox2 activate the pluripotency-related genes through the putative OCT-SOX enhancers in the early ICM. Furthermore, we observed a substantial reorganization of chromatin landscape and transcriptome from the morula to the early ICM stages, which was partially driven by Oct4 and Sox2, highlighting their pivotal role in promoting the developmental trajectory toward the ICM. Our study provides new insights into the establishment of the pluripotency network in mouse preimplantation embryos.

Keywords:  Oct4; Sox2; chromatin accessibility; developmental biology; embryonic development; inner cell mass; mouse; transcriptome

DOI:  https://doi.org/10.7554/eLife.100735
Nat Commun. 2025 Feb 24. 16(1): 1939

Maternal PRDM10 activates essential genes for oocyte-to-embryo transition.

Michelle K Y Seah, Brenda Y Han, Yan Huang, Louise J H Rasmussen, Andrina J Stäubli, Judith Bello-Rodríguez, Andrew Chi-Ho Chan, Maxime Gasnier, Heike Wollmann, Ernesto Guccione, Daniel M Messerschmidt.

PR/SET domain-containing (PRDM) proteins are metazoan-specific transcriptional regulators that play diverse roles in mammalian development and disease. Several members such as PRDM1, PRDM14 and PRDM9, have been implicated in germ cell specification and homoeostasis and are essential to fertility-related processes. Others, such as PRDM14, PRDM15 and PRDM10 play a role in early embryogenesis and embryonic stem cell maintenance. Here, we describe the first PRDM family member with a maternal effect. Absence of maternal Prdm10 results in catastrophic failure of oocyte-to-embryo transition and complete arrest at the 2-cell stage. We describe multiple defects in oocytes, zygotes and 2-cell stage embryos relating to the failure to accumulate PRDM10 target gene transcripts in the egg. Transcriptomic analysis and integration of genome-wide chromatin-binding data reveals new and essential PRDM10 targets, including the cytoskeletal protein encoding gene Septin11. We demonstrate that the failure to express maternal Septin11, in the absence of maternal PRDM10, disrupts Septin-complex assembly at the polar body extrusion site in MII oocytes. Our study sheds light into the essentiality of maternal PRDM10, the requirement of the maternal Septin-complex and the likely evolutionary conservation of this regulatory axis in human female germ cells.

DOI: https://doi.org/10.1038/s41467-025-56991-8
bioRxiv. 2025 Feb 11. pii: 2025.02.10.637507. [Epub ahead of print]

A cluster of RNA Polymerase II molecules is stably associated with an active gene.

Apratim Mukherjee, Manya Kapoor, Kareena Shankta, Samantha Fallacaro, Raymond D Carter, Puttachai Ratchasanmuang, Yara I Haloush, Mustafa Mir.

In eukaryotic nuclei, transcription is associated with discrete foci of RNA Polymerase II (RNAPII) molecules. How these clusters interact with genes and their impact on transcriptional activity remain heavily debated. Here we take advantage of the naturally occurring increase in transcriptional activity during Zygotic Genome Activation (ZGA) in Drosophila melanogaster embryos to characterize the functional roles of RNAPII clusters in a developmental context. Using single-molecule tracking and lattice light-sheet microscopy, we find that RNAPII cluster formation depends on transcription initiation and that cluster lifetimes are reduced upon transcription elongation. We show that single clusters are stably associated with active gene loci during transcription and that cluster intensities are strongly correlated with transcriptional output. Our data suggest that prior to ZGA, RNAPII clusters prime genes for activation, whereas after ZGA, clusters are composed mostly of elongating molecules at individual genes.

DOI: https://doi.org/10.1101/2025.02.10.637507
Development. 2025 Feb 26. pii: dev.204278. [Epub ahead of print]

ETV4 and ETV5 orchestrate FGF-mediated lineage specification and epiblast maturation during early mouse development.

Claire S Simon, Woonyung Hur, Vidur Garg, Ying-Yi Kuo, Kathy K Niakan, Anna-Katerina Hadjantonakis.

