bims-ginsta Biomed News
on Genome instability
Issue of 2025–08–03
29 papers selected by
Jinrong Hu, National University of Singapore
  1. Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst.
  2. Piezo1 balances membrane and cortex tension to stabilize intercellular junctions and maintain epithelial barrier.
  3. Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures.
  4. A spatiotemporal atlas of mouse gastrulation and early organogenesis to explore axial patterning and project in vitro models onto in vivo space.
  5. Live imaging endogenous transcription factor dynamics reveals mechanisms of epiblast and primitive endoderm fate segregation.
  6. Diffusing protein binders to intrinsically disordered proteins.
  7. Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry.
  8. Cohesin-mediated stabilization of the CCAN complex at kinetochores in mitosis.
  9. Dynamic Proteome Landscape During Preimplantation Human Embryo Development and Trophectoderm Stem Cell-Differentiation.
  10. Predicting the translation efficiency of messenger RNA in mammalian cells.
  11. Ca2+-driven cytoplasmic backflow ensures spindle anchoring in fertilized mouse eggs.
  12. SMCHD1 maintains heterochromatin, genome compartments and epigenome landscape in human myoblasts.
  13. Modeling heart rhythm using human engineered heart tissues.
  14. Spatiotemporal H2O2 flashes coordinate actin cytoskeletal remodeling and regulate cell migration and wound healing.
  15. Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals.
  16. N-cadherin mechanosensing in ovarian follicles controls oocyte maturation and ovulation.
  17. Stress granule clearance mediated by V-ATPase-interacting protein NCOA7 mitigates ovarian aging.
  18. USP17L promotes the 2-cell-like program through deubiquitination of H2AK119ub1 and ZSCAN4.
  19. eIF1 and eIF5 dynamically control translation start site fidelity.
  20. Meteorins regulate the formation of the left-right organizer and the establishment of vertebrate body asymmetry.
  21. PAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation, with relevance to human fertility.
  22. Formation control between leader and migratory follower tissues allows coordinated growth.
  23. HIF-independent oxygen sensing via KDM6A regulates ferroptosis.
  24. Epithelial cell membrane perforation induces allergic airway inflammation.
  25. Nucleosomes specify co-factor access to p53.
  26. Altered translation elongation contributes to key hallmarks of aging in the killifish brain.
  27. Dual lineage origins contribute to neocortical astrocyte diversity.
  28. Mammalian cells measure the extracellular matrix area and respond through switching the adhesion state.
  29. A resource of RNA-binding protein motifs across eukaryotes reveals evolutionary dynamics and gene-regulatory function.
  1. Nat Commun. 2025 Jul 28. 16(1): 6922
    Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst.
    Claire S Simon, Afshan McCarthy, Laura Woods, Desislava Staneva, Martin Proks, Nazmus Salehin, Georgia Lea, Qiulin Huang, Madeleine Linneberg-Agerholm, Alex Faulkner, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Meenakshi Choudhary, Mary Herbert, Courtney W Hanna, Joshua M Brickman, Kathy K Niakan.
      Studies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naïve human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and maintain molecular markers of the epiblast. Our functional study demonstrates the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner.
    DOI:  https://doi.org/10.1038/s41467-025-61830-x
  2. J Cell Sci. 2025 Jul 31. pii: jcs.263938. [Epub ahead of print]
    Piezo1 balances membrane and cortex tension to stabilize intercellular junctions and maintain epithelial barrier.
    Ahsan Javed, Aki Stubb, Clémentine Villeneuve, Satu-Marja Myllymäki, Franziska Peters, Matthias Rübsam, Carien M Niessen, Leah C Biggs, Sara A Wickström.
      Formation of the skin barrier is essential for organismal survival and tissue homeostasis. Barrier formation requires positioning of functional tight junctions (TJ) to the most suprabasal viable layer of the epidermis through a mechanical circuit that is driven by generation of high tension at adherens junctions. However, what allows the sensing of tension build-up at these adhesions and how this tension is balanced to match the requirements of tissue mechanical properties is unclear. Here we show that the mechanosensitive ion channel Piezo1 is essential for the maturation of intercellular junctions into functional, continuous adhesions. Deletion of Piezo1 results in an imbalance of cell contractility and membrane tension, leading to a delay in adhesion maturation. Consequently, the requirement for Piezo1 activity can be bypassed by lowering contractility or elevating membrane tension. In vivo, Piezo1 function in adhesion integrity becomes essential only in aged mice where alterations in tissue mechanics lead to impaired tight junctions and barrier dysfunction. Collectively these studies reveal an essential function of Piezo1 in the timely establishment and maintenance of cell-cell junctions within a mechanically tensed epidermis.
    Keywords:  Cell-cell contacts; Epidermis; Mechanotransduction; Piezo1
    DOI:  https://doi.org/10.1242/jcs.263938
  3. Cell. 2025 Jul 22. pii: S0092-8674(25)00749-4. [Epub ahead of print]
    Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures.
    Yingjie Ding, Yuesheng Zuo, Bin Zhang, Yanling Fan, Gang Xu, Zhongyi Cheng, Shuai Ma, Shuaiqi Fang, Ao Tian, Dandan Gao, Xi Xu, Qiaoran Wang, Yaobin Jing, Mengmeng Jiang, Muzhao Xiong, Jiaming Li, Zichu Han, Shuhui Sun, Si Wang, Fuchu He, Jiayin Yang, Jing Qu, Weiqi Zhang, Guang-Hui Liu.
      Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized organ-level aging trajectories. Temporal analysis revealed an aging inflection around age 50, with blood vessels being a tissue that ages early and is markedly susceptible to aging. We further defined a plasma proteomic signature of aging that matches its tissue origins and identified candidate senoproteins, including GAS6, driving vascular and systemic aging. Together, our findings lay the groundwork for a systems-level understanding of human aging through the lens of proteins.
