bims-ginsta Biomed News
on Genome instability
Issue of 2025–09–07
fifty-four papers selected by
Jinrong Hu, National University of Singapore
  1. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  2. An inducible model of human post-implantation development derived from primed and naive stem cells.
  3. Epithelial tension controls intestinal cell extrusion.
  4. Divergent evolutionary strategies pre-empt tissue collision in gastrulation.
  5. Efficient stem cell-derived mouse embryo models for environmental studies.
  6. Dynamic and atypical E-cadherin-based attachments mediate melanoblast migration through confined epithelial spaces.
  7. Patterned invagination prevents mechanical instability during gastrulation.
  8. Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
  9. Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing.
  10. Preventing CpG hypermethylation in oocytes safeguards mouse development.
  11. Patterns of Mitochondrial ATP Predict Tissue Folding.
  12. Translational repression by 4E-T is crucial to maintain the prophase-I arrest in vertebrate oocytes.
  13. DNA methylation influences human centromere positioning and function.
  14. Rewiring of cortical glucose metabolism fuels human brain cancer growth.
  15. Cell-type-specific enrichment of somatic aneuploidy in the mammalian brain.
  16. Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.
  17. Transcription factors SP5 and SP8 drive primary cilia formation in mammalian embryos.
  18. DNA2 enables growth by restricting recombination-restarted replication.
  19. Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
  20. Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes.
  21. Proteo-transcriptomic reprogramming and resource reallocation define the aging mammalian brain.
  22. Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
  23. CLDN10-driven lineage decision in an amnion and primordial germ cell progenitor at the amnion-epiblast boundary in primates.
  24. Sensitive Detection of Intercellular Tensile Forces via Cas12a-Assisted Membrane Molecular Probes.
  25. Understanding human embryogenesis by building programmable stem cell-based models.
  26. Allocation of resources among multiple daughter cells.
  27. Hepatocyte metabolic adaptations during pregnancy and lactation.
  28. Modeling the human maternal-fetal interface.
  29. Clonal expansion of alveolar fibroblast progeny drives pulmonary fibrosis in mouse models.
  30. Interactions between the genome and the nuclear lamina are multivalent and cooperative.
  31. Mechanisms of nuclear segregation in a multinucleate multibudding yeast.
  32. Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development.
  33. Single-cell transcriptomic and genomic changes in the ageing human brain.
  34. A single-cell transcriptomic landscape characterizes the endocrine system aging in the mouse.
  35. Galectin-3 induces neurodevelopmental apical-basal polarity and regulates gyrification.
  36. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
  37. Target RNA recognition drives PIWI∗ complex assembly for transposon silencing.
  38. Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain-tumor growth.
  39. TBX3 advances the developmental chromatin landscape toward the hepatic fate.
  40. Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.
  41. Competition for microtubule lattice spacing between a microtubule expander and compactor.
  42. Phagocytic clearance of targeted cells with a synthetic ligand.
  43. Expansion of human pluripotent stem cell-induced nephron progenitor cells (iNPCs) and the generation of nephron organoids from iNPCs.
  44. Inflammation awakens dormant cancer cells by modulating the epithelial-mesenchymal phenotypic state.
  45. Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia.
  46. pH variations enable guanine crystal formation within iridosomes.
  47. The role of actin dynamics in vesicle formation during clathrin mediated endocytosis.
  48. A thermodynamic perspective on mammalian neural crest ingression.
  49. Ndc80 complex, a conserved coupler for kinetochore-microtubule motility, is a sliding molecular clutch.
  50. Exploring Basement Membrane Dynamics through Cross-Scale Imaging, Manipulation, and Molecular Mapping.
  51. Multiple overlapping binding sites determine transcription factor occupancy.
  52. Polysome sorting controls mRNA localization and protein fate.
  53. ATG conjugation-dependent/independent mechanisms underlie lysosomal stress-induced TFEB regulation.
  54. Unified mass imaging maps the lipidome of vertebrate development.
  1. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  2. Cell Stem Cell. 2025 Aug 25. pii: S1934-5909(25)00297-8. [Epub ahead of print]
    An inducible model of human post-implantation development derived from primed and naive stem cells.
    Seiya Oura, Leijie Li, Jun Wu.
      Early post-implantation human development is poorly understood due to limited access to natural embryos. Integrated stem cell-based embryo models (SCBEMs) offer an alternative, but current models face challenges in reproducibility, efficiency, and genomic stability. Here, we developed inducible SCBEMs (iSCBEMs) by combining primed human pluripotent stem cells (hPSCs) with transgene-induced extraembryonic cells derived from naive hPSCs. iSCBEMs recapitulate several key features of early post-implantation development, including amniotic-, yolk sac-, and chorionic-like cavity formation, differentiation of syncytiotrophoblast-like cells forming lacunae, bilaminar disk formation, anterior-posterior axis establishment, and early gastrulation. Single-cell RNA sequencing revealed that iSCBEMs recapitulate key cell types and developmental transitions characteristic of Carnegie stage 5-6 (CS5-CS6) embryos. We further traced the origins of amnion-, yolk sac endoderm-, and extraembryonic mesoderm-like cells, providing insights into their developmental trajectories. Although imperfect, human iSCBEMs represent a robust and valuable model for studying early post-implantation development, overcoming the limitations of natural embryo accessibility.
    Keywords:  SCBEM; amniotic cavity; bilaminar disk; gastrulation; human pluripotent stem cells; hypoblast; stem cell-based embryo model; trophoblast; yolk sac
    DOI:  https://doi.org/10.1016/j.stem.2025.08.005
  3. Science. 2025 Sep 04. 389(6764): eadr8753
    Epithelial tension controls intestinal cell extrusion.
    Daniel Krueger, Willem Kasper Spoelstra, Dirk Jan Mastebroek, Rutger N U Kok, Shanie Wu, Mike Nikolaev, Marie Bannier-Hélaouët, Nikolche Gjorevski, Matthias Lutolf, Johan van Es, Jeroen van Zon, Sander J Tans, Hans Clevers.
      Cell extrusion is essential for homeostatic self-renewal of the intestinal epithelium. Extrusion is thought to be triggered by crowding-induced compression of cells at the intestinal villus tip. In this study, we found instead that a local "tug-of-war" competition between contractile cells regulated extrusion in the intestinal epithelium. We combined quantitative live microscopy, optogenetic induction of tissue tension, genetic perturbation of myosin II activity, and local disruption of the basal cortex in mouse intestines and intestinal organoids. These approaches revealed that a dynamic actomyosin network generates tension throughout the intestinal villi, including the villus tip region. Mechanically weak cells unable to maintain this tension underwent extrusion. Thus, epithelial barrier integrity depends on intercellular mechanics.
    DOI:  https://doi.org/10.1126/science.adr8753
  4. Nature. 2025 Sep 03.
    Divergent evolutionary strategies pre-empt tissue collision in gastrulation.
    Bipasha Dey, Verena Kaul, Girish Kale, Maily Scorcelletti, Michiko Takeda, Yu-Chiun Wang, Steffen Lemke.
      Metazoan development proceeds through a series of morphogenetic events that sculpt body plans and organ structures1,2. In the early embryo, these processes occur concurrently such that forces generated in neighbouring tissues can impose mechanical stresses on each other3-5, potentially disrupting development and consequently decreasing fitness. How organisms evolved mechanisms to mitigate inter-tissue mechanical conflicts remains unclear. Here, we combined phylogenetic survey, quantitative live imaging and functional mechanical perturbation to investigate mechanical stress management during gastrulation across the insect order of flies (Diptera). We identify two distinct cellular mechanisms that prevent tissue collision between the expanding head and trunk. In Cyclorrhapha, a monophyletic subgroup including Drosophila melanogaster, active out-of-plane deformation of a transient epithelial fold, called the cephalic furrow, acts as a mechanical sink to pre-empt head-trunk collision. Genetic and optogenetic ablation of the cephalic furrow leads to accumulation of compressive stress, tissue buckling at the head-trunk boundary and late-stage embryonic defects in the head and nervous system. By contrast, the non-cyclorrhaphan Chironomus riparius lacks cephalic furrow formation and instead undergoes widespread out-of-plane division that reduces the duration and spatial extent of head expansion. Re-orienting head mitosis from in-plane to out-of-plane in Drosophila partially suppresses tissue buckling, showing that it can function as an alternative mechanical sink. Our data suggest that mechanisms of mechanical stress management emerge and diverge in response to inter-tissue conflicts during early embryonic development.
    DOI:  https://doi.org/10.1038/s41586-025-09447-4
  5. Dev Cell. 2025 Aug 26. pii: S1534-5807(25)00504-0. [Epub ahead of print]
    Efficient stem cell-derived mouse embryo models for environmental studies.
    Victoria Jorgensen, Min Bao, Sergi Junyent, Christoph M Häfelfinger, Laura Amaya, Zhaodi Liao, Brian A Williams, Dong-Yuan Chen, Amanda Wu, Matt Thomson, Magdalena Zernicka-Goetz.
      Blastoids are stem cell-derived structures that mimic natural blastocysts by incorporating all three lineages: trophectoderm, epiblast, and primitive endoderm. However, current methods often yield incomplete structures that fail to cavitate or to form a proper primitive endoderm. To overcome these limitations, we develop a modular approach by aggregating three murine stem cell types: embryonic stem cells (ESCs), ESCs with inducible GATA4 expression (iG4-ESCs), and trophoblast stem cells (TSCs). This method yields cavitated blastocyst-like structures-termed iG4-blastoids-with approximately 80% efficiency. Single-cell RNA sequencing confirms their close resemblance to mature mouse blastocysts. Notably, culturing iG4-blastoids without FGF4 enhances specification of the invasive mural trophectoderm, and approximately 12% of structures undergo post-implantation-like morphogenesis in vitro. Using this model, we show that caffeine, alcohol, nicotine, and amino acid variations affect iG4-blastoids and natural embryos similarly, underscoring their utility as a robust model for investigating the impact of diverse environmental factors on embryogenesis.
