bims-ginsta Biomed News
on Genome instability
Issue of 2026–07–26
37 papers selected by
Jinrong Hu, National University of Singapore
  1. Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
  2. Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1.
  3. The actin crosslinker Fimbrin is required for force sensing at tricellular junctions.
  4. Mapping mesenchymal diversity in the human small intestine and organoids.
  5. Signaling mechanisms and dynamics governing the myocardial-epicardial fate switch during human cardiogenesis.
  6. A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.
  7. UTR-ly unexpected: RNA chaperones tame intrinsically disordered proteins.
  8. Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
  9. Promoter strength and position govern promoter competition through transcript-dependent insulation.
  10. Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
  11. SYCP2 recruits HORMAD2 to chromosome axes for unsynapsed chromatin silencing and synapsis surveillance in meiosis.
  12. Intrinsically disordered regions restrain genomic targeting of RNA and histone demethylases in mammals and plants.
  13. Spatially resolved single-cell atlas reveals the macroevolutionary trajectory of animal hearts.
  14. Senescent cells cluster CTCF on nuclear speckles to instruct an alternative splicing program.
  15. A genetically encoded sensor of ionic stress links cellular proton dynamics to sleep.
  16. GCL pruning of PIP3 establishes the soma-germline boundary.
  17. Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development.
  18. PAK4 promotes vertex remodeling to maintain epithelial integrity and barrier function.
  19. PLA2G2F suppresses ferroptosis through phospholipid remodeling.
  20. Integrated Single-cell Proteomic and Transcriptomic Landscape of Mouse Folliculogenesis.
  21. Multiscale biophysical control of epithelial shape transitions during animal development.
  22. Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.
  23. Leiomodin 2 is a processive pointed-end elongator of actin filaments.
  24. Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.
  25. Quantitative computerized analysis demonstrates strongly compartmentalized tissue deformation patterns underlying mammalian heart tube formation.
  26. RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability.
  27. Localized PD-1 CAR T therapy reprograms neuroinflammation.
  28. Genetic background sets the trajectory of experimental cancer evolution.
  29. A 3D genome atlas of human tonsil and the role of loop extrusion in B cell somatic hypermutation.
  30. High and intermittent hydrostatic pressure promotes maturation of engineered cardiac tissues derived from human pluripotent stem cells.
  31. Reactive oxygen species stimulate Paneth cell plasticity and diminish antimicrobial function.
  32. Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure.
  33. PRKCI-ECT2 copy number gain promotes developmental reprogramming and metastatic competence in lung adenocarcinoma.
  34. Single-cell chromatin state transitions during epigenetic memory formation.
  35. Biomolecular condensates can function as inherent catalysts.
  36. The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.
  37. The missing link: Piccolino is essential for tethering synaptic vesicles to rod photoreceptor ribbons.
  1. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600323123
    Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
    Xifan Wang, Jiping Yang, Chen Jin, Xizhe Wang, Daniela Contreras, Melody Devos, Maggie M Kane, Michael G Rosenfeld, Yousin Suh.
      Reproductive aging in mice leads to estropause, characterized by estrous cycle irregularity and eventual cessation, yet its underlying mechanism remains unclear. Here, we present a comprehensive single-cell atlas of mouse ovaries across precisely defined reproductive stages-from young (regular cycling) through the estropausal transition (regular vs. irregular cycling) to post-estropause (acyclic)-and of ovary-specific senescent cells defined by high senescence-associated β-galactosidase activity. We mapped transcriptomic dynamics of ovarian aging and characterized the molecular features of ovarian senescent cells. Our analyses revealed that during the estropausal transition, irregularly cycling ovaries exhibited accelerated aging and cellular senescence features compared with regularly cycling counterparts, including increased transcriptional noise, altered conserved aging pathways such as oxidative phosphorylation and proteostasis, hormone dysregulation in granulosa cells, and elevated expression of the senescence marker Cdkn1a and senescence-associated secretory phenotype factors. This atlas delineates the cellular and molecular hallmarks of mouse ovarian aging and ovary-specific senescent cells, providing a resource for understanding the mechanisms underlying the estropausal transition.
    Keywords:  aging; cellular senescence; estropausal transition; ovary; single-cell RNA-seq
    DOI:  https://doi.org/10.1073/pnas.2600323123
  2. Mol Cell. 2026 Jul 22. pii: S1097-2765(26)00457-0. [Epub ahead of print]
    Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1.