    Keywords:  aging; aging clock; amyloid; biomarker; inflammation; protein; proteomics; senokine; senoprotein; vascular aging
    DOI:  https://doi.org/10.1016/j.cell.2025.06.047
  4. Cell Rep. 2025 Jul 28. pii: S2211-1247(25)00818-6. [Epub ahead of print]44(8): 116047
    A spatiotemporal atlas of mouse gastrulation and early organogenesis to explore axial patterning and project in vitro models onto in vivo space.
    Luke T G Harland, Tim Lohoff, Noushin Koulena, Nico Pierson, Constantin Pape, Farhan Ameen, Jonathan Griffiths, Bart Theeuwes, Nicola K Wilson, Anna Kreshuk, Wolf Reik, Jennifer Nichols, Long Cai, John C Marioni, Berthold Göttgens, Shila Ghazanfar.
      During gastrulation, mouse epiblast cells form the three germ layers that establish the body plan and initiate organogenesis. While single-cell atlases have advanced our understanding of lineage diversification, spatial aspects of differentiation remain poorly defined. Here, we applied spatial transcriptomics to mouse embryos at embryonic (E) E7.25 and E7.5 days and integrated these data with existing E8.5 spatial and E6.5-E9.5 single-cell RNA-seq atlases. This resulted in a spatiotemporal atlas of over 150,000 cells with 82 refined cell-type annotations. The resource enables exploration of gene expression dynamics across anterior-posterior and dorsal-ventral axes, uncovering spatial logic guiding mesodermal fate decisions in the primitive streak. We also developed a computational pipeline to project additional single-cell datasets into this framework for comparative analysis. Freely accessible through an interactive web portal, this atlas offers a valuable tool for the developmental and stem cell biology communities to investigate mouse embryogenesis in a spatial and temporal context.
    Keywords:  CP: Developmental biology; CP: Genomics; axial patterning; gastrulation; gastruloids; mouse development; organogenesis; single cell transcriptomics; spatial transcriptomics; spatiotemporal atlas
    DOI:  https://doi.org/10.1016/j.celrep.2025.116047
  5. Curr Biol. 2025 Jul 26. pii: S0960-9822(25)00897-8. [Epub ahead of print]
    Live imaging endogenous transcription factor dynamics reveals mechanisms of epiblast and primitive endoderm fate segregation.
    Rebecca P Kim-Yip, David Denberg, Denis F Faerberg, Hayden Nunley, Isabella Leite, Madeleine Chalifoux, Bradley Joyce, Jared Toettcher, Bin Gu, Eszter Posfai.
      The segregation of the epiblast (EPI) and primitive endoderm (PE) cell types in the preimplantation mouse embryo is not only a crucial decision that sets aside the precursors of the embryo proper from extraembryonic cells, respectively, but also has served as a central model to study a key concept in mammalian development: how much of developmental patterning is predetermined vs. stochastically emergent. Here, we address this question by quantitative live imaging of multiple endogenously tagged transcription factors key to this fate decision and trace their dynamics at a single-cell resolution through the formation of EPI and PE cell fates. Strikingly, we reveal an initial symmetry breaking event, the formation of a primary EPI cell lineage, and show that this is linked to the dynamics of the prior inner cell mass/trophectoderm fate decision through the expression of SOX2. This primary EPI lineage, through fibroblast growth factor (FGF) signaling, induces an increase in the transcription factor GATA6 in other inner cell mass cells, setting them on the course toward PE differentiation. Interestingly, this trajectory can switch during a defined developmental window, leading to the emergence of secondary EPI cells. Finally, we show that early expression levels of NANOG, which are seemingly stochastic, can bias whether a cell's trajectory switches to secondary EPI or continues as PE. Our data give unique insight into how fate patterning is initiated and propagated during unperturbed embryonic development through the interplay of lineage-history-biased and stochastic cell-intrinsic molecular features, unifying previous models of EPI/PE segregation.
    Keywords:  GATA6; ICM; NANOG; SOX2; blastocyst; epiblast; live imaging; mouse; preimplantation embryo; primitive endoderm
    DOI:  https://doi.org/10.1016/j.cub.2025.07.031
  6. Nature. 2025 Jul 30.
    Diffusing protein binders to intrinsically disordered proteins.
    Caixuan Liu, Kejia Wu, Hojun Choi, Hannah L Han, Xueli Zhang, Joseph L Watson, Green Ahn, Jason Z Zhang, Sara Shijo, Lydia L Good, Charlotte M Fischer, Asim K Bera, Alex Kang, Evans Brackenbrough, Brian Coventry, Derrick R Hick, Seema Qamar, Xinting Li, Justin Decarreau, Stacey R Gerben, Wei Yang, Inna Goreshnik, Dionne Vafeados, Xinru Wang, Mila Lamb, Analisa Murray, Sebastian Kenny, Magnus S Bauer, Andrew N Hoofnagle, Ping Zhu, Tuomas P J Knowles, David Baker.
      Proteins that bind to intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) with high affinity and specificity could be useful for therapeutic and diagnostic applications1-4. However, a general methodology for targeting IDPs or IDRs has yet to be developed. Here we show that starting only from the target sequence of the input, and freely sampling both target and binding protein conformations, RFdiffusion5 can generate binders to IDPs and IDRs in a wide range of conformations. We used this approach to generate binders to the IDPs amylin, C-peptide, VP48 and BRCA1_ARATH in diverse conformations with a dissociation constant (Kd) ranging from 3 to 100 nM. For the IDRs G3BP1, common cytokine receptor γ-chain (IL-2RG) and prion protein, we diffused binders to β-strand conformations of the targets, obtaining Kd between 10 and 100 nM. Fluorescence imaging experiments show that the binders bind to their respective targets in cells. The G3BP1 binder disrupts stress granule formation in cells, and the amylin binder inhibits amyloid fibril formation and dissociates existing fibres, enables targeting of both monomeric and fibrillar amylin to lysosomes, and increases the sensitivity of mass spectrometry-based amylin detection. Our approach should be useful for creating binders to flexible IDPs or IDRs spanning a wide range of intrinsic conformational preferences.