    Keywords:  GATA4; blastocyst; blastoid; embryo models; epiblast; primitive endoderm; screening; trophectoderm; xenobiotics
    DOI:  https://doi.org/10.1016/j.devcel.2025.08.004
  6. bioRxiv. 2025 Aug 21. pii: 2025.08.20.671360. [Epub ahead of print]
    Dynamic and atypical E-cadherin-based attachments mediate melanoblast migration through confined epithelial spaces.
    Denay J K Richards, Brandon M Trejo, Parijat Sil, Abhishek Biswas, Rebecca A Jones, Lionel Larue, Danelle Devenport.
      Epithelial tissues are populated with accessory cells such as immune cells, sensory cells, and pigment-producing melanocytes, which must migrate through and intercalate between tightly adherent epithelial cells. Although much is known about how cells migrate through interstitial spaces consisting of predominantly of collagen-rich ECM and mesenchyme, how cells migrate through confined epithelial spaces without impairing barrier function is far less understood. Here, using live imaging of the mouse epidermis, we captured the migration of embryonic melanocytes (melanoblasts) while simultaneously visualizing the basement membrane or epithelial surfaces. We show that melanoblasts migrate through both basal and suprabasal layers of the epidermis and hair follicles where they use keratinocyte surfaces, as well as the basement membrane, as substrates for migration. We show that melanoblasts form atypical and dynamic E-cadherin based attachments to surrounding keratinocytes that largely lack the cytoplasmic catenins known to anchor E-cadherin to the actin cytoskeleton. We show E-cadherin is needed in both melanoblasts and keratinocytes to stabilize migratory protrusions, and that depleting E-cadherin in melanoblasts results in reduced motility and ventral depigmentation in adult mice. These findings illustrate how migratory cells co-opt the cell-cell adhesion machinery connecting adjacent epithelial cells to invade between and migrate through them without interrupting the skin barrier.
    DOI:  https://doi.org/10.1101/2025.08.20.671360
  7. Nature. 2025 Sep 03.
    Patterned invagination prevents mechanical instability during gastrulation.
    Bruno C Vellutini, Marina B Cuenca, Abhijeet Krishna, Alicja Szałapak, Carl D Modes, Pavel Tomancak.
      Mechanical forces are crucial for driving and shaping tissue morphogenesis during embryonic development1-3. However, their relevance for the evolution of development remains poorly understood4. Here we show that an evolutionary novelty of fly embryos-the patterned embryonic invagination known as the cephalic furrow5-7-has a mechanical role during Drosophila gastrulation. By integrating in vivo experiments and in silico simulations, we demonstrate that the head-trunk boundary of the embryo is under increased compressive stress due to the concurrent formation of mitotic domains and germ band extension and that the cephalic furrow counteracts these stresses, preventing mechanical instabilities during gastrulation. Then, by comparing the genetic patterning of species with and without the cephalic furrow, we find evidence that changes in the expression of the transcription factor buttonhead are associated with the evolution of the cephalic furrow. These results suggest that the cephalic furrow may have evolved through the genetic stabilization of morphogenesis in response to the mechanical challenges of dipteran gastrulation. Together, our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.
    DOI:  https://doi.org/10.1038/s41586-025-09480-3
  8. Nat Mater. 2025 Sep 05.
    Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
    Donia W Ahmed, Matthew L Tan, Yuchen Liu, Jackson Gabbard, Esther Gao, Avinava Roy, Michael M Hu, Firaol S Midekssa, Miriam Stevens, Fulei Wuchu, Minal Nenwani, Jingyi Xia, Adam Abraham, Deepak Nagrath, Lin Han, Rachel L Zemans, Brendon M Baker, Claudia Loebel.
      Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study pathophysiologic cell function. However, the initiation of fibrosis has largely been overlooked, due to challenges in recapitulating early stages of disease progression within the native extracellular microenvironment. Here, using visible-light-mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo mouse and human lung tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell mechanosensing, differentiation, and nascent protein deposition and remodelling. However, the inhibition of cytoskeletal tension, mechanosensitive signalling pathways or integrin engagement reduced epithelial cell spreading and differentiation. Our findings emphasize the role of local extracellular matrix crosslinking and nascent protein deposition in early stage tissue fibrosis and have implications for ex vivo disease modelling and applications to other tissues.
    DOI:  https://doi.org/10.1038/s41563-025-02329-0
  9. Nat Cell Biol. 2025 Sep 02.
    Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing.
    Nan Xu, Hyein S Cho, James O S Hackland, Silvia Benito-Kwiecinski, Nathalie Saurat, Oliver Harschnitz, Marco Vincenzo Russo, Ralph Garippa, Gabriele Ciceri, Lorenz Studer.
      Embryonic development follows a conserved sequence of events across species, yet the pace of development is highly variable and particularly slow in humans. Species-specific developmental timing is largely recapitulated in stem cell models, suggesting a cell-intrinsic clock. Here we use directed differentiation of human embryonic stem cells into neuroectoderm to perform a whole-genome CRISPR-Cas9 knockout screen and show that the epigenetic factors Menin and SUZ12 modulate the speed of PAX6 expression during neural differentiation. Genetic and pharmacological loss-of-function of Menin or SUZ12 accelerate cell fate acquisition by shifting the balance of H3K4me3 and H3K27me3 at bivalent promoters, thereby priming key developmental genes for faster activation upon differentiation. We further reveal a synergistic interaction of Menin and SUZ12 in modulating differentiation speed. The acceleration effects were observed in definitive endoderm, cardiomyocyte and neuronal differentiation paradigms, pointing to chromatin bivalency as a general driver of timing across germ layers and developmental stages.
    DOI:  https://doi.org/10.1038/s41556-025-01751-5
  10. Dev Cell. 2025 Aug 29. pii: S1534-5807(25)00505-2. [Epub ahead of print]
    Preventing CpG hypermethylation in oocytes safeguards mouse development.
    Yumiko K Kawamura, Evgeniy A Ozonov, Panagiotis Papasaikas, Takashi Kondo, Nhuong V Nguyen, Michael B Stadler, Sebastien A Smallwood, Haruhiko Koseki, Antoine H F M Peters.
      Except for regulatory CpG-island sequences, genomes of most mammalian cells are widely DNA-methylated. In oocytes, though, DNA methylation (DNAme) is largely confined to transcribed regions. The mechanisms restricting de novo DNAme in oocytes and their relevance thereof for zygotic genome activation and embryonic development are largely unknown. Here we show that KDM2A and KDM2B, two histone demethylases, prevent genome-wide accumulation of histone H3 lysine 36 di-methylation, thereby impeding DNMT3A-catalyzed DNAme. We demonstrate that aberrant DNAme at CpG islands inherited from Kdm2a/Kdm2b double-mutant oocytes represses gene transcription in two-cell embryos. Aberrant maternal DNAme impairs pre-implantation embryonic development, which is suppressed by Dnmt3a deficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte methylome, thereby conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient for erasing aberrant DNAme from maternal chromatin, and that early development is susceptible to gene dosage haplo-insufficiency effects.
    Keywords:  CpG island; DNA methylation; KDM2A; KDM2B; PRC1; Polycomb; embryogenesis; maternal epigenetic inheritance; oocyte; reprogramming
    DOI:  https://doi.org/10.1016/j.devcel.2025.08.005
  11. bioRxiv. 2025 Aug 31. pii: 2025.08.31.673364. [Epub ahead of print]
    Patterns of Mitochondrial ATP Predict Tissue Folding.
    Bezia Lemma, Megan Rothstein, Pengfei Zhang, Bridget Waas, Marcus Kilwein, Safiya Topiwala, Sherry X Zhang, Anvitha Sudhakar, Katharine Goodwin, Elizabeth R Gavis, Ricardo Mallarino, Andrej Kosmrlj, Celeste M Nelson.
      The construction of complex tissue shapes during embryonic development results from spatial patterns of gene expression and mechanical forces fueled by chemical energy from ATP hydrolysis. We find that chemical energy is similarly patterned during morphogenesis. Specifically, mitochondria are locally enriched at the apical sides of epithelial cells during apical constriction, which is widely used across the animal kingdom to fold epithelial tissues. Timelapse imaging, spatial transcriptomics, and measurements of oxygen consumption rate reveal that mitochondrial density, potential, and ATP increase in epithelial cells prior to actomyosin contraction and tissue folding, which is prevented by inhibiting oxidative phosphorylation. Mitochondrial enrichment and apicobasal patterning are conserved during apical constriction in flies, chicks, and mice, and these subcellular patterns can be used to predict computationally patterns of tissue folding. These findings highlight a spatial dimension of bioenergetics in embryonic development.
    DOI:  https://doi.org/10.1101/2025.08.31.673364
  12. Nat Commun. 2025 Aug 28. 16(1): 8051
    Translational repression by 4E-T is crucial to maintain the prophase-I arrest in vertebrate oocytes.
    Andreas Heim, Shiya Cheng, Jan Orth, Florian Stengel, Melina Schuh, Thomas U Mayer.