  Cell fate decisions in early mammalian embryos are tightly regulated processes crucial for proper development. While FGF signaling plays key roles in early embryo patterning, its downstream effectors remain poorly understood. Our study demonstrates that the transcription factors Etv4 and Etv5 are critical mediators of FGF signaling in cell lineage specification and maturation in mouse embryos. We show that loss of Etv5 compromises primitive endoderm formation at pre-implantation stages. Furthermore, Etv4/5 deficiency delays naïve pluripotency exit and epiblast maturation, leading to elevated NANOG and reduced OTX2 expression within the blastocyst epiblast. As a consequence of delayed pluripotency progression, Etv4/5 deficient embryos exhibit anterior visceral endoderm migration defects post-implantation, a process essential for coordinated embryonic patterning and gastrulation initiation. Our results demonstrate the successive roles of these FGF signaling effectors in early lineage specification and embryonic body plan establishment, providing new insights into the molecular control of mammalian development.

Keywords:  ETV; Epiblast; FGF; Pluripotency; Primitive endoderm

DOI:  https://doi.org/10.1242/dev.204278
FEBS J. 2025 Feb 22.

Epigenetic control of cell identities from epiblast to gastrulation.

Katrin M Schüle, Simone Probst.

  Epigenetic modifications of chromatin are essential for the establishment of cell identities during embryogenesis. Between embryonic days 3.5-7.5 of murine development, major cell lineage decisions are made that discriminate extraembryonic and embryonic tissues, and the embryonic primary germ layers are formed, thereby laying down the basic body plan. In this review, we cover the contribution of dynamic chromatin modifications by DNA methylation, changes of chromatin accessibility, and histone modifications, that in combination with transcription factors control gene expression programs of different cell types. We highlight the differences in regulation of enhancer and promoter marks and discuss their requirement in cell lineage specification. Importantly, in many cases, lineage-specific targeting of epigenetic modifiers is carried out by pioneer or master transcription factors, that in sum mediate the chromatin landscape and thereby control the transcription of cell-type-specific gene programs and thus, cell identities.

Keywords:  DNA methylation; embryonic stem cells; epigenetics; gastrulation; germ layers; histone modifications; mouse embryo; nucleosome remodeling; transcription factors

DOI:  https://doi.org/10.1111/febs.70024
Zygote. 2025 Feb 25. 1-11

The temporal control and activity of maternal zsquildlike-A/hnrnpaba during zebrafish embryogenesis indicate a role in early pattern formation.

Nicole Molnar, Allie Capik, Amgad Ishak, Natella Maglakelidze, Luke J Pasick, Billie Reneker, Alyse Volino, Marcia L O'Connell.

  During embryogenesis in Danio rerio (zebrafish), the earliest morphological patterning events are dependent on the precise temporal translation and/or localization of specific maternal mRNAs/proteins. Dorsoventral patterning in particular requires the translocation of maternal factors that are present in the Balbiani Body from the vegetal region of the unfertilized egg to the future dorsal side of the embryo (Fuentes et al., 2020), leading to the localized activation of the β-catenin pathway in the cells in that region. Since zebrafish are chordates, this dorsoventral patterning then leads to the formation of neural tissue on the dorsal side of the embryo. What is not yet clear is the identity of all maternal and zygotic factors that first establish dorsoventral patterning, and which factors lead to the establishment of neural versus non-neural tissue. Taking an evolutionary approach to this question, we investigated a gene in zebrafish, zsquidlike-A (hnrnpaba), that is homologous to a key dorsoventral patterning gene in fruit flies (Drosophila melanogaster) called squid (Kelley, 1993). While dorsoventral patterning in flies and fish looks quite different both morphologically and at the molecular level, we demonstrate that not only has a key dorsoventral patterning gene in flies been conserved in fish, maternal fish zsquidlike-A protein is synthesized precisely as dorsoventral patterning is unfolding in fish embryos, and in its absence, dorsoventral patterning is severely disrupted.

Keywords:  Squid; bilaterian; embryogenesis; morpholino; zebrafish

DOI:  https://doi.org/10.1017/S0967199425000024
bioRxiv. 2025 Feb 12. pii: 2025.02.10.637566. [Epub ahead of print]

Protein degradation and growth dependent dilution substantially shape mammalian proteomes.

Andrew Leduc, Nikolai Slavov.