    DOI:  https://doi.org/10.1038/s41586-025-09248-9
  7. Nature. 2025 Jul 30.
    Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry.
    Debasish Paul, Derek L Bolhuis, Hualong Yan, Sudipto Das, Xia Xu, Christina C Abbate, Lisa M M Jenkins, Michael J Emanuele, Thorkell Andresson, Jing Huang, John G Albeck, Nicholas G Brown, Steven D Cappell.
      Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation1. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/CCDH1) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCDH1 through the degradation of key glycolytic enzymes2, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Here we show that cells resolve this paradox by transiently inactivating the APC/C during cell cycle entry, which allows a transient metabolic shift favouring glycolysis. After mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein CDH1 at the amino terminus causes it to partially dissociate from the APC/C. This partial inactivation of the APC/C leads to the accumulation of PFKFB3, a rate-limiting enzyme for glycolysis, promoting a metabolic shift towards glycolysis. Delayed accumulation of phosphatase activity later removes CDH1 phosphorylation, restoring full APC/C activity, and shifting cells back to favouring oxidative phosphorylation. Thus, cells coordinate the simultaneous demands of cell cycle progression and metabolism through an incoherent feedforward loop, which transiently inhibits APC/C activity to generate a pulse of glycolysis that is required for mammalian cell cycle entry.
    DOI:  https://doi.org/10.1038/s41586-025-09328-w
  8. Curr Biol. 2025 Jul 22. pii: S0960-9822(25)00877-2. [Epub ahead of print]
    Cohesin-mediated stabilization of the CCAN complex at kinetochores in mitosis.
    Julian Haase, Koly Aktar, Mary Kate Bonner, Leonard Colin, Hindol Gupta, Briana E Marinoni, David O Morgan, Alexander E Kelly.
      The constitutive centromere-associated network (CCAN) of the inner kinetochore links CENP-A-containing nucleosomes of the centromere to the outer kinetochore, ensuring accurate chromosome segregation during mitosis. CCAN binding at the centromere is stabilized upon mitotic entry, but the underlying mechanisms remain unclear. Here, we demonstrate that cohesin is essential for CCAN stability. The chromosomal passenger complex (CPC), independently of its kinase subunit Aurora B, regulates cohesin-mediated CCAN stability via heterochromatin protein-1 (HP1), Haspin kinase, and phosphorylation of the cohesin-release factor WAPL, which weakens WAPL's affinity for PDS5B. While cohesin depletion disrupts CCAN stability, neither separase-mediated cohesin cleavage nor depletion of the cohesion-essential Esco2 acetyltransferase affects CCAN stability, indicating that cohesin stabilizes the CCAN independently of sister chromatid cohesion. Furthermore, we show that WAPL phosphorylation maintains a centromere-proximal pool of cohesin and promotes the formation of the primary constriction. These findings establish a non-cohesive function of cohesin in stabilizing the CCAN during mitosis and suggest that cohesin-mediated organization of centromeric chromatin strengthens kinetochore engagement to ensure faithful chromosome segregation.
    Keywords:  Aurora B; CCAN; CENP-C; CPC; HP1; WAPL; centromere; cohesin; kinetochore; non-cohesive
    DOI:  https://doi.org/10.1016/j.cub.2025.07.011
  9. Proteomics. 2025 Aug 01. e70017
    Dynamic Proteome Landscape During Preimplantation Human Embryo Development and Trophectoderm Stem Cell-Differentiation.
    Alin Rai, Qi Hui Poh, Hiroaki Okae, Takahiro Arima, Mehdi Totonchi, David W Greening.
      Embryo development involves fertilization of a mature ovum, which, after sequential cell divisions (2-,4-8-cells and morula), undergoes differentiation into implantation competent blastocyst. The blastocyst comprises of inner cell mass surrounded by an outer layer of cells called the trophoblast (TSblast) that, upon attachment to the endometrium, differentiates into extravillous trophoblasts (EVTs) that facilitates embryo invasion into the endometrium for intrauterine embryo development, and syncytiotrophoblast (ST) that form the placenta. Such cellular differentiation stages are critical for embryogenesis and implantation, although the protein expression landscape remains poorly understood in humans. Using quantitative mass spectrometry analysis, we systematically monitored the protein expression landscape and their dynamic regulation between human ovum (M2), 8-cell embryo, and blastocysts stages, and trophoblast lineage-specific differentiation into EVTs and ST. Proteins temporally regulated from M2-8 cell-blastocyst stage displayed significant enrichment for metabolic protein networks. We specifically identified 156 proteins associated with 8-cell embryos to blastocyst development, 54 displayed similar correlation at the transcriptomic level including mitochondrial, junction/secretory granule-associated proteins that carry glycolytic, antioxidant, and telomerase maintenance functions. We reveal a striking lineage-specific reprogramming of TSblast proteome during fate-specification. These findings extend our knowledge of the sequential order of protein landscape reprogramming and processes during early human embryogenesis and trophoblast function. SUMMARY: Although genomic and transcriptomic studies have provided key understanding of the genetic programs underlying preimplantation embryo development, the protein expression landscape remains unexplored. Here, a quantitative proteomic study of human preimplantation embryo stages reveal a dynamic proteome landscape from M2, 8-cell, and blastocyst stage, and during trophoblast stem cell (TS) differentiation. Identified key factors in early human embryos and lineage-specific trophoblast proteome profiles, further correlated with transcriptomic analyses. This direct proteomic analysis provides a quantitative and temporal analysis of the dynamic protein expression in human embryos during preimplantation development and a powerful resource to enable further mechanistic studies on human trophoblast development and function.
    Keywords:  blastocyst; human embryo; proteomics; reproduction; stem cells; trophoblasts
    DOI:  https://doi.org/10.1002/pmic.70017
  10. Nat Biotechnol. 2025 Jul 25.
    Predicting the translation efficiency of messenger RNA in mammalian cells.
    Dinghai Zheng, Logan Persyn, Jun Wang, Yue Liu, Fernando Ulloa-Montoya, Can Cenik, Vikram Agarwal.