      Meiotic maturation of vertebrate oocytes occurs in the near-absence of transcription. Thus, female fertility relies on timely translational activation of maternal transcripts stockpiled in full-grown prophase-I-arrested oocytes. However, how expression of these mRNAs is suppressed to maintain the long-lasting prophase-I arrest remains mysterious. Utilizing fast-acting TRIM-Away, we demonstrate that acute loss of the translation repressor 4E-T triggers spontaneous release from prophase-I arrest in mouse and frog oocytes. This is due to untimely expression of key meiotic drivers like c-Mos and cyclin-B1. Notably, mutant 4E-T associated with premature ovarian insufficiency in women fails to maintain the prophase-I arrest in Xenopus oocytes. We further show that 4E-T association with eIF4E and PATL2 is critical for target mRNA binding and repression. Thus, 4E-T is a central factor in translational repression of mRNAs stockpiled in full-grown oocytes for later activation and, therefore, essential to sustain the oocyte pool throughout the reproductive lifespan of female vertebrates.
    DOI:  https://doi.org/10.1038/s41467-025-62971-9
  13. Nat Genet. 2025 Sep 04.
    DNA methylation influences human centromere positioning and function.
    Catalina Salinas-Luypaert, Danilo Dubocanin, Rosa Jooyoung Lee, Lorena Andrade Ruiz, Riccardo Gamba, Marine Grison, Leonid Velikovsky, Annapaola Angrisani, Andrea Scelfo, Yuan Xu, Marie Dumont, Viviana Barra, Therese Wilhelm, Guillaume Velasco, Marialucrezia Losito, René Wardenaar, Claire Francastel, Floris Foijer, Geert J P L Kops, Karen H Miga, Nicolas Altemose, Daniele Fachinetti.
      Maintaining the epigenetic identity of centromeres is essential to prevent genome instability. Centromeres are epigenetically defined by the histone H3 variant CENP-A. Prior work in human centromeres has shown that CENP-A is associated with regions of hypomethylated DNA located within large arrays of hypermethylated repeats, but the functional importance of these DNA methylation (DNAme) patterns remains poorly understood. To address this, we developed tools to perturb centromeric DNAme, revealing that it causally influences CENP-A positioning. We show that rapid loss of methylation results in increased binding of centromeric proteins and alterations in centromere architecture, leading to aneuploidy and reduced cell viability. We also demonstrate that gradual centromeric DNA demethylation prompts a process of cellular adaptation. Altogether, we find that DNAme causally influences CENP-A localization and centromere function, offering mechanistic insights into pathological alterations of centromeric DNAme.
    DOI:  https://doi.org/10.1038/s41588-025-02324-w
  14. Nature. 2025 Sep 03.
    Rewiring of cortical glucose metabolism fuels human brain cancer growth.
    Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O'Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U Kothari, Navyateja Korimerla, Donna M Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C Andren, Junyoung O Park, Johanna Ten Hoeve, Vijay Tarnal, Kimberly A Redic, Nathan R Qi, Joshua L Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Krithika Suresh, Jann N Sarkaria, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Erina Vlashi, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.
      The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.
    DOI:  https://doi.org/10.1038/s41586-025-09460-7
  15. Neuron. 2025 Sep 03. pii: S0896-6273(25)00590-2. [Epub ahead of print]113(17): 2814-2821.e2
    Cell-type-specific enrichment of somatic aneuploidy in the mammalian brain.
    Eran A Mukamel, Hanqing Liu, M Margarita Behrens, Joseph R Ecker.
      Somatic mutations alter the genomes of a subset of an individual's brain cells, impacting gene regulation and contributing to disease processes. Mosaic single-nucleotide variants have been characterized with single-cell resolution in the brain, but we have limited information about large-scale structural variation such as whole-chromosome duplication or loss. We used a dataset of over 415,000 single-cell DNA methylation and chromatin conformation profiles from the adult mouse brain to comprehensively identify and characterize aneuploid cells. Somatic trisomy events were strongly enriched on chromosome 16, which is syntenic with human chromosome 21. We also observed a specific enrichment of chromosome gain and loss events in specific cell types, including Pons neurons and oligodendrocyte precursor cells. Chromosome 16 trisomy occurred in multiple cell types and across brain regions, suggesting that nondisjunction is a recurrent feature of somatic structural variation in the brain.
    Keywords:  DNA methylation; Down syndrome; aneuploidy; brain; mosaicism; mouse; neuron; single cell; somatic mutation; trisomy
    DOI:  https://doi.org/10.1016/j.neuron.2025.08.006
  16. Cell. 2025 Aug 26. pii: S0092-8674(25)00926-2. [Epub ahead of print]
    Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.
    Kaile Wang, Rui Ye, Shanshan Bai, Zhenna Xiao, Lei Yang, Jianzhuo Li, Chenling Tang, Emi Sei, Jinyu Peng, Anna K Casasent, Steven H Lin, Chandandeep Nagi, Alastair M Thompson, Savitri Krishnamurthy, Nicholas E Navin.
      Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin. In contrast to bulk studies, wellDR-seq enabled the study of subclone-level gene-dosage relationships, which showed near-linear correlations in large chromosomal segments and extensive variation at the single-gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes as well as sporadic copy-number aberrations in non-cancer cells. Overall, these data reveal complex relationships between copy number and gene expression in single cells, improving our understanding of breast cancer progression.
    Keywords:  DNA copy number; aneuploidy; breast cancer genomics; breast cancer progression; gene dosage effects; single-cell DNA and RNA sequencing; single-cell multiomics; single-cell sequencing; tumor evolution; wellDR-seq
    DOI:  https://doi.org/10.1016/j.cell.2025.08.012
  17. Science. 2025 Aug 28. 389(6763): eadt5663
    Transcription factors SP5 and SP8 drive primary cilia formation in mammalian embryos.
    Yinwen Liang, Richard Koche, Ravindra B Chalamalasetty, Daniel N Stephen, Mark W Kennedy, Zhimin Lao, Yunong Pang, Ying-Yi Kuo, Moonsup Lee, Francisco Pereira Lobo, Xiaofeng Huang, Anna-Katerina Hadjantonakis, Terry P Yamaguchi, Kathryn V Anderson, Alexandra L Joyner.
      Although specific transcription factors (TFs) are known to regulate cell fate decisions, the degree to which they can stimulate formation of specific cell organelles is less clear. We used a multiomics comparison of the transcriptomes of ciliated and unciliated embryonic cells to identify TFs up-regulated in ciliated cells. We also used conditional genetics in mouse embryos and stem cells and found that the TFs SP5 and SP8 regulate cilia formation and gene expression. In embryos lacking Sp5 and Sp8, primary and motile cilia were shorter than normal and reduced in number across cell types, contributing to situs inversus and hydrocephalus. Moreover, expression of SP8 was sufficient to induce primary cilia in unciliated cells. This work will facilitate the study of cilia assembly using stem cell models and promote further understanding of human ciliopathies.
    DOI:  https://doi.org/10.1126/science.adt5663
  18. Nature. 2025 Sep 03.
    DNA2 enables growth by restricting recombination-restarted replication.
    Jessica J R Hudson, Rowin Appanah, David Jones, Kathryn Davidson, Alice M Budden, Alina Vaitsiankova, Kok-Lung Chan, Keith W Caldecott, Antony M Carr, Ulrich Rass.
      Nuclease-helicase DNA2 is a multifunctional genome caretaker that is essential for cell proliferation in a range of organisms, from yeast to human1-4. Bi-allelic DNA2 mutations that reduce DNA2 concentrations cause a spectrum of primordial dwarfism disorders, including Seckel and Rothmund-Thomson-related syndromes5-7. By contrast, cancer cells frequently express high concentrations of DNA2 (refs. 8-11). The mechanism that precludes cell proliferation in the absence of DNA2 and the molecular aetiology of DNA2-linked diseases remain elusive. Here we used yeast and human cells to demonstrate that DNA2 suppresses homologous recombination-restarted replication and checkpoint activation at stalled DNA replication forks. Loss of this control mechanism upon degradation of DNA2 in human cells causes recombination-dependent DNA synthesis and build-up of RPA-bound single-stranded DNA in the G2 phase of the cell cycle. Consequently, DNA2 deprivation triggers the DNA damage checkpoint and invariably leads to ATR-p21-dependent cell-cycle exit before mitosis. These findings explain why DNA2 is essential for cell proliferation and reveal that replication fork processing to restrict recombination is indispensable for avoiding cellular senescence. Stochastic entry into senescence stifles the proliferative potential of cells following the expression of a Seckel syndrome patient-derived DNA2 hypomorph or partial degradation of DNA2, providing a conceptual framework to explain global growth failure in DNA2-linked primordial dwarfism disorders.
    DOI:  https://doi.org/10.1038/s41586-025-09470-5
  19. EMBO Rep. 2025 Aug 29.
    Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
    Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  20. J Cell Sci. 2025 Sep 05. pii: jcs.264350. [Epub ahead of print]
    Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes.
    Yubo Zou, Nicolas Allen, Emaan Rauf, Deborah Leckband.