    Suhee Chang, Ryan Kawalerski, Mehmet Tardu, Sophie Martin, Kristin S Koutmou, Jeff Coller.
      Ribosome dynamics during mRNA translation elongation regulate mRNA stability. Yet, known regulators of ribosome transit, such as codon usage, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator. Using reporter constructs encoding co-translationally unstructured proteins and RNA sequencing under proteotoxic stress, we show that Zuo1 is required for selective destabilization of transcripts whose nascent peptides fail to fold properly. This process relies on the co-translational mRNA decay factor Not5, which detects slowed ribosomes. 35S labeling indicates that nascent peptide folding defects correlate with reduced elongation rates in a Zuo1-dependent manner, and ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome pausing. These findings position Zuo1 as a key mediator linking nascent peptide folding status to ribosome dynamics and mRNA stability. Furthermore, this work suggests an expanded role for Not5 beyond codon optimality sensing.
    Keywords:  Not5; Zuo1; elongation rate; mRNA degradation; mRNA stability; post-transcriptional regulation; protein chaperones; protein folding; ribosome speed
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.041
  3. Dev Cell. 2026 Jul 24. pii: S1534-5807(26)00270-4. [Epub ahead of print]
    The actin crosslinker Fimbrin is required for force sensing at tricellular junctions.
    Nilay Taneja, Claire A Looney, Michael F Moubarak, Meriel J McGovern, Kenji Yeoh, Jennifer A Zallen.
      Epithelial cells sense and respond to mechanical forces by reinforcing connections between adherens junctions and the actin cytoskeleton. Tricellular junctions are key sites of mechanotransduction in epithelial cells, but how force responses are coordinated at these structures during epithelial remodeling is poorly understood. We show that the actin crosslinking protein Fimbrin is recruited by forces to tricellular junctions in Drosophila and promotes actin reorganization and cell adhesion during epithelial remodeling. In the absence of Fimbrin, cells fail to reorganize actin or recruit junction-stabilizing proteins to tricellular junctions under tension, disrupting cell adhesion. Conversely, increasing Fimbrin activity constitutively activates multiple force-response pathways, aberrantly stabilizing adhesion. We show that Fimbrin directs force responses by amplifying actomyosin contractility, and that force-regulated actin remodeling and Plastin3 and Afadin localization occur at tricellular junctions in the mouse embryo. These results suggest that conserved mechanisms underlie force responses at tricellular junctions in fly and mouse epithelia.
    Keywords:  Drosophila; Fimbrin; Mechanotransduction; actin crosslinker; actin cytoskeleton; cell adhesion; epithelial morphogenesis; myosin
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.001
  4. Nat Cell Biol. 2026 Jul 22.
    Mapping mesenchymal diversity in the human small intestine and organoids.
    Kelli F Johnson, Xiangning Dong, Yu-Hwai Tsai, Angeline Wu, Sydney G Clark, Abigail Vallie, Sha Huang, Charlie J Childs, Rachel K Zwick, Ian Glass, Katherine D Walton, Ophir D Klein, Jason R Spence.
      The organization of diverse mesenchymal populations during human small intestinal development is critical for tissue architecture and function yet remains poorly defined. Here, to construct a comprehensive, tissue-scale map of the developing human small intestine at single cell resolution, we leveraged single-cell RNA-sequencing data to build a Xenium spatial transcriptomics gene panel covering the cell diversity of the human small intestine. We defined five subpopulations occupying discrete anatomical locations within the lamina propria and submucosa-the subepithelial cells, lamina propria fibroblasts, submucosal fibroblasts, smooth muscle cells and CXCL13+ fibroblasts. Our data establish molecular markers to distinguish these populations in both sequencing and imaging data. We leverage this high-resolution atlas to interrogate cell-cell signalling, benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this resource can incorporate relative spatial organization into tissue analysis, with broad implications for modelling development, regeneration and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02027-2
  5. Sci Adv. 2026 Jul 24. 12(30): eaee5316
    Signaling mechanisms and dynamics governing the myocardial-epicardial fate switch during human cardiogenesis.
    Min Zhou, Congge Li, Ruize Kong, Xiaobo Wang, Yu Yin, Da Wang, Zongyong Ai, Baohua Niu, Zhenlin Liu, Tianqing Li.