Cellular protein concentrations are maintained through a balance of synthesis and clearance. Clearance occurs through both protein degradation and growth-dependent dilution. At slow growth, clearance is dominated by degradation, which leads to the accumulation of long lived proteins. At fast growth, however, it is dominated by dilution, preventing this accumulation. Thus, the concentration of long lived proteins will be reduced unless cells compensate by preferentially increasing synthesis rates. To determine the dominant regulatory mechanisms, we quantified the degree of compensation between activated and resting human B cells and across mouse tissues. The results indicate that growth-dependent dilution is insufficiently compensated for by changes in protein synthesis, and it accounts for over a third of the concentration changes between high and low growth conditions. Furthermore, we find that about 25 % of the differences in protein concentration across all tissues are controlled by protein clearance. When comparing only slowly growing tissues such as the brain and pancreas, clearance differences explain as much as 42 %. Within a tissue or cell type, clearance variation is sufficient to account for 50 % of the abundance variation for all measured proteins at slow growth, contrasted with 7 % at fast growth. Thus, our model unifies previous observations with our new results and highlights a context-dependent and larger than previously appreciated contribution of protein degradation in shaping protein variation both across the proteome and across cell states.

DOI: https://doi.org/10.1101/2025.02.10.637566
bioRxiv. 2025 Feb 13. pii: 2025.02.12.637942. [Epub ahead of print]

Totipotency and high plasticity in an embryo with a stereotyped, invariant cleavage program.

Amber Q Rock, Mansi Srivastava.

Animal embryos begin as totipotent zygotes, which undergo cell divisions and produce progeny with restricted fate potentials over time. However, the timing of when totipotency is lost and the processes through which embryonic cells acquire fates vary across species. Embryos with invariant cleavage programs, e.g. of nematodes and spiralians, tend to show early restriction of blastomere potency and limited robustness to perturbation, particularly after asymmetric cleavages have occurred. In contrast, embryos with variant cleavage programs, e.g. of vertebrates, tend to specify fates later in development and correspondingly show higher plasticity at early stages. Here, we investigate the embryos of the acoel Hofstenia miamia , which represents an understudied phylum (Xenacoelomorpha) that is distantly related to well-studied developmental systems. Given the invariant 'duet' cleavage program observed in H. miamia embryos, we found unexpected robustness in this species. Isolated 4-cell stage macromeres, the products of an asymmetric, fate specifying cleavage, were totipotent, forming whole organisms upon isolation. Notably, these isolated macromeres produced pharyngeal and neuronal tissues, which they do not produce during normal development. This assay is highly reproducible and can be done at high throughput in H. miamia , making this species an ideal system to investigate the causes of totipotency after specification. Photoconversion-based lineage tracing revealed that rescued cell types are not merely replaced by neoblasts, the adult pluripotent stem cells in H. miamia , suggesting that the macromere's totipotency is the result of changes in the fate potentials of early embryonic cells. Remarkably, all blastomeres at the 8-cell stage were capable of reprogramming their fates in embryo reconstitution assays. By assembling different subsets of 8-cell stage blastomeres, none of which are totipotent on their own, we determined that a minimal unit of two blastomeres, one macromere that produces gut and neoblasts and one micromere that is specified to produce muscle and epidermis, was sufficient to develop into a hatchling worm. Future studies of this system could identify the precise mechanisms that can enable tremendous plasticity, including post-zygotic totipotency, in an embryo with well-defined cellular lineages.

DOI: https://doi.org/10.1101/2025.02.12.637942
Genes Dev. 2025 Feb 27.

The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation.

Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla.

  The regulatory circuitry of cell-specific transcriptional programs is thought to be influenced by transposable elements (TEs), whereby TEs serve as raw material for the diversification and genome-wide distribution of genetic elements that contain cis-regulatory activity. However, the transcriptional activators of TEs in relevant physiological contexts are largely unknown. Here, we undertook an evolutionary approach to identify regulators of two main families of MERVL, a major regulator of transcription during early mouse development. Using a combination of phyloregulatory, transcriptomic, and loss-of-function approaches, we demonstrate that SRF is a novel regulator of MERVL and embryonic transcription during zygotic genome activation. By resolving the phylogenetic history of two major MERVL families, we delineate the evolutionary acquisition of SRF and DUX binding sites and show that the acquisition of the SRF site precedes that of DUX. SRF contributes to embryonic transcription through the regulation of MERVLs, which in turn serve as promoters for host genes. Our work identifies new transcriptional regulators and TEs that shape the gene expression programs in early embryos and highlights the process of TE domestication via the sequential acquisition of transcription factor binding sites and coevolution with the host.