      The mechanisms by which mRNA sequences specify translational control remain poorly understood in mammalian cells. Here we generate a transcriptome-wide atlas of translation efficiency (TE) measurements encompassing more than 140 human and mouse cell types from 3,819 ribosomal profiling datasets. We develop RiboNN, a state-of-the-art multitask deep convolutional neural network, and classic machine learning models to predict TEs in hundreds of cell types from sequence-encoded mRNA features. While most earlier models solely considered the 5' untranslated region (UTR) sequence, RiboNN integrates how the spatial positioning of low-level dinucleotide and trinucleotide features (that is, including codons) influences TE, capturing mechanistic principles such as how ribosomal processivity and tRNA abundance control translational output. RiboNN predicts the translational behavior of base-modified therapeutic RNA and explains evolutionary selection pressures in human 5' UTRs. Finally, it detects a common language governing mRNA regulatory control and highlights the interconnectedness of mRNA translation, stability and localization in mammalian organisms.
    DOI:  https://doi.org/10.1038/s41587-025-02712-x
  11. Curr Biol. 2025 Jul 23. pii: S0960-9822(25)00859-0. [Epub ahead of print]
    Ca2+-driven cytoplasmic backflow ensures spindle anchoring in fertilized mouse eggs.
    Takaya Totsuka, Miho Ohsugi, Takashi Akera.
      Female meiosis is highly asymmetric, producing a large egg and a small polar body to preserve maternal storage essential for embryogenesis. To achieve asymmetric division, the egg spindle must maintain its cortical position until fertilization completes meiosis. In mice, fertilization triggers chromosome segregation, followed by spindle rotation to achieve the perpendicular orientation relative to the cortex, leading to the extrusion of one set of chromosomes. However, it was unknown how the spindle maintains its cortical position while rotating. Here, we developed a high-resolution live-imaging method to investigate spindle dynamics during fertilization. Our results indicate that Ca2+ oscillations put the brakes on spindle rotation by transiently reversing cytoplasmic streaming and that this cytoplasmic backflow secures the spindle localization at the cortex. Mechanistically, Ca2+ oscillations drive cortical actomyosin contraction to induce the cytoplasmic backflow. Altogether, this work revealed a previously unknown role of Ca2+ oscillations in maintaining spindle position, ensuring the highly asymmetric divisions inherent to female meiosis.
    Keywords:  Ca(2+) oscillations; actomyosin contraction; cytoplasmic streaming; fertilization; live imaging; meiosis II; mouse egg; second polar body extrusion; spindle dynamics
    DOI:  https://doi.org/10.1016/j.cub.2025.06.073
  12. Nat Commun. 2025 Jul 26. 16(1): 6900
    SMCHD1 maintains heterochromatin, genome compartments and epigenome landscape in human myoblasts.
    Zhijun Huang, Wei Cui, Ishara Ratnayake, Kristin L Gallik, Lorna Cohen, Rabi Tawil, Gerd P Pfeifer.
      Mammalian genomes are subdivided into euchromatic A compartments that contain mostly active chromatin, and inactive, heterochromatic B compartments. However, it is not well understood how A and B genome compartments are established and maintained. Here we study SMCHD1, an SMC-like protein best known for its role in X chromosome inactivation, in human male myoblasts. SMCHD1 colocalizes with Lamin B1 and the heterochromatin mark H3K9me3. Loss of SMCHD1 leads to extensive heterochromatin and Lamin B1 depletion at the nuclear lamina, acquisition of active chromatin states and increased DNA methylation along chromosomes. In absence of SMCHD1, long range intra-chromosomal contacts between B compartments are lost while many new TADs and loops are formed. Inactivation of SMCHD1 promotes numerous B to A compartment transitions accompanied by activation of silenced genes. The data suggests that SMCHD1 functions as an anchor for heterochromatin domains at the nuclear lamina ensuring that these domains are poorly accessible to DNA methyltransferases and to epigenome modification enzymes that typically operate in active chromatin. Thus, the properties of SMCHD1 in heterochromatin maintenance extend well beyond its role in X chromosome inactivation.
    DOI:  https://doi.org/10.1038/s41467-025-62211-0
  13. Nat Protoc. 2025 Aug 01.
    Modeling heart rhythm using human engineered heart tissues.
    Chengyi Tu, Arianne Caudal, Yu Liu, Sanjiv M Narayan, Joseph C Wu.
      Heart rate is both an indicator and modulator of cardiovascular health. Prolonged elevation in heart rate or irregular heart rhythm can trigger the onset of cardiac dysfunction, a condition termed 'tachycardia-induced cardiomyopathy'. While large animals have historically served as the primary model for studying this condition owing to their similar resting heart rates to humans, their use is limited by cost and throughput constraints. We recently developed the first engineered model of tachycardia-induced cardiomyopathy to overcome this technical bottleneck. Our model uses matured human engineered myocardium coupled with programmable electrical stimulation to emulate the pathophysiological changes in human heart rhythm. This in vitro model, capable of acutely and chronically modulating both beating rate and rhythm, recapitulated the clinical hallmarks of tachycardia-induced cardiomyopathy, and its utility was further validated via molecular comparisons against data from a canine model and human patients. Moreover, this model has improved the throughput and relevance to human genetics, enabling deep mechanistic explorations that were previously impossible. Here we present a comprehensive workflow detailing the fabrication and maturation of human engineered heart tissue, assembly of the electrical pacing system, functional analysis using open-source software and preparation for proteomic and transcriptomic analyses. This 5-week Protocol could be implemented by an experienced bench scientist with strong expertise in cell culture, ideally involving stem cell-derived cardiomyocytes. Given the broad implications of heart rhythm alterations in various cardiac conditions, this workflow can be employed with other biophysical and chemical cues to generate more complex and physiologically relevant cardiac models.