      We present evidence that the association of Epithelial (E)-cadherin (CHD1) extracellular domain and epidermal growth factor receptor (EGFR, ErbB1) is obligatory for cadherin force transduction signaling. E-cadherin and EGFR associate at cell surfaces, independent of their cytoplasmic domains, and tension on E-cadherin activates EGFR signaling. Using engineered cadherin mutants that disrupt co-immunoprecipitation with EGFR, but not adhesion, we show that the hetero-receptor complex is required to mechanically activate signaling and downstream cytoskeletal remodeling at cadherin adhesions. The mutants localized the essential region on E-cadherin to the extracellular region and domain 4, EC4. The ectodomain is also required for hetero-receptor co-localization at intercellular junctions. Although the E-cadherin mutants disrupt EGFR signaling, integrin pre-activation together with tension rescues cytoskeletal reinforcement at cadherin adhesions, confirming the role of integrins in intercellular force transduction. Furthermore, although E-cadherin suppresses EGFR-mediated proliferation, in response to extracellular matrix stiffening, the force-sensitive hetero-receptor complex regulates growth factor-dependent epithelial proliferation. These findings support the hypothesis that E-cadherin complexes with EGFR are mechano-switches at cell-cell contacts that directly couple intercellular force fluctuations to mitogen-dependent signaling.
    Keywords:  Cadherin; Epidermal growth factor receptor; Mechano-transduction
    DOI:  https://doi.org/10.1242/jcs.264350
  21. bioRxiv. 2025 Aug 19. pii: 2025.08.14.669896. [Epub ahead of print]
    Proteo-transcriptomic reprogramming and resource reallocation define the aging mammalian brain.
    Nisha Hemandhar-Kumar, Verena Kluever, Svenja V Kaufmann, Cornelius Bergmann, Kanaan Mousaei, Miguel Tomas, Miguel Correa Marrero, Avika Chopra, Misa Hirose, Mercè Pallas, Coral Sanfeliu, Saleh M Ibrahim, Andre Fischer, Tiago F Outeiro, Henning Urlaub, Tatjana Tchumatchenko, Carlos López Otín, Eugenio F Fornasiero.
      Brain aging is a major risk for neurodegeneration, yet the underlying molecular mechanisms remain poorly understood. Here we performed an integrative proteo-transcriptomic analysis of the aging mouse brain, uncovering molecular signatures of aging through the assessment of protein aggregation, mRNA relocalization, and comparative proteomics across eight models of premature aging and neurodegeneration. We identified dynamic changes in physiological aging highlighting differences in synaptic maintenance and energy-allocation. These were linked to changes associated with fundamental protein biochemical properties such as size and net charge. Network analysis highlighted a decrease in mitochondrial complex I proteins not compensated at the mRNA level. Aggregation of 60S ribosome subunits indicated deteriorating translation efficiency and was accompanied by mitochondrial and proteasomal imbalance. The analysis of the nine models revealed key similarities and differences between physiological aging and pathology. Overall, our study provides an extensive resource on molecular aging, and offers insights into mechanisms predisposing to neurodegeneration, easily accessible at our Brain Aging and Molecular Atlas Project (BrainAging-MAP) website.
    DOI:  https://doi.org/10.1101/2025.08.14.669896
  22. Nat Aging. 2025 Sep 02.
    Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
    Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Manish Mishra, Rihao Qu, Emily L Goldberg, Sviatoslav Sidorov, Payal Damani-Yokota, Stephen T Yeung, Camille Khairallah, David Gonzalez, Taverlyn M Shepard, Christina Camell, Maxim N Artyomov, Yuval Kluger, Kamal M Khanna, Vishwa Deep Dixit.
      Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00952-9
  23. Genome Biol. 2025 Sep 02. 26(1): 263
    CLDN10-driven lineage decision in an amnion and primordial germ cell progenitor at the amnion-epiblast boundary in primates.
    Nikola Sekulovski, Amber E Carleton, Anusha Rengarajan, Chien-Wei Lin, Maliha Kabir, Lauren N Juga, Allison E Whorton, Lauren E Elberfeld, Jenna C Wettstein, Jenna K Schmidt, Thaddeus G Golos, Kenichiro Taniguchi.
       BACKGROUND: A growing body of evidence from primate embryos as well as in vitro systems supports the notion that amnion and primordial germ cell (PGC) lineage progressing cells share a common precursor.
    RESULTS: To gain comprehensive transcriptomic insights into this critical but poorly understood precursor and its progeny, we examine the evolving transcriptome of a developing human pluripotent stem cell-derived model of amnion and PGC formation at the single cell level. This analysis reveals several continuous amniotic fate progressing states with state-specific markers. Additionally, a progenitor-like cell, that displays bi-potential characteristics for amnion and PGC-like cell lineages and is marked by CLDN10, is identified. Strikingly, we find that expression of CLDN10 is restricted to the amnion-epiblast boundary region in our human post-implantation amniotic sac model as well as in peri-gastrula cynomolgus macaque embryos; moreover, this boundary region presents amnion and PGC progenitor-like transcriptional characteristics. Furthermore, our loss of function analysis shows that CLDN10 promotes amniotic but suppresses PGC-like fate.
    CONCLUSIONS: Overall, based on the single cell transcriptomic resource in this study, we identify a CLDN10+ amnion and PGC progenitor-like population at the amnion-epiblast boundary of the primate peri-gastrula, and present additional molecular clues as to how amnion and PGC may be formed at the amnion-epiblast boundary in human peri-gastrula.
    DOI:  https://doi.org/10.1186/s13059-025-03751-y
  24. Nano Lett. 2025 Aug 28.
    Sensitive Detection of Intercellular Tensile Forces via Cas12a-Assisted Membrane Molecular Probes.
    Murali Mohana Rao Singuru, Priyanka Bhattacharyya, Hari Priya Sriramakrishnan, Mingxu You.
      Intercellular forces are critical for shaping cells, driving migration, and guiding tissue development and morphogenesis. However, these transient and low-intensity forces are still challenging to detect. Here, we developed a Force-Responsive Cas12a-assisted Tension Sensor (FRCTS), which leverages the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas12a technology to enable more reliable detection of cumulative molecular force events generated at cell-cell junctions. FRCTS incorporates a lipid-modified DNA hairpin to spontaneously anchor onto live-cell membranes. The hairpin unfolds upon molecular tension exerted by neighboring cells through an integrin or cadherin receptor and reveals a hidden strand to activate Cas12a. Cas12a activation leads to an irreversible cleavage of a fluorogenic reporter on the cell surface, causing cumulative cell membrane fluorescence signals for recording intercellular force events. After systematic optimization, we applied FRCTS to quantify E-cadherin/N-cadherin mechanical correlations during the epithelial-mesenchymal transition. This modular and sensitive FRCTS platform can potentially be used for assessing various intercellular mechanotransduction processes.
    Keywords:  CRISPR-Cas12a; DNA probes; cellular forces; mechanotransduction
    DOI:  https://doi.org/10.1021/acs.nanolett.5c02983
  25. Trends Cell Biol. 2025 Sep 02. pii: S0962-8924(25)00179-5. [Epub ahead of print]
    Understanding human embryogenesis by building programmable stem cell-based models.
    Carly Guiltinan, Gerrald A Lodewijk, Sayaka Kozuki, S Ali Shariati.
      Stem cell-based embryo models provide an alternative system to study an elusive period of development. Programmed mouse embryo models have recently been generated by activating two endogenous regulatory elements via epigenome editing. In this forum article, we discuss this achievement along with the potential of translating it to engineering models of human embryogenesis.
    Keywords:  CRISPR activation; embryo models; epigenome editing; stem cells
    DOI:  https://doi.org/10.1016/j.tcb.2025.08.003
  26. J Cell Biol. 2025 Nov 03. pii: e202504177. [Epub ahead of print]224(11):
    Allocation of resources among multiple daughter cells.
    Alison C E Wirshing, Roberto Alonso-Matilla, Michelle Yan, Samra Khalid, Analeigha V Colarusso, David Odde, Daniel J Lew.
      Cell division commonly produces two daughter cells, but there are many exceptions where large cells produce multiple daughters. Multiple fission of some green algae and bacteria; cellularization during embryogenesis of plants and insects; and growth of Ichthyosporeans, Chytrids, and Apicomplexans all provide variations on this theme. In some yeast species, a large multinucleate mother cell grows multiple buds (daughters) simultaneously. Here, we address how mothers partition growth equally among their buds in the multi-budding yeast Aureobasidium pullulans. Bud growth is directed by actin cable networks that appear to be optimized for even partitioning despite complex cell geometries. Even partitioning does not rely on compensatory mechanisms to adjust bud volumes but rather stems directly from effective equalization of polarity sites. These results reveal how conserved cell polarity and cytoskeletal networks are adapted to build complex morphologies in fungi.
    DOI:  https://doi.org/10.1083/jcb.202504177
  27. Cell. 2025 Aug 25. pii: S0092-8674(25)00921-3. [Epub ahead of print]
    Hepatocyte metabolic adaptations during pregnancy and lactation.
    Li Yang, Yu Zhang, Xin-Xin Yu, Yu-Heng Zhou, Shuang He, Liu Yang, Tong-Yun Mao, Jun-Ge Yang, Ying Wu, Qi-Qi Zheng, Xun-Kai Li, Hou-Zao Chen, Cheng-Ran Xu.
      The liver undergoes metabolic adaptations during gestation and lactation to meet evolving physiological demands, yet the precise processes, regulatory mechanisms, and functions remain unclear. Using high-resolution single-cell RNA sequencing, we systematically characterized hepatocyte adaptations in mice across pregnancy and postpartum stages. We discovered a cyclical hepatocyte trajectory ("pregnancy clock") that governs metabolic changes during gestation and postpartum recovery, reverting to pregestational states in non-lactating mice. Lactation induced a distinct branching trajectory characterized by elevated lipid synthesis and export. Deletion of glycoprotein 130 (gp130) disrupted hepatic adaptations during pregnancy, impairing fetal growth, whereas acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) deficiency postpartum impaired hepatic lipid biosynthesis and export, reducing milk lipid content and compromising offspring development. Comparative analysis with sheep highlighted conserved hepatic metabolic adaptation pathways despite genetic divergence between species. These insights clarify hepatocyte plasticity during pregnancy and lactation, identifying potential therapeutic targets to optimize maternal-fetal health and lactation performance, with implications for reproductive biology and livestock management.