      The signaling mechanisms and developmental dynamics that govern the divergence of myocardial and epicardial lineages during human heart development remain poorly understood. Here, we developed a human pluripotent stem cell-based cardiac development model and employed time-course single-cell RNA sequencing to delineate cardiac lineage specification trajectories. We identified retinoic acid (RA) as a critical fate switch at the cardiac mesoderm stage. RA instructs epicardial lineage commitment of cardiac mesoderm through a primed-epicardium to proepicardium-like population and finally to epicardium, a process requiring precise BMP modulation. Conversely, RA absence directs cardiac mesoderm along a default myocardial pathway, yielding developing and mature cardiomyocytes. Both trajectories are governed by the hierarchical activation of key transcription factors. Our study integrates signaling and dynamics to elucidate the temporal regulatory network of the RA-BMP axis in human cardiac fate determination. These findings provide fundamental insights into human cardiogenesis and a crucial roadmap for modeling heart disease and advancing regenerative strategies.
    DOI:  https://doi.org/10.1126/sciadv.aee5316
  6. Cell. 2026 Jul 20. pii: S0092-8674(26)00757-9. [Epub ahead of print]
    A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.
    Meredith N Nix, Sai Gourisankar, Kevin J Bowman, Sabin A Nettles, Haopeng Yang, Brendan G Dwyer, Roman C Sarott, Hind Abuzaid, Michael M Martinez, Nick Phillips, Vincent Cabaud, Artur Hakobyan, Vahram Arakelov, Garik Petrosyan, Aram Davtyan, Yanlan Wang, Juste M Simanauskaite, Bryan A Romero, Hannah M Jones, Andrey Krokhotin, Tara N Lowensohn, Lei Chen, Cara Low, Hannes Vogel, Mark M Davis, Daniel Fernandez, Tinghu Zhang, Michael R Green, Stephen M Hinshaw, Nathanael S Gray, Gerald R Crabtree.
      Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.
    Keywords:  BCL6; CIP; DLBCL; chemically induced proximity; lymphoma; lysine acetyltransferases; transcription
    DOI:  https://doi.org/10.1016/j.cell.2026.06.037
  7. Cell. 2026 Jul 23. pii: S0092-8674(26)00710-5. [Epub ahead of print]189(15): 4519-4521
    UTR-ly unexpected: RNA chaperones tame intrinsically disordered proteins.
    Miriam Linsenmeier, James Shorter.
      How do cells ensure that complex, multidomain proteins fold correctly? Luo et al. reveal a self-contained solution. The 3' UTR of an mRNA co-translationally chaperones the protein it encodes, preventing intrinsically disordered regions from making inappropriate contacts. This functionality, localized to mesh-like condensates, challenges Anfinsen's dogma and opens therapeutic possibilities.
    DOI:  https://doi.org/10.1016/j.cell.2026.06.023
  8. Nat Cell Biol. 2026 Jul 20.
    Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
    Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song.
      Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia-reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia-reoxygenation. This stress-responsive ITM2C-MIRO2-MFF-DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria-lysosome communication in mediating lysosomal quality control during ischaemia-reperfusion and related stresses.
    DOI:  https://doi.org/10.1038/s41556-026-02010-x
  9. Nat Genet. 2026 Jul 20.
    Promoter strength and position govern promoter competition through transcript-dependent insulation.
    Mervenaz Koska, Masahiro Nagano, Tomek Swigut, Alistair Nicol Boettiger, Anders S Hansen, Joanna Wysocka.
      Long-range competition among promoters within a shared regulatory landscape has been implicated in development and disease, but the determinants of promoter competition remain unclear. Here we introduce diverse promoters into defined genomic sites within the Sox2 locus and measure how these insertions attenuate endogenous Sox2 expression. We find that the level of reduction in endogenous Sox2 transcription is correlated with the strength of the inserted promoter. Transcription from the inserted promoter is required for competition, with longer transcripts resulting in more competition. The inserted active promoter and its associated transcriptional unit function as an insulator, rendering competition position dependent. Competition is counteracted by the HUSH-mediated silencing of the inserted promoters. Together, our work uncovers the rules governing promoter competition, highlights its impact on tuning gene expression levels and genome evolution, and suggests that transcriptional units producing transcripts of sufficient level and length can mediate insulation independently of CTCF and cohesin.
    DOI:  https://doi.org/10.1038/s41588-026-02691-y
  10. Nat Struct Mol Biol. 2026 Jul 23.
    Direct coupling of human TOM and TIM22 complexes drives mitochondrial carrier import.
    Xiaolong Liu, Hongjun Cai, Hao Wang, Xueyin Zhou, Yutong Zhang, Shuai Liu, Jiajun Zhu, Long Li.