    DOI:  https://doi.org/10.1038/s41596-025-01217-w
  14. Nat Commun. 2025 Jul 25. 16(1): 6868
    Spatiotemporal H2O2 flashes coordinate actin cytoskeletal remodeling and regulate cell migration and wound healing.
    Maurice O'Mara, Suisheng Zhang, Ulla G Knaus.
      Well-organized repair of damaged barrier epithelia is vital for infection control, resolution of inflammation, and enduring physical protection. Cysteine thiol and methionine oxidation are connected to cytoskeletal rearrangements in cell migration and wound healing, but how localized redox signaling is achieved to regulate dynamic processes remains elusive. Here, we identify DUOX2, a mucosal barrier NADPH oxidase, as vesicle-incorporated H2O2 source, localizing to sites of cytoskeletal reorganization, and facilitating tunneling nanotube and lamellipodia formation. Using traceable fluorescent DUOX2 and the membrane-bound H2O2 sensor HyPer7-MEM enabled insight into DUOX2 vesicle trafficking and H2O2 generation at sites of actin polymerization and dynamic remodeling. Stable expression or ablation confirmed DUOX2 generated H2O2 as a catalyst for cell-cell connections, random motility and directed migration. We identify a signaling axis from the mechanosensor PIEZO1 to DUOX2 and FER tyrosine kinase activation to initiate retraction wave-mediated efficient wound closure in epithelial cells, a prerequisite for barrier integrity.
    DOI:  https://doi.org/10.1038/s41467-025-62272-1
  15. Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00853-8. [Epub ahead of print]44(8): 116082
    Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals.
    Jingyi Li, Jiansen Lu, Jiayu Chen, Qianzheng Fu, Zhenhuan Jiang, Shaorong Gao, Fuchou Tang.
      Meiotic recombination initiates via DNA double-strand breaks (DSBs) at specialized hotspots, while the regulation of meiotic recombination hotspots in females remain elusive due to the scarcity of embryonic stage germ cells (EGCs). Here, we mapped genome-wide active recombination hotspots and estimated their activities in female EGCs at single-cell resolution, revealing the high variability in hotspot usage frequency among individual germ cells. Further investigation of nucleosome positioning and histone modifications at recombination hotspots revealed that PRDM9-mediated open chromatin and flanking H3K4me3 established earlier at high-frequency hotspots compared with less frequently used ones. Unexpectedly, although recombination hotspots usually distributed outside of heterochromatin, H3K9me3 was clearly enriched around hotspots in females, forming a unique H3K4me3/H3K9me3 bivalent state. And we showed that an appropriate H3K9me3 level may be required for downstream DSB repairs. Together, our results provided understanding about the landscape and epigenomic regulation of recombination hotspots in females.
    Keywords:  CP: Developmental biology; H3K4me3-H3K9me3 bivalency; ULI-NChIP-seq; embryonic stage germ cells; low-input MNase-seq; meiotic recombination hotspots; single-cell ATAC-seq
    DOI:  https://doi.org/10.1016/j.celrep.2025.116082
  16. Elife. 2025 Jul 29. pii: RP92068. [Epub ahead of print]13
    N-cadherin mechanosensing in ovarian follicles controls oocyte maturation and ovulation.
    Alaknanda Emery, Orest W Blaschuk, Doan T Dinh, Tim McPhee, Rouven Becker, Andrew D Abell, Krzysztof M Mrozik, Andrew C W Zannettino, Rebecca L Robker, Darryl L Russell.
      The cell adhesion molecule N-cadherin (CDH2) is a membrane component of adherens junctions which regulates tissue morphogenesis and architecture. In the follicles of mammalian ovaries, N-cadherin adherens junctions are present between granulosa cells, cumulus cells, and at the interface of cumulus cell transzonal projections and the oocyte. We demonstrate a mechanosensory role of N-cadherin integrating tissue structure and hormonal regulation of follicular morphogenic events including expansion of the cumulus-oocyte complex (COC) matrix, oocyte maturation, and ovulation. Two small molecule N-cadherin antagonists inhibited COC maturation in vitro. Transcriptome profiling revealed that targets of β-catenin and YAP1 pathways were dysregulated by N-cadherin antagonists. In vivo, N-cadherin antagonist significantly reduced ovulation in mice compared to controls (11 vs 26 oocytes/ovary; p = 5.8 × 10-6). Ovarian follicles exhibited structural dysgenesis with granulosa and cumulus cell layers becoming disorganised and the connection between cumulus cells and the oocyte disrupted and the transcriptome again indicated altered mechanical sensing causing dysregulation of the Hippo/YAP and β-catenin pathways and extracellular matrix reorganisation. Granulosa-specific N-cadherin depletion in Cdh2Fl/FL;Amhr2Cre/+ also showed significantly altered mechanosensitive gene expression and reduced ovulation. Our findings demonstrate a critical role for N-cadherin in ovarian follicular development and ovulation, and the potential to inhibit ovulation through targeting this signalling mechanism.
    Keywords:  cell biology; cell signalling; contraception; mechanotransduction; mouse; oocyte; ovary; ovulation
    DOI:  https://doi.org/10.7554/eLife.92068
  17. Nat Aging. 2025 Jul 31.
    Stress granule clearance mediated by V-ATPase-interacting protein NCOA7 mitigates ovarian aging.
    Ting Dong, Nianyu Li, Huirui Wang, Hanbing Zhu, Yinghui Gao, Yue Liu, Fang Fang, Xiaojie Fu, Pinxin Si, Cheng Li, Mei Li, Fei Wang, Shidou Zhao, Ting Guo, Linlin Cui, Xinyi Jiang, Xiaohui Liu, Han Zhao, Yingying Qin, Zi-Jiang Chen, Hongxiang Lou, Xue Jiao.
      Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expression of NCOA7, a stress-response protein related to granulosa cell senescence in women with physiological and pathological ovarian aging. NCOA7 deletion accelerates oxidative stress-related cellular senescence, ovarian aging and fecundity decline in mice. Mechanistically, NCOA7 partitions into the stress granule containing G3BP1-V-ATPase and facilitates autophagic degradation of stress granules to relieve stress. Boosting granulophagy with rapamycin or lipid nanoparticle-based mRNA delivery of NCOA7 accelerates stress granule clearance, alleviating cellular senescence in human granulosa cells and delaying ovarian aging in mice. This study depicts a mechanism for ovarian resilience to stress and provides potential targets for therapeutic strategies to alleviate ovarian aging.