    Keywords:  ACSS2; JAK/STAT signaling; gestation; gp130; hepatocyte adaptations; lactation; maternal liver function; pregnancy clock; sheep hepatocytes; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2025.08.007
  28. Cell Stem Cell. 2025 Sep 04. pii: S1934-5909(25)00296-6. [Epub ahead of print]32(9): 1321-1345
    Modeling the human maternal-fetal interface.
    Vladyslav Bondarenko, Margherita Yayoi Turco.
      Stem cells and organoids enable the modeling of various aspects of human development in vitro, yet integrating them to study maternal-fetal interactions remains challenging. In this review, we explore the current in vitro models of the endometrium, placenta, and embryo and identify key challenges associated with their integration, including the establishment of morpho-functional complexity, spatiotemporal coordination, and appropriate in vivo benchmarking. We propose an interdisciplinary perspective that emphasizes a shift from "building blocks" to "building interactions." Altogether, we provide a discussion on the challenges and prospects for advancing mechanistic understanding of intrauterine human development and the maternal-fetal interface.
    Keywords:  bioengineering; embryo; endometrium; human development; maternal-fetal interactions; organoids; placenta; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.08.004
  29. J Clin Invest. 2025 Aug 28. pii: e191826. [Epub ahead of print]
    Clonal expansion of alveolar fibroblast progeny drives pulmonary fibrosis in mouse models.
    Christopher Molina, Tatsuya Tsukui, Imran S Khan, Xin Ren, Wenli Qiu, Michael Matthay, Paul Wolters, Dean Sheppard.
      Pulmonary fibrosis has been called a fibroproliferative disease but the functional importance of proliferating fibroblasts to pulmonary fibrosis has not been systematically examined. In response to alveolar injury, resting alveolar fibroblasts differentiate into fibrotic fibroblasts that express high levels of collagens. However, what role, if any, proliferation plays in the accumulation of fibrotic fibroblasts remains unclear. Through EdU incorporation, genetic lineage tracing, and single cell RNA sequencing, we resolve the proliferation dynamics of lung fibroblasts during post-injury fibrogenesis. Our data show substantial DNA replication in progeny of alveolar fibroblasts in two models of pulmonary fibrosis. By genetically labeling individual cells, we observe clonal expansion of alveolar fibroblast descendants principally in regions of fibrotic remodeling. The transcriptome of proliferating fibroblasts closely resembles that of fibrotic fibroblasts, suggesting that fibroblasts can first differentiate into fibrotic fibroblasts and then proliferate. Genetic ablation of proliferating fibroblasts and selective inhibition of cytokinesis in alveolar fibroblast descendants significantly mitigates pulmonary fibrosis and rescues lung function. Furthermore, fibroblasts in precision-cut lung slices from human fibrotic lungs exhibit higher proliferation rates than those in non-diseased lungs. This work establishes fibroblast proliferation as a critical driver of pulmonary fibrosis and suggests that specifically targeting fibroblast proliferation could be a new therapeutic strategy for fibrotic diseases.
    Keywords:  Cell biology; Fibrosis; Pulmonology
    DOI:  https://doi.org/10.1172/JCI191826
  30. Nat Struct Mol Biol. 2025 Sep 01.
    Interactions between the genome and the nuclear lamina are multivalent and cooperative.
    Lise Dauban, Mathias Eder, Marcel de Haas, Vinícius H Franceschini-Santos, J Omar Yañez-Cuna, Moreno Martinovic, Tom van Schaik, Christ Leemans, Hans Teunissen, Koen Rademaker, Miguel Martinez Ara, Martijn Verkuilen, Elzo de Wit, Bas van Steensel.
      Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here we designed an efficient LAD 'scrambling' approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that, in mouse embryonic stem cells, a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighboring sequences to the NL. Genes drawn toward the NL showed often but not always reduced expression and increased H3K9me3 levels. Furthermore, neighboring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus.
    DOI:  https://doi.org/10.1038/s41594-025-01655-w
  31. J Cell Biol. 2025 Nov 03. pii: e202504068. [Epub ahead of print]224(11):
    Mechanisms of nuclear segregation in a multinucleate multibudding yeast.
    Claudia A Petrucco, Alex W Crocker, Alison C E Wirshing, Analeigha V Colarusso, Maya Waarts, Amy S Gladfelter, Daniel J Lew.
      Budding yeasts present an especially challenging geometry for segregation of chromosomes, which must be delivered across the narrow mother-bud neck into the bud. Studies in the model yeast Saccharomyces cerevisiae have revealed an elaborate set of mechanisms that selectively orient one mitotic spindle pole toward the bud and then drive spindle elongation along the mother-bud axis, ensuring nuclear segregation between mother and bud. It is unclear how these pathways might be adapted to yield similar precision in more complex cell geometries. Here, we provide the first description of the dynamics of mitosis in a multinucleate, multibudding yeast, Aureobasidium pullulans, and identify many unexpected differences from uninucleate yeasts. Mitotic spindles do not orient along the mother-bud axis prior to anaphase, and accurate nuclear segregation often occurs after spindle disassembly. Cortical Num1-dynein forces pull highly mobile nuclei into buds, and once a nucleus enters a bud, it discourages others from entering, ensuring that most daughters inherit only one nucleus.
    DOI:  https://doi.org/10.1083/jcb.202504068
  32. Nat Struct Mol Biol. 2025 Sep 02.
    Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development.
    Ane Iturbide, Mayra L Ruiz Tejada Segura, Camille Noll, Kenji Schorpp, Ina Rothenaigner, Elias R Ruiz-Morales, Gabriele Lubatti, Ahmed Agami, Kamyar Hadian, Antonio Scialdone, Maria-Elena Torres-Padilla.
      
    DOI:  https://doi.org/10.1038/s41594-025-01661-y
  33. Nature. 2025 Sep 03.
    Single-cell transcriptomic and genomic changes in the ageing human brain.
    Ailsa M Jeffries, Tianxiong Yu, Jennifer S Ziegenfuss, Allie K Tolles, Christina E Baer, Cesar Bautista Sotelo, Yerin Kim, Zhiping Weng, Michael A Lodato.
      Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process1. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life2. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.
    DOI:  https://doi.org/10.1038/s41586-025-09435-8
  34. Protein Cell. 2025 Sep 01. pii: pwaf074. [Epub ahead of print]
    A single-cell transcriptomic landscape characterizes the endocrine system aging in the mouse.
    Ran Wei, Zhehao Du, Jue Wang, Jinlong Bi, Wencong Lyu, Haochen Wang, Jianuo He, Fanju Meng, Lijun Zhang, Chao Zhang, Chen Zhang, Wei Tao.
      The endocrine system is crucial for maintaining overall homeostasis. However, its cellular signatures have not been elucidated during aging. Here, we conducted the first-ever single-cell transcriptomic profiles from eight endocrine organs in young and aged mice, revealing the activation of cell-type-specific aging pathways, such as loss of proteostasis, genomic instability and reactive oxygen species (ROS). Among six sex-shared endocrine organs, aging severely impaired gene expression networks in functional endocrine cells, accompanied by enhanced immune infiltration and unfolded protein response (UPR). Mechanism investigations showed that expanded aging-associated exhausted T cells activated MHC-I-UPR axis across functional endocrine cells by releasing GZMK. The inhibition of GZMK receptors by small chemical molecules counteracted the UPR and senescence, suggesting the immune infiltration is a possible driver of endocrine aging. Machine learning identified CD59 as a novel aging feature in sex-shared functional endocrine cells. For two sex-specific endocrine organs, both aged ovaries and testes showed enhanced immune responses. Meanwhile, cell-type-specific aging-associated transcriptional changes revealed an enhanced ROS mainly in aged theca cells of ovaries, while aged spermatogonia in testes showed impaired DNA repair. This study provides a comprehensive analysis of endocrine system aging at single-cell resolution, offering profound insights into mechanisms of endocrine aging.
    Keywords:  aging; endocrine system; immune infiltration; single-cell RNA-seq
    DOI:  https://doi.org/10.1093/procel/pwaf074
  35. Sci Adv. 2025 Sep 05. 11(36): eadt5859
    Galectin-3 induces neurodevelopmental apical-basal polarity and regulates gyrification.
    Luana Campos Soares, Ning Huang, Hana Bernhardova, Viviana Macarelli, Marva Chan, Lara Nikel, Sara Bandiera, Dongnan Yan, Dhanu Gupta, Elisa M Cruz, Talia Vasaturo-Kolodner, James M Hillis, Matthew Wood, Mootaz Salman, Zoltán Molnár, Eric O'Neill, Francis G Szele.