Keywords:  MERVL; mouse embryos; retrotransposons; transcription

DOI:  https://doi.org/10.1101/gad.352270.124
Development. 2025 Feb 27. pii: dev.204311. [Epub ahead of print]

Construction of an Atlas of transcription factor binding during mouse development identifies popular regulatory regions.

Anna Nordin, Gianluca Zambanini, Mattias Jonasson, Tamina Weiss, Yorick van de Grift, Pierfrancesco Pagella, Claudio Cantù.

  Gene regulators physically associate to the genome, in a combinatorial fashion, to drive tissue-specific gene expression. Uncovering the genome-wide activity of all gene regulators across tissues is therefore needed to understand gene regulation during development. Here, we take a first step towards this goal. Using CUT&RUN, we systematically mapped genome-wide binding profiles of key transcription factors and cofactors that mediate ontogenetically relevant signaling pathways in select mouse tissues at two developmental stages. Computation of the datasets unveiled tissue and time-specific activity for each gene regulator. We identified "popular" regulatory regions that are bound by a multitude of regulators, which tend to be more evolutionarily conserved. Consistently, they lie near the TSS of genes whose dysregulation causes early embryonic lethality. Moreover, the human homologs of these regions are similarly bound by many gene regulators and are highly conserved, indicating a retained relevance for human development. This work constitutes a decisive step towards understanding how the genome is simultaneously read and used by gene regulators in a holistic fashion to drive embryonic development.

Keywords:  CUT&RUN; Chromatin; Development; Gene regulation; Transcription factors

DOI:  https://doi.org/10.1242/dev.204311
Food Chem Toxicol. 2025 Feb 20. pii: S0278-6915(25)00109-7. [Epub ahead of print]199 115342

BHPF inhibits early embryonic development in mice by disrupting maternal-to-zygotic transition and mitochondrial function.

Zhiming Ding, Hongzhen Ruan, Yujie Wang, Liuliu Dong, Caiyun Wu, Yunxia Cao, Huifen Xiang, Dan Liang.

  Fluorene-9-bisphenol (BHPF), a prevalent substitute for bisphenol A (BPA), has become a widespread endocrine disruptor found in numerous consumer products. Despite extensive research on its toxicological profile, the specific effects of BHPF on reproduction, particularly during early embryonic development, remain unclear. Therefore, in our study, we used an in vitro culture system of mouse embryos to treat fertilized eggs with different concentrations of BHPF, and applied immunofluorescence, cell live staining and transcriptome sequencing to explore the effects of BHPF on early embryonic development and related mechanisms. Our study demonstrates that BHPF exposure causes significant developmental arrest in early embryonic stages. Transcriptomic analysis revealed that BHPF exposure altered gene expression at the 2-cell stage, notably impairing zygotic genome activation and maternal mRNA degradation, which disrupted the maternal-to-zygotic transition. Furthermore, BHPF exposure impaired mitochondrial function, as illustrated by altered mitochondrial distribution, reduced membrane potential, and decreased ATP production. Oxidative stress and DNA damage in 2-cell embryos were linked to the accumulation of reactive oxygen species and superoxide anions induced by BHPF. Additionally, BHPF-treated embryos exhibited altered histone modification patterns, suggesting epigenetic disruptions. Overall, these results indicate that BHPF has the potential to disrupt early embryonic development, raising concerns regarding its safety as a BPA substitute.

Keywords:  BHPF; Embryo; Maternal-zygote transition; Mitochondrial dysfunction; Mouse

DOI:  https://doi.org/10.1016/j.fct.2025.115342
Dev Cell. 2025 Feb 24. pii: S1534-5807(25)00064-4. [Epub ahead of print]

Deletion of a single CTCF motif at the boundary of a chromatin domain with three FGF genes disrupts gene expression and embryonic development.

Shreeta Chakraborty, Nina Wenzlitschke, Matthew J Anderson, Ariel Eraso, Manon Baudic, Joyce J Thompson, Alicia A Evans, Lilly M Shatford-Adams, Raj Chari, Parirokh Awasthi, Ryan K Dale, Mark Lewandoski, Timothy J Petros, Pedro P Rocha.