    DOI:  https://doi.org/10.1038/s43587-025-00927-w
  18. Nat Commun. 2025 Aug 01. 16(1): 7071
    USP17L promotes the 2-cell-like program through deubiquitination of H2AK119ub1 and ZSCAN4.
    Panpan Shi, Xukun Lu, Kairang Jin, Linlin Liu, Guoxing Yin, Wenying Wang, Jiao Yang, Lijuan Wang, Lijun Dong, Wei Xie, Lin Liu.
      In mouse, minor zygotic genome activation (ZGA) precedes and is essential for major ZGA in two-cell (2C) embryos. A subset of ZGA genes (known as "2C" genes) are also activated in a rare population of embryonic stem cells (ESCs) (2C-like cells). However, the functions of the 2C genes are not fully understood. Here, we find that one family of the 2C genes, Usp17l, plays critical roles in transcriptional and post-translational regulation of the 2C-like state in mESCs. Specifically, USP17LE, a member of the USP17L family, deubiquitinates H2AK119ub1 and promotes the expression of Dux and the downstream 2C genes and retrotransposons. Moreover, USP17LE deubiquitinates and stabilizes ZSCAN4. In mouse pre-implantation embryos, Dux is marked by strong H2AK119ub1 except for the 1-cell and early 2-cell stages. Usp17le overexpression reduces H2AK119ub1 and promotes Dux and 2C gene activation. Thus, our findings identify USP17L as a potential regulator of the 2C program.
    DOI:  https://doi.org/10.1038/s41467-025-62303-x
  19. Nat Struct Mol Biol. 2025 Jul 28.
    eIF1 and eIF5 dynamically control translation start site fidelity.
    Rosslyn Grosely, Carlos Alvarado, Ivaylo P Ivanov, Oliver B Nicholson, Joseph D Puglisi, Thomas E Dever, Christopher P Lapointe.
      Human translation initiation requires accurate recognition of translation start sites. While AUG codons are canonical start sites, non-AUG codons are also used, typically with lower efficiency. The initiator tRNA and initiation factors eIF1 and eIF5 control recognition. How they distinguish different start sites yet allow flexible recognition remains unclear. Here we used real-time single-molecule assays and an in vitro reconstituted human system to reveal how eIF1 and eIF5 direct start site selection. eIF1 binds initiation complexes in two modes: stable binding during scanning, followed by transient, concentration-dependent rebinding after start site recognition. Termination of eIF1 rebinding requires transient and concentration-dependent binding by eIF5, which allows the formation of translation competent ribosomes. Non-AUG start sites differentially stabilize eIF1 and destabilize eIF5 binding, blocking initiation at multiple points. We confirmed these opposing effects in human cells. Collectively, our findings uncover that eIF1 and eIF5 directly compete to bind initiation complexes and illuminate how their dynamic interplay tunes the fidelity of start site recognition, which has broad connections to health and disease.
    DOI:  https://doi.org/10.1038/s41594-025-01629-y
  20. Elife. 2025 Aug 01. pii: RP105430. [Epub ahead of print]14
    Meteorins regulate the formation of the left-right organizer and the establishment of vertebrate body asymmetry.
    Fanny Eggeler, Jonathan Boulanger-Weill, Flavia De Santis, Laura Belleri, Karine Duroure, Thomas O Auer, Shahad Albadri, Filippo Del Bene.
      While the exterior of vertebrate bodies appears bilaterally symmetrical, internal organ positioning and morphology frequently exhibit left-right (L-R) asymmetries. In several vertebrates, including human, mouse, frog, and zebrafish, left-right symmetry-breaking during embryonic development is initiated by a ciliated organ called the Node or left-right organizer. Within the Node, a leftward flow of extraembryonic fluid named the Nodal flow mediates the asymmetric expressions of Nodal factors. Although downstream Nodal pathway components leading to the establishment of the embryonic left-right axis are well known, less is known about the development and formation of the embryonic Node itself. Here, we reveal a novel role for the Meteorin protein family in the establishment of the left-right axis and in the formation of Kupffer's vesicle, the Node equivalent structure in zebrafish. We show that the genetic inactivation of each or all three members of the zebrafish Meteorin family (metrn, metrn-like a, and metrn-like b) leads to defects in properties of the Kupffer's vesicle, caused by impaired assembly and migration of the Kupffer's vesicle forming dorsal forerunner cells. In addition, we demonstrate that Meteorins genetically interact with integrins ItgαV and Itgβ1b, regulating the dorsal forerunner cell clustering, and that meteorins loss-of-function results in disturbed Nodal factor expression and consequently in randomized or symmetric heart looping and jogging. These results identify a new role for the Meteorin protein family in the left-right asymmetry patterning during embryonic vertebrate development.
    Keywords:  Meteorin; developmental biology; embryonic development; left-right asymmetry; zebrafish
    DOI:  https://doi.org/10.7554/eLife.105430
  21. Nat Commun. 2025 Aug 01. 16(1): 7079
    PAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation, with relevance to human fertility.
    Kehui Xiang, David P Bartel.
      In oocytes of mammals and other animals, gene regulation is mediated primarily through changes in poly(A)-tail length. Here, we introduce PAL-AI, an integrated neural network machine-learning model that accurately predicts tail-length changes in maturing oocytes of frogs and mammals. We show that PAL-AI learned known and previously unknown sequence elements and their contextual features that control poly(A)-tail length, enabling it to predict tail-length changes resulting from 3'-untranslated region single-nucleotide substitutions. It also predicted tail-length-mediated translational changes, allowing us to nominate genes important for oocyte maturation. When comparing predicted tail-length changes in human oocytes with genomic datasets of the All of Us Research Program and gnomAD, we found that genetic variants predicted to disrupt tail lengthening have been under negative selection in the human population, thereby linking mRNA tail lengthening to human female fertility.