      Apical-basal polarity (ABP) establishment and maintenance is necessary for proper brain development, yet how it is controlled is unclear. Galectin-3 (Gal-3) has been previously implicated in ABP of epithelial cells, and, here, we find that it is apically expressed in human embryonic stem cells (hESCs) during neural induction. Gal-3 blockade disrupts ABP and alters the distribution of junctional proteins in hESC-derived neural rosettes and is rescued by addition of recombinant Gal-3. Transcriptomics analysis shows that blocking Gal-3 regulates expression of genes responsible for nervous system development and cell junction assembly, among others. Last, Gal-3 blockade during embryonic development in vivo reduces horizontal cell divisions, disturbs cortical layering of neural progenitors, and induces gyrification. These data uncover a regulatory mechanism for ABP in the brain and warrant caution in modulating Gal-3 during pregnancy.
    DOI:  https://doi.org/10.1126/sciadv.adt5859
  36. Science. 2025 Sep 04. eadk7978
    Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
    Huihui Huang, Yi Wang, Zsuzsanna K Zsengeller, Joshua M Gorham, Vamsidhara Vemireddy, Amanda J Clark, Hui Pan, Jonathan M Dreyfuss, Vasantha Jotwani, Michael G Shlipak, Mark J Sarnak, Chirag R Parikh, Heather Thiessen-Philbrook, Ronit Katz, Sushrut S Waikar, Nicole J Lake, Monkol Lek, Wen Shi, Daniela Puiu, Yun Soo Hong, Jonathan G Seidman, Dan E Arking, Samir M Parikh.
      Somatically acquired mitochondrial DNA mutations accumulate with age, but the mechanisms and consequences are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored ATP generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (p < 10-7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
    DOI:  https://doi.org/10.1126/science.adk7978
  37. Mol Cell. 2025 Sep 04. pii: S1097-2765(25)00657-4. [Epub ahead of print]85(17): 3288-3305.e6
    Target RNA recognition drives PIWI∗ complex assembly for transposon silencing.
    Júlia Portell-Montserrat, Laszlo Tirian, Changwei Yu, Giacomo Silvestri, Ulrich Hohmann, Dominik Handler, Peter Duchek, Laura Fin, Clemens Plaschka, Julius Brennecke.
      PIWI-clade Argonaute proteins and their associated PIWI-interacting RNAs (piRNAs) are essential guardians of genome integrity, silencing transposable elements through distinct nuclear and cytoplasmic pathways. Nuclear PIWI proteins direct heterochromatin formation at transposon loci, while cytoplasmic PIWIs cleave transposon transcripts to initiate piRNA amplification. Both processes rely on target RNA recognition by PIWI-piRNA complexes, yet how this leads to effector recruitment is unclear. Here, we show that target engagement triggers formation of complexes, termed PIWI∗-comprising a PIWI protein, a piRNA-target duplex, a GTSF family protein, and Maelstrom-that serve as molecular platforms recruiting downstream effectors. In Drosophila, nuclear Piwi∗ engages the SFiNX complex to establish heterochromatin, while cytoplasmic Aubergine∗ complexes recruit the helicase Spindle-E to promote piRNA biogenesis. Evolutionary analysis reveals that PIWI∗ formation is conserved across metazoans, uncovering an ancient mechanism coupling piRNA-guided target recognition to effector function. These findings define a unifying molecular principle for PIWI-mediated silencing across cellular compartments.
    Keywords:  Argonaute proteins; Drosophila; PIWI-piRNA pathway; germ line biology; heterochromatin biology; piRNA biogenesis; protein structure prediction; small RNA pathways; transposon silencing
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.007
  38. Neuron. 2025 Aug 27. pii: S0896-6273(25)00591-4. [Epub ahead of print]
    Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain-tumor growth.
    Corina Anastasaki, Rui Mu, Chloe M Kernan, Xuanwei Li, Rasha Barakat, Joshua P Koleske, Yunqing Gao, Olivia M Cobb, Xinguo Lu, Charles G Eberhart, Joanna J Phillips, Jennifer M Strahle, Sonika Dahiya, Steven J Mennerick, Fausto J Rodriguez, David H Gutmann.
      Direct and paracrine neuron-cancer interactions govern tumor development and progression. While neuron-elaborated neurotransmitters, like glutamate, support neoplastic growth, the mechanism underlying tumor intracellular mitogenic signaling and proliferation remains an unresolved question in cancer neuroscience. Herein, we discover that glutamate receptor (GluR) stimulation phosphorylates sarcoma proto-oncogene (Src) to activate platelet-derived growth factor (PDGF) receptor-α (PDGFRα)-dependent extracellular-regulated kinase (ERK) signaling and drive glioma growth. Using single-cell transcriptomic datasets and unique laboratory-generated humanized models of the most common brain tumor in children (pilocytic astrocytoma [PA]), we identify glutamatergic pathway enrichment in tumor cells, where glutamate increases PA proliferation without changing membrane depolarization. Aberrant GRID2 and GRIK3 GluR expression increases rat sarcoma (RAS)/ERK signaling by selective Src-mediated PDGFRα activation. Moreover, genetic or pharmacologic GRID2/GRIK3 and PDGFRA inhibition reduce PDGFRα/RAS/ERK activation, PA cell proliferation, and PA xenograft growth. Taken together, these observations establish a conceptual framework for understanding similar neurotransmitter dependencies in other cancers.
    Keywords:  ERK signaling; cancer neuroscience; glutamate receptor; pediatric brain tumor; receptor tyrosine kinase
    DOI:  https://doi.org/10.1016/j.neuron.2025.08.005
  39. Dev Cell. 2025 Jun 17. pii: S1534-5807(25)00325-9. [Epub ahead of print]
    TBX3 advances the developmental chromatin landscape toward the hepatic fate.
    Tabea L Stephan, Rebecca Cullum, Sibyl Drissler, Ashleigh Thomas, Bettina M Fuglerud, Makenna Clement-Ranney, Jeremy Lotto, Nicole A J Krentz, Stephen A Duncan, Pamela A Hoodless.
      By mapping histone modifications in a human stem cell model of hepatic differentiation, we identified an enhancer landscape that is dynamic and stage specific, with many primed at the definitive endoderm stage. While hepatic enhancers gained active histone modifications, non-hepatic enhancers lost H3K4me1 after hepatic specification. T-box transcription factor 3 (TBX3) was found to bind to hepatic enhancers and promoters. TBX3 binding was transient, and only upon the dissociation of TBX3 from its bound regions were active histone modifications acquired. Subsequently, transcription was activated, supporting a role for TBX3 in directly activating the hepatic lineage. Constitutive overexpression of TBX3 indicated that dissociation of TBX3 is crucial for gene activation. TBX3 did not bind to any pancreatic regulatory regions directly, indicating indirect repression of the pancreatic lineage. Together, this suggests that TBX3 plays a role in identifying and bookmarking hepatic enhancers and promoters during specification, which subsequently will be activated to drive cell identity.
    Keywords:  ChIP-seq; TBX3; cell fate; chromatin dynamics; development; enhancers; gene regulation; histone modifications; liver
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.014
  40. Cancer Lett. 2025 Aug 29. pii: S0304-3835(25)00578-6. [Epub ahead of print] 218008
    Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.
    Hunter C Herriage, Cameron L Hughes, Sarah K Fahey, Brian R Calvi.
      Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, RasG12V promoted continued divisions of polyploid daughter cells with elevated genome instability. RasG12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, RasG12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.
    Keywords:  Drosophila; endocycling; epithelium; oncogenes; polyploidy; tumorigenesis
    DOI:  https://doi.org/10.1016/j.canlet.2025.218008
  41. Curr Biol. 2025 Aug 27. pii: S0960-9822(25)01025-5. [Epub ahead of print]
    Competition for microtubule lattice spacing between a microtubule expander and compactor.
    Alexandra L Paquette, Sofía Cruz Tetlalmatzi, Justin A G Haineault, Yining Li, Nadja Finkel, Adam G Hendricks, Gary J Brouhard, Muriel Sébastien.
      Microtubules exist in expanded and compacted states, as defined by the lattice spacing of αβ-tubulin dimers. Changes in lattice spacing have been linked to factors such as GTP-hydrolysis, the binding of microtubule-associated proteins (MAPs), the tubulin code, and microtubule bending. These diverse factors exert opposing molecular driving forces on the microtubule lattice that push lattice spacing toward expanded or compacted states. To better understand how these opposing forces are reconciled, we developed in vitro and cell-based model systems for the competition between a microtubule expander (paclitaxel) and a microtubule compactor (doublecortin or DCX). Using an in vitro reconstitution approach, we show that paclitaxel expands microtubules cooperatively. In cells, high concentrations of paclitaxel cause DCX to relocalize to compacted lattices found at concave bends. When the concentration of DCX is increased, however, we find that DCX re-compacts the previously expanded microtubules in vitro. Consistently, high expression levels of DCX prevent its relocalization in paclitaxel-treated cells. When the competition between paclitaxel and DCX is "balanced," we observe a complex phenotype: DCX simultaneously localizes to both long, straight clusters and concave bends, whereas other regions on the microtubule network remain DCX free. We conclude that multiple lattice spacings can coexist in cells. Our results indicate that competition for microtubule lattice spacing is a critical aspect of microtubule physiology.
    Keywords:  SiR-tubulin; compaction; docetaxel; doublecortin; epothilone D; expansion; lattice spacing; microtubule; paclitaxel
    DOI:  https://doi.org/10.1016/j.cub.2025.07.080
  42. Nat Biomed Eng. 2025 Sep 03.
    Phagocytic clearance of targeted cells with a synthetic ligand.
    Yuki Yamato, Jun Suzuki.