  Chromatin domains delimited by CTCF can restrict the range of enhancer action. However, disruption of some domain boundaries results in mild gene dysregulation and phenotypes. We tested whether perturbing a domain with multiple developmental regulators would lead to more severe outcomes. We chose a domain with three FGF ligand genes-Fgf3, Fgf4, and Fgf15-that control different murine developmental processes. Heterozygous deletion of a 23.9-kb boundary defined by four CTCF sites led to ectopic interactions of the FGF genes with enhancers active in the brain and induced FGF expression. This caused orofacial clefts, encephalocele, and fully penetrant perinatal lethality. Loss of the single CTCF motif oriented toward the enhancers-but not the three toward the FGF genes-recapitulated these phenotypes. Our works shows that small sequence variants at particular domain boundaries can have a surprisingly outsized effect and must be considered as potential sources of gene dysregulation in development and disease.

Keywords:  CTCF; FGF; epigenetics; gene regulation; nuclear organization

DOI:  https://doi.org/10.1016/j.devcel.2025.02.002
Elife. 2025 Feb 26. pii: RP100705. [Epub ahead of print]13

Multi-omics analyses and machine learning prediction of oviductal responses in the presence of gametes and embryos.

Ryan M Finnerty, Daniel J Carulli, Akshata Hedge, Yanli Wang, Frimpong Boadu, Sarayut Winuthayanon, Jianlin Jack Cheng, Wipawee Winuthayanon.

  The oviduct is the site of fertilization and preimplantation embryo development in mammals. Evidence suggests that gametes alter oviductal gene expression. To delineate the adaptive interactions between the oviduct and gamete/embryo, we performed a multi-omics characterization of oviductal tissues utilizing bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and proteomics collected from distal and proximal at various stages after mating in mice. We observed robust region-specific transcriptional signatures. Specifically, the presence of sperm induces genes involved in pro-inflammatory responses in the proximal region at 0.5 days post-coitus (dpc). Genes involved in inflammatory responses were produced specifically by secretory epithelial cells in the oviduct. At 1.5 and 2.5 dpc, genes involved in pyruvate and glycolysis were enriched in the proximal region, potentially providing metabolic support for developing embryos. Abundant proteins in the oviductal fluid were differentially observed between naturally fertilized and superovulated samples. RNA-seq data were used to identify transcription factors predicted to influence protein abundance in the proteomic data via a novel machine learning model based on transformers of integrating transcriptomics and proteomics data. The transformers identified influential transcription factors and correlated predictive protein expressions in alignment with the in vivo-derived data. Lastly, we found some differences between inflammatory responses in sperm-exposed mouse oviducts compared to hydrosalpinx Fallopian tubes from patients. In conclusion, our multi-omics characterization and subsequent in vivo confirmation of proteins/RNAs indicate that the oviduct is adaptive and responsive to the presence of sperm and embryos in a spatiotemporal manner.

Keywords:  C57BL/6J; Mus; Mus musculus; cell biology; mouse; oviduct; preimplantation embryo; sperm; superovulation

DOI:  https://doi.org/10.7554/eLife.100705
Cells Dev. 2025 Feb 24. pii: S2667-2901(25)00019-1. [Epub ahead of print] 204012

Dorsoventral patterning beyond the gastrulation stage: Interpretation of early dorsoventral cues and modular development mediated by zic1/zic4.

Toru Kawanishi, Hiroyuki Takeda.

Dorsoventral (DV) patterning is fundamental to vertebrate development, organizing the entire body across different germ layers. Although early DV axis formation, centered on the Spemann-Mangold organizer through the BMP activity gradient, has been extensively studied, the mechanisms shaping DV traits during later development remain largely unexplored. In this review, we highlight recent findings, especially from studies involving the Double anal fin (Da) spontaneous mutant of the small teleost medaka (Oryzias latipes), focusing on the roles of zic1 and zic4 (zic1/zic4) in regulating late DV patterning. These genes establish the dorsal domain of the trunk by converting the initial BMP gradient into distinct on/off spatial compartments within somites and their derivatives, acting as selector genes that define dorsal-specific traits, including myotome structure, body shape, and dorsal fin development. We also discuss how the zic-mediated dorsal domain is established and maintained from embryogenesis through adulthood. Furthermore, we provide evidence that zic-dependent action on the dorsal characteristics is dosage-dependent. We propose that the zic1/zic4-mediated DV patterning mechanism may represent a conserved regulatory framework that has been adapted to support the diverse body plans observed across vertebrate species.

DOI: https://doi.org/10.1016/j.cdev.2025.204012