    DOI:  https://doi.org/10.1038/s41467-025-62171-5
  22. Sci Adv. 2025 Aug;11(31): eads2310
    Formation control between leader and migratory follower tissues allows coordinated growth.
    Toru Kawanishi, Takamichi Sushida, Tony Y-C Tsai, Hiroyuki Takeda, Sean G Megason.
      Coordinated growth of multiple tissues is fundamental to shaping our body, but the underlying mechanisms remain underexplored. In zebrafish embryos, midline tissues composed of the notochord, floorplate, and hypochord elongate synchronously with their lengths aligned. We show that floorplate and hypochord cells collectively migrate posteriorly along the nascent notochord extracellular matrix as it extends posteriorly, maintaining the tripartite configuration. Fibroblast growth factor-mediated migration in a spatially graded manner causes cell stretching, which triggers Yap-dependent proliferation and controls floorplate and hypochord growth. Supported by mathematical modeling, we further suggest that their growth is fine-tuned by mechanical tethering to the notochord via cadherin 2 at the posterior end. We propose that the notochord instructs and sustains the tripartite formation via leader-follower formation control, a strategy from engineering that spatially organizes multiple agents to coordinate the growth of the midline tissues.
    DOI:  https://doi.org/10.1126/sciadv.ads2310
  23. Mol Cell. 2025 Jul 15. pii: S1097-2765(25)00580-5. [Epub ahead of print]
    HIF-independent oxygen sensing via KDM6A regulates ferroptosis.
    Alexander M Minikes, Pei Liu, Hua Wang, Jiachen Hu, Hanan Alwaseem, Yueming Li, Xuejun Jiang.
      Ferroptosis, a metabolic cell death process driven by iron-dependent phospholipid peroxidation, is implicated in various pathologies, including cancer. While metabolic factors such as glucose, lipids, and multiple amino acids have all been demonstrated to modulate ferroptosis, the role of oxygen, another fundamental metabolic component, in ferroptosis is not fully understood. Here, we show that cells acclimated to a low oxygen environment develop marked resistance to ferroptosis, and this resistance is independent of canonical oxygen-sensing pathway mediated by prolyl hydroxylases (PHDs) and HIF transcription factors. Instead, hypoxia suppresses ferroptosis by inhibiting KDM6A, a tumor suppressor and oxygen-dependent histone demethylase, leading to reduced expression of its transcriptional targets, including lipid metabolic enzymes ACSL4 and ETNK1, thus rewiring cellular phospholipid profile to a ferroptosis-resistant state. Relevant to cancer, pharmacological inhibition of the oncogenic histone methyltransferase EZH2, which opposes KDM6A activity, restored ferroptosis sensitivity of xenograft bladder tumor tissues harboring KDM6A mutation.
    Keywords:  ACSL4; ETNK1; KDM6A; KMT2D; bladder cancer; cancer therapy; ferroptosis; hypoxia; lipid metabolism; oxygen sensing
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.001
  24. Nature. 2025 Jul 30.
    Epithelial cell membrane perforation induces allergic airway inflammation.
    Kejian Shi, Yao Lv, Chunqiu Zhao, Huan Zeng, Yeqiong Wang, Yuxuan Liu, Lin Li, She Chen, Pu Gao, Feng Shao, Mo Xu.
      Allergens that induce allergic airway inflammation are highly diverse, but they commonly activate type 2 immune responses1,2. Airway epithelial cells are crucial in allergen sensing3-5. However, the shared features among diverse allergens that elicit similar innate responses, and their epithelial detection mechanisms, remain poorly defined1,2,6-9. Here we identify pore-forming proteins as one of the common stimuli of allergic airway inflammation and reveal their immune-activation mechanisms. Using the prevalent mould allergen Alternaria alternata as a model, we established an in vitro system to investigate type 2 innate immune sensing. A six-step biochemical fractionation identified Aeg-S and Aeg-L as the core immune-stimulatory components. Biochemical reconstitution and cryo-electron microscopy reveal that these proteins form 16- to 20-mer transmembrane pore complexes. Their cooperative perforation acts as a bona fide type 2 immune adjuvant to support antigen-specific T helper 2 and immunoglobulin E responses. Genetically engineered A. alternata strains that lack pore-forming activity do not induce allergic responses in mice. Furthermore, pore-forming proteins from various species, despite structural and membrane target differences, are sufficient to trigger respiratory allergies. Perforations in airway epithelial cells initiate allergic responses through two mechanisms: one triggers IL-33 release, and the other involves Ca2+ influx, which activates MAPK signalling and type 2 inflammatory gene expression. These findings provide insight into how type 2 immune responses detect common perturbations caused by structurally diverse stimuli. Targeting downstream signalling of epithelial perforation may open new avenues for treating respiratory allergies.
    DOI:  https://doi.org/10.1038/s41586-025-09331-1
  25. Mol Cell. 2025 Jul 23. pii: S1097-2765(25)00577-5. [Epub ahead of print]
    Nucleosomes specify co-factor access to p53.
    Deyasini Chakraborty, Colby R Sandate, Luke Isbel, Georg Kempf, Joscha Weiss, Simone Cavadini, Lukas Kater, Jan Seebacher, Zuzanna Kozicka, Lisa Stoos, Ralph S Grand, Dirk Schübeler, Alicia K Michael, Nicolas H Thomä.