      During the process of engulfment, phosphatidylserine is exposed on the surface of dead cells as an 'eat-me' signal and is recognized by Protein S (ProS), a secreted factor that also binds to the Mer tyrosine kinase (MerTK) on phagocytes. Despite its robust activity, this engulfment mechanism has not been exploited for therapeutic purposes. Here we develop a synthetic protein modality called Crunch (connector for removal of unwanted cell habitat) by modifying ProS, inspired by the high engulfment capability of the ProS-MerTK pathway. In Crunch, the phosphatidylserine-binding motif of ProS is replaced with a nanobody or single-chain variable fragment that recognizes the surface proteins of targeted cells. Green fluorescent protein nanobody-conjugated Crunch eliminates green fluorescent protein-expressing melanoma cells in transplantation mouse models. In addition, CD19+B cells are eliminated by anti-CD19 single-chain variable fragment-conjugated Crunch, resulting in a therapeutic effect on systemic lupus erythematosus. Both mouse and human versions of Crunch are effective, establishing this synthetic ligand as a promising tool for the elimination of targeted cells.
    DOI:  https://doi.org/10.1038/s41551-025-01483-9
  43. Nat Protoc. 2025 Aug 29.
    Expansion of human pluripotent stem cell-induced nephron progenitor cells (iNPCs) and the generation of nephron organoids from iNPCs.
    Biao Huang, Pedro Medina, Tianyi Ma, Megan E Schreiber, Zhongwei Li.
      Nephron progenitor cells (NPCs) have a central role in kidney organogenesis: they self-renew and differentiate into nephrons, the functional units of the kidney. Human pluripotent stem cells (hPSCs) can transiently produce induced nephron progenitor-like cells (iNPCs), which then differentiate into nephron organoids. Here, we describe a protocol to purify and expand the hPSC-derived iNPCs in a regular monolayer culture format with an optimized iNPC culture medium. Under this culture condition, iNPCs are programmed to a state with their transcriptome much closer to primary human NPCs than the transient hPSC-derived iNPCs. By following this protocol, iNPC lines can be derived from any hPSC lines, exhibiting a stable cell proliferation rate and retaining NPC marker gene expression over long-term culture. We also describe a protocol to generate nephron organoids from the iNPC lines. These iNPC-derived nephron organoids show minimal off-target cell types compared to hPSC-derived kidney organoids, with enhanced podocyte maturity. This protocol consists of a modified 10-d protocol to generate iNPCs from hPSCs, an iNPC expansion phase with a unique chemically defined iNPC expansion medium called 'hNPSR-v2' and a stepwise 21-d differentiation protocol to generate nephron organoids from iNPCs on an air-liquid interface. Experience in culturing and differentiating hPSCs is required to conduct this protocol, which can be executed within 1.5-2 months.
    DOI:  https://doi.org/10.1038/s41596-025-01236-7
  44. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2515009122
    Inflammation awakens dormant cancer cells by modulating the epithelial-mesenchymal phenotypic state.
    Jingwei Zhang, Jingwen Zhang, Longfei Han, Shiyi Wu, Jie Li, Elinor Ng Eaton, Bingbing Yuan, Ferenc Reinhardt, Hao Li, Patrick C Strasser, Sunny Das, Joana Liu Donaher, Md Imtiaz Khalil, Haiping Jiang, Alexander Deuschel, Danni Lin, Carolin Sebastiany, Mariana Maranga, Salomé Shubitidze, Xiaofei Liu, Arthur W Lambert, Yun Zhang, Yana Liu, Lufei Sui, Sarah Elmiligy, Umberto Pozza, Rauf Günsay, Ranjan Mishra, Jose Velarde, Sonia Iyer, Whitney S Henry, Kipp Weiskopf, Guihai Feng, Tobiloba E Oni, Randolph S Watnick, Xin Li, Robert A Weinberg.
      The awakening of dormant disseminated cancer cells appears to be responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, nonproliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, lung inflammation induced by the chemotherapeutic agent bleomycin effectively awakens dormant cancer cells, providing useful models for studying metastatic awakening. Mechanistically, the awakened cells shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire tumorigenicity and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their tumor-initiating ability, doing so without ongoing heterotypic signaling from the lung microenvironment. Epidermal growth factor receptor ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.
    Keywords:  breast cancer; cancer dormancy and awakening; cancer metastasis; epithelial–mesenchymal transition; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2515009122
  45. Science. 2025 Sep 04. 389(6764): 1043-1048
    Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia.
    Nina Kumowski, Steffen Pabel, Jana Grune, Noor Momin, Van K Ninh, Laura Stengel, Kyle I Mentkowski, Yoshiko Iwamoto, Yi Zheng, I-Hsiu Lee, Jessica Matthias, Jan O Wirth, Fadi E Pulous, Hana Seung, Alexandre Paccalet, Charlotte G Muse, Kenneth K Y Ting, Paul Delgado, Andrew J M Lewis, Vaishali Kaushal, Antonia Kreso, Dennis Brown, Sikander Hayat, Rafael Kramann, Filip K Swirski, Kamila Naxerova, Daniel C Propheter, Lora V Hooper, Michael A Moskowitz, Kevin R King, Nadia Rosenthal, Maarten Hulsmans, Matthias Nahrendorf.
      Ventricular tachycardia disrupts the heart's coordinated pump function, leading to sudden cardiac death. Neutrophils, which are recruited in high numbers to the ischemic myocardium, promote these arrhythmias. Comparing neutrophils with macrophages, we found that resistin-like molecule γ (Retnlg or RELMγ) was the most differentially expressed gene in mouse infarcts. RELMγ is part of a pore-forming protein family that defends the host against bacteria by perforating their membranes. In mice with acute infarcts, leukocyte-specific Retnlg deletion reduced ventricular tachycardia. RELMγ elicited membrane defects that allowed cell exclusion dyes to enter the cardiomyocyte interior and also caused delayed afterdepolarizations and later cardiomyocyte death, both of which are strong arrhythmogenic triggers. Human resistin likewise attacked membranes of liposomes and mammalian cells. We describe how misdirected innate immune defense produces membrane leaks and ventricular arrhythmia.
    DOI:  https://doi.org/10.1126/science.adp7361
  46. Nat Chem Biol. 2025 Sep 02.
    pH variations enable guanine crystal formation within iridosomes.
    Zohar Eyal, Rachael Deis, Anna Gorelick-Ashkenazi, Yuval Barzilay, Yonatan Broder, Asher Perry Kellum, Neta Varsano, Michal Hartstein, Andrea Sorrentino, Ron Rotkopf, Ifat Kaplan-Ashiri, Katya Rechav, Rebecca Metzler, Lothar Houben, Leeor Kronik, Peter Rez, Dvir Gur.
      Many animals produce vivid colors by reflecting and amplifying light with stacked guanine crystals within membrane-bound organelles called iridosomes. While the presence of guanine crystals in iridosomes is well documented, the mechanisms facilitating the accumulation of water-insoluble guanine and driving its crystallization remain unclear. Here we used cryo-electron microscopy, live-cell pH imaging, pharmacological perturbations and spectroscopy to study iridosome maturation in zebrafish. Cryo-electron and synchrotron-based soft X-ray microscopies revealed that amorphous guanine initially accumulates in early-stage iridosomes in its protonated state. Live-cell imaging with a pH sensor demonstrated that early iridosomes are acidic, with pH gradually neutralizing during development. Inhibiting V-ATPase disrupted this acidification and significantly reduced crystal formation, indicating its role in pH regulation. Our findings reveal insights into the molecular mechanisms facilitating guanine formation within iridosomes, emphasizing the pivotal role of pH alternations in the precise formation of biogenic crystals.
    DOI:  https://doi.org/10.1038/s41589-025-02020-0
  47. bioRxiv. 2025 Aug 19. pii: 2025.08.18.670928. [Epub ahead of print]
    The role of actin dynamics in vesicle formation during clathrin mediated endocytosis.
    Jie Yuan, Yen T B Tran, Tomasz J Nawara, Alexa L Mattheyses.
      Clathrin-mediated endocytosis (CME) is an important internalization route for macromolecules, lipids, and membrane receptors in eukaryotic cells. During CME, the plasma membrane invaginates and pinches off forming a clathrin coated vesicle. We previously identified heterogeneity in this process with clathrin coated vesicles forming though multiple routes including simultaneous clathrin accumulation and membrane invagination (constant curvature; CCM) as well as membrane bending after accumulation of flat clathrin (flat to curved; FTC). The architectural dynamics of vesicle formation could be influenced by osmotic or confining pressure, membrane stiffness, fluid force, or cytoskeletal arrangement. Whether these biophysical factors regulate the heterogeneity of vesicle formation dynamics is not well understood. To address this, we investigated the interconnected roles of actin and membrane tension in CME using simultaneous two-wavelength axial ratiometry (STAR) microscopy with nanometer-scale axial resolution. First, we treated Cos-7 cells with latrunculin A (LatA) to inhibit actin polymerization and found the total number of clathrin coated vesicles increased significantly, short-lifetime curved events especially. The proportion of vesicles formed following the FTC model was reduced, the membrane curved sooner after clathrin recruitment, and vesicles were less stable in the x-y plane compared to control. Next, we disrupted actin branching by inhibiting Arp2/3 with CK-869. We found an increased delay between membrane invagination and clathrin recruitment, reduced number of curved events, increased vesicle stability and an increase in the FTC model compared to control. As loss of actin filaments also reduces membrane tension, we treated Cos7 with high osmolality to decrease membrane tension and observed similar result with LatA treated group except vesicle stability stayed unchanged. This suggested the increased curved events in LatA groups may result from reduced membrane tension. We conclude actin polymerization promotes FTC while actin branching promotes vesicle formation though the CCM.