      Pioneer transcription factors (TFs) engage chromatinized DNA motifs. However, it is unclear how the resultant TF-nucleosome complexes are decoded by co-factors. In humans, the TF p53 regulates cell-cycle progression, apoptosis, and the DNA damage response, with a large fraction of p53-bound sites residing in nucleosome-harboring inaccessible chromatin. We examined the interaction of chromatin-bound p53 with co-factors belonging to the ubiquitin proteasome system (UPS). At two distinct motif locations on the nucleosome (super-helical location [SHL]-5.7 and SHL+5.9), the E3 ubiquitin ligase E6-E6AP was unable to bind nucleosome-engaged p53. The deubiquitinase USP7, on the other hand, readily engages nucleosome-bound p53 in vitro and in cells. A corresponding cryo-electron microscopy (cryo-EM) structure shows USP7 engaged with p53 and nucleosomes. Our work illustrates how chromatin imposes a co-factor-selective barrier for p53 interactors, whereby flexibly tethered interaction domains of co-factors and TFs govern compatibility between co-factors, TFs, and chromatin.
    Keywords:  genome regulation; transcription; transcription co-factors
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.027
  26. Science. 2025 Jul 31. 389(6759): eadk3079
    Altered translation elongation contributes to key hallmarks of aging in the killifish brain.
    Domenico Di Fraia, Antonio Marino, Jae Ho Lee, Erika Kelmer Sacramento, Mario Baumgart, Sara Bagnoli, Till Balla, Felix Schalk, Stephan Kamrad, Rui Guan, Cinzia Caterino, Chiara Giannuzzi, Pedro Tomaz da Silva, Amit Kumar Sahu, Hanna Gut, Giacomo Siano, Max Tiessen, Eva Terzibasi-Tozzini, Eugenio F Fornasiero, Julien Gagneur, Christoph Englert, Kiran R Patil, Clara Correia-Melo, Danny D Nedialkova, Judith Frydman, Alessandro Cellerino, Alessandro Ori.
      Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain's biology-the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.
    DOI:  https://doi.org/10.1126/science.adk3079
  27. Nat Commun. 2025 Jul 30. 16(1): 6992
    Dual lineage origins contribute to neocortical astrocyte diversity.
    Jiafeng Zhou, Ilaria Vitali, Sergi Roig-Puiggros, Awais Javed, Iva Cantando, Matteo Puglisi, Paola Bezzi, Denis Jabaudon, Christian Mayer, Riccardo Bocchi.
      Astrocytes are not a uniform population but exhibit diverse morphological, molecular, and functional characteristics. However, how this diversity originates and becomes establishes during development, remains largely unknown. Here, using single-cell RNA sequencing and spatial transcriptomics, we identify five astrocyte subtypes with unique molecular features, spatial distributions and functions in the mouse neocortex and characterize essential regulators for their formation. Using TrackerSeq to trace clonally related astrocytes, we identify two distinct lineages that give rise to these five subtypes. One lineage derives from Emx1+ radial glial cells that initially generate neurons and later switch to astrocyte production. The other, with minimal neuronal output, predominantly produces a distinct subset of astrocytes marked by Olig2. Olig2 knockout disrupts lineage specification, leading to changes at molecular, morphological and functional levels. These findings shed light on the cellular mechanisms underlying astrocyte diversity, highlighting the presence of multiple radial glial cell subtypes responsible for generating cortical astrocyte subtypes.
    DOI:  https://doi.org/10.1038/s41467-025-61829-4
  28. Nat Commun. 2025 Jul 25. 16(1): 6870
    Mammalian cells measure the extracellular matrix area and respond through switching the adhesion state.
    Xiaole Wang, Pengli Wang, Lihang Zhang, Tianyu Xu, Seungkuk Ahn, Upnishad Sharma, Han Yu, Nico Strohmeyer, Daniel J Müller.
      Mammalian cells adjust integrin-mediated adhesion based on the composition and structure of the extracellular matrix (ECM). However, how spatially confined ECM ligands regulate cell adhesion initiation remains unclear. Here, we investigate how cells adapt early adhesion to different ECM protein areas. Through combining microcontact printing with single-cell force spectroscopy we measure cell adhesion initiation and strengthening to defined areas of ECM proteins. HeLa cells and mouse embryonic fibroblasts gradually increase adhesion with collagen I or fibronectin area, while reaching maximum adhesion force to ECM patterns having areas above certain thresholds. On much smaller patterns, both cell types switch to a different state and considerably increase the adhesion force per ECM protein area, which they strengthen much faster. This spatially enhanced adhesion state does not require talin or kindlin, indicating a fundamentally different adhesion mechanism. Mechanotransduction seems to play integrin and cell type-specific roles in the spatially enhanced adhesion state.
    DOI:  https://doi.org/10.1038/s41467-025-62153-7
  29. Nat Biotechnol. 2025 Jul 25.
    A resource of RNA-binding protein motifs across eukaryotes reveals evolutionary dynamics and gene-regulatory function.
    Alexander Sasse, Debashish Ray, Kaitlin U Laverty, Cyrus L Tam, Mihai Albu, Hong Zheng, Yevgen Levdansky, Olga Lyudovyk, Taykhoom Dalal, Kate Nie, Cedrik Magis, Cedric Notredame, Eugene Valkov, Matthew T Weirauch, Timothy R Hughes, Quaid Morris.
      RNA-binding proteins (RBPs) are key regulators of gene expression; however, their RNA-binding specificities, that is, motifs, have not been comprehensively determined. Here we introduce Eukaryotic Protein-RNA Interactions (EuPRI), a freely available resource of RNA motifs for 34,746 RBPs from 690 eukaryotes. EuPRI includes in vitro binding data for 504 RBPs, including newly collected RNAcompete data for 174 RBPs, along with thousands of predicted motifs. We predict these motifs with an algorithm, Joint Protein-Ligand Embedding, which can detect distant homology relationships and map specificity-determining peptides. EuPRI quadruples the number of available RBP motifs, expanding the motif repertoire across all major eukaryotic clades and assigning motifs to the majority of human RBPs. We demonstrate the utility of EuPRI for inferring post-transcriptional function and evolutionary relationships by identifying rapid, recent evolution of post-transcriptional regulatory networks in worms and plants, in contrast to the vertebrate RNA motif set, which has remained relatively stable after a large expansion between the metazoan and vertebrate ancestors.
    DOI:  https://doi.org/10.1038/s41587-025-02733-6
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