    DOI:  https://doi.org/10.1101/2025.08.18.670928
  48. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2504185122
    A thermodynamic perspective on mammalian neural crest ingression.
    Clarissa C Pasiliao, Evan C Thomas, Theodora Yung, Min Zhu, Hirotaka Tao, Yu Sun, Sidhartha Goyal, Sevan Hopyan.
      The ingression of neural crest cells from an ectodermal to a mesodermal layer is regulated by instructive, directional cues and potentially stochastic, biophysical parameters such as differential cell adhesion and tension heterogeneity. However, a cohesive framework in which to consider how various influences contribute to ingression remains elusive. Here, we observe the cell behaviors of the murine neural crest in three dimensions over time and apply a free energy framework to more wholly understand why cells ingress. Guided by work on granular matter that provides a path by which to define the roles of stochastic mechanisms in nonequilibrium systems, we measured and manipulated biophysical parameters in vivo. The data suggest that an energy barrier to cell ingression is overcome by a combination of relatively favorable cell adhesion energies, high cell shape fluctuations, and entropic cell packing configurations. Under those conditions, cell ingression may proceed spontaneously. Recognized biophysical cues likely tilt these parameters to make the process more robust. The results imply that dissipative mechanisms which transiently disorder tissue may underlie some morphogenetic events. Variations of a thermodynamic framework can potentially be applied to integrate various inputs that drive morphogenesis in different contexts.
    Keywords:  biophysics; mouse embryo; neural crest ingression; thermodynamics; time-lapse lightsheet imaging
    DOI:  https://doi.org/10.1073/pnas.2504185122
  49. Sci Adv. 2025 Sep 05. 11(36): eadx0005
    Ndc80 complex, a conserved coupler for kinetochore-microtubule motility, is a sliding molecular clutch.
    Vladimir M Demidov, Ivan V Gonchar, Suvranta K Tripathy, Fazly I Ataullakhanov, Ekaterina L Grishchuk.
      Chromosome motion at spindle microtubule plus ends relies on dynamic molecular bonds between kinetochores and proximal microtubule walls. Under opposing forces, kinetochores move bidirectionally along these walls while remaining near the ends, yet how continuous wall sliding occurs without end detachment remains unclear. Using ultrafast force-clamp spectroscopy, we show that single Ndc80 complexes, the primary microtubule-binding kinetochore component, exhibit processive, bidirectional sliding. Plus end-directed forces induce a mobile catch bond in Ndc80, increasing frictional resistance and restricting sliding toward the tip. Conversely, forces pulling Ndc80 away from the plus end trigger mobile slip-bond behavior, facilitating sliding. This dual behavior arises from force-dependent modulation of the Nuf2 calponin-homology domain's microtubule binding, identifying this subunit as a friction regulator. We propose that Ndc80's ability to modulate sliding friction provides the mechanistic basis for the kinetochore's end coupling, enabling its slip-clutch behavior.
    DOI:  https://doi.org/10.1126/sciadv.adx0005
  50. Matrix Biol. 2025 Sep 02. pii: S0945-053X(25)00081-2. [Epub ahead of print]
    Exploring Basement Membrane Dynamics through Cross-Scale Imaging, Manipulation, and Molecular Mapping.
    Kohei Omachi, Hironobu Fujiwara.
      The basement membrane (BM), a specialized extracellular matrix (ECM), provides structural support for epithelial, endothelial, and other parenchymal cells. Once considered a static scaffold, the BM is now recognized as a dynamic and complex nanostructure composed of a diversity of molecules that actively regulate cell behavior and tissue organization. Its molecular composition, assembly, and remodeling are precisely controlled in a tissue- and stage-specific manner, contributing to the regulation of local and global mechanical properties and biochemical signaling. Understanding BM structure and function requires integrated approaches across biological scales-from nanoscale molecular interactions to tissue-level architecture. In this review, we highlight advances in three methodological areas: (1) imaging techniques that reveal BM nanostructure and dynamics, (2) manipulation strategies that uncover causal roles of BM components, and (3) omics-based approaches that map BM composition and cellular sources. Integrating these strategies enables the bridging of molecular events and organ-level functions, offering new insights into how the BM is involved in development, homeostasis, and disease progression. The aim of this review is to provide researchers with a comprehensive perspective on evolving tools for dissecting BM structure, dynamics, and function.
    Keywords:  ECM atlas; Extracellular matrix; basement membrane; live imaging; manipulation; super-resolution imaging
    DOI:  https://doi.org/10.1016/j.matbio.2025.09.001
  51. Nature. 2025 Sep 03.
    Multiple overlapping binding sites determine transcription factor occupancy.
    Shubham Khetan, Brent S Carroll, Martha L Bulyk.
      Transcription factors (TFs) regulate gene expression by interacting with DNA in a sequence-specific manner. High-throughput in vitro technologies, such as protein-binding microarrays1-6 and HT-SELEX (high-throughput systematic evolution of ligands by exponential enrichment)7,8, have revealed the DNA-binding specificities of hundreds of TFs. However, they have limited ability to reliably identify lower-affinity DNA binding sites, which are increasingly recognized as important for precise spatiotemporal control of gene expression9-19. Here, to address this limitation, we developed protein affinity to DNA by in vitro transcription and RNA sequencing (PADIT-seq), with which we comprehensively assayed the binding preferences of six TFs to all possible ten-base-pair DNA sequences, detecting hundreds of novel, lower-affinity binding sites. The expanded repertoire of lower-affinity binding sites revealed that nucleotides flanking high-affinity DNA binding sites create overlapping lower-affinity sites that together modulate TF genomic occupancy in vivo. We propose a model in which TF binding is not determined by individual binding sites, but rather by the sum of multiple, overlapping binding sites. The overlapping binding model explains how competition between paralogous TFs for shared high-affinity binding sites is determined by flanking nucleotides that create differential numbers of overlapping, lower-affinity binding sites. Critically, the model transforms our understanding of noncoding-variant effects, revealing how single nucleotide changes simultaneously alter multiple overlapping sites to additively influence gene expression and human traits, including diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09472-3
  52. Trends Cell Biol. 2025 Aug 30. pii: S0962-8924(25)00181-3. [Epub ahead of print]
    Polysome sorting controls mRNA localization and protein fate.
    Adham Safieddine, Jonathan Bizarro, Soha Salloum, Hervé Le Hir, Edouard Bertrand.
      RNA localization and local translation are widespread phenomena that play key roles in a plethora of cellular processes ranging from embryo patterning to general cellular functions. The traditional paradigm assigns localization elements to cis-acting RNA sequences which assemble into complexes that regulate mRNA transport and translation, and the mRNA is generally transported while remaining translationally silent. However, recent evidence has shown that the nascent protein can also play an essential role in RNA localization and can enable polysomes to control their own transport and be delivered where and when they are needed. Two such examples are reviewed: translation factories and centrosomal mRNAs. Their comparison highlights the key role of cotranslational interactions in the spatiotemporal control of protein synthesis and protein fate.
    Keywords:  EJC; HSP90/R2TP chaperone (PAQosome); centrosomal mRNAs; cotranslational assembly; mRNA localization; polysome transport
    DOI:  https://doi.org/10.1016/j.tcb.2025.08.005
  53. J Cell Biol. 2025 Oct 06. pii: e202307079. [Epub ahead of print]224(10):
    ATG conjugation-dependent/independent mechanisms underlie lysosomal stress-induced TFEB regulation.
    Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura.
      TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and TRIP6 accumulate on lysosomes during lysosomal damage, and interact with TFEB mainly in ATG conjugation system-deficient cells, presumably blocking TFEB activation. TFEB activation by several other stresses also involves either Mode I or Mode II. Our results pave the way for a unified understanding of TFEB regulatory mechanisms from the perspective of the ATG conjugation system under a variety of cellular stresses.
    DOI:  https://doi.org/10.1083/jcb.202307079
  54. Nat Methods. 2025 Sep 03.
    Unified mass imaging maps the lipidome of vertebrate development.
    Halima Hannah Schede, Leila Haj Abdullah Alieh, Laurel Ann Rohde, Antonio Herrera, Anjalie Schlaeppi, Guillaume Valentin, Alireza Gargoori Motlagh, Albert Dominguez Mantes, Chloe Jollivet, Jonathan Paz-Montoya, Laura Capolupo, Irina Khven, Andrew C Oates, Giovanni D'Angelo, Gioele La Manno.
      Embryo development entails the formation of anatomical structures with distinct biochemical compositions. Compared with the wealth of knowledge on gene regulation, our understanding of metabolic programs operating during embryogenesis is limited. Mass spectrometry imaging (MSI) has the potential to map the distribution of metabolites across embryo development. Here we established uMAIA, an analytical framework for the joint analysis of large MSI datasets, which enables the construction of multidimensional metabolomic atlases. Employing this framework, we mapped the four-dimensional (4D) distribution of over a hundred lipids at micrometric resolution in Danio rerio embryos. We discovered metabolic trajectories that unfold in concert with morphogenesis and revealed spatially organized biochemical coordination overlooked by bulk measurements. Interestingly, lipid mapping revealed unexpected distributions of sphingolipid and triglyceride species, suggesting their involvement in pattern establishment and organ development. Our approach empowers a new generation of whole-organism metabolomic atlases and enables the discovery of spatially organized metabolic circuits.
    DOI:  https://doi.org/10.1038/s41592-025-02771-7
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