      Metabolite carriers that control essential metabolite transport are imported into mitochondria through the TOM and TIM22 complexes. How TOM and TIM22 coordinate in human mitochondria has remained largely unknown. Here we show that human TOM and TIM22 assemble into a supercomplex that seamlessly couples carrier translocation across the outer and inner membranes, unlike in yeast where the two complexes appear to function separately. Cryo-electron microscopy structures of the human TOM-TIM22 supercomplex reveal unpaired carrier transmembrane segments traversing the TOM channel along a hydrophobic path and exiting through an unexpected lateral groove outside the channel. The membrane-bound small Tim subunits provide the substrate entry site for TIM22, while a membrane-exposed groove of TIM22 serves as the exit for carrier insertion into the inner membrane. These findings provide insights into the human carrier translocation pathway at molecular resolution and establish the TOM-TIM22 supercomplex as a central organizing unit of mitochondrial carrier import.
    DOI:  https://doi.org/10.1038/s41594-026-01849-w
  11. Nat Commun. 2026 Jul 23. pii: 7122. [Epub ahead of print]17(1):
    SYCP2 recruits HORMAD2 to chromosome axes for unsynapsed chromatin silencing and synapsis surveillance in meiosis.
    Kavya Raveendran, Sarai Valerio-Cabrera, Arkasarathi Gope, Vladyslav Telychko, Geen George, Christin Richter, Tanja Scholte, Matthias Weigel, Anastasiia Bondarieva, Andreas Petzold, Andreas Dahl, Kevin D Corbett, Attila Tóth.
      Faithful chromosome segregation during meiosis requires accurate recombination and synapsis of homologous chromosomes. These processes are monitored in mammals by checkpoints involving the meiotic HORMA-domain proteins HORMAD1 and HORMAD2, which bind unsynapsed chromosome axes and promote activation of the DNA damage-response kinase ATR independently of DNA double-strand breaks (DSBs). However, the in vivo mechanism for axial HORMAD1 and HORMAD2 recruitment and its relevance to checkpoint signaling remain unclear, although the chromosome-axis component SYCP2 has been proposed to contain a candidate HORMAD-binding closure motif (CM). We show that deletion of the SYCP2 CM disrupts SYCP2-HORMAD2 complexes and selectively prevents HORMAD2 axis binding without affecting axis assembly, recombination, or axial HORMAD1 recruitment. Consequently, ATR accumulation and signaling on unsynapsed axes are reduced, and the prophase checkpoint malfunctions, manifesting in aberrant elimination of synapsis-proficient spermatocytes and persistence of asynaptic oocytes, which reflect sex-specific characteristics of checkpoint mechanisms. The phenotypes of SYCP2-CM-deficient and HORMAD2-null mice are indistinguishable, establishing the requirement for HORMAD2 axis recruitment in synapsis surveillance. We propose that axial recruitment generates a HORMAD2 scaffold that drives clustering-mediated ATR network activation independently of DSBs, thereby linking chromosome-axis architecture to synapsis quality control in mammalian meiosis.
    DOI:  https://doi.org/10.1038/s41467-026-75839-3
  12. Nat Genet. 2026 Jul 23.
    Intrinsically disordered regions restrain genomic targeting of RNA and histone demethylases in mammals and plants.
    Liudan Jiang, Long Zhao, Jiangbo Wei, Bochen Jiang, Yu Xiao, Fan Yang, Xiaolin Zeng, Chuan He.
      Intrinsically disordered regions (IDRs) are widely recognized as facilitators of chromatin regulation. However, their potential role as regulatory restraints remains poorly understood. Here we reveal that the C-terminal IDR of mammalian ALKBH5 anchors its main activity to mRNA, limiting chromatin engagement in mouse embryonic stem cells. IDR deletion redirects ALKBH5 to chromatin-associated noncoding RNAs, driving widespread chromatin opening and transcriptional activation. This mechanism extends to histone demethylases, where IDR deletion also results in broad removal of repressive histone marks, leading to increased chromatin accessibility and activation of transposable elements. Building on these insights, we applied IDR deletion to engineer ALKBH5 and its plant homologs. Overexpression of these IDR-deleted ALKBH5 demethylases enhanced Arabidopsis root growth and markedly increased rice yield. Our findings uncover a conserved role for IDRs in restraining chromatin access by RNA and histone demethylases and establish a strategy to reprogram chromatin through endogenous plant proteins for crop improvement.
    DOI:  https://doi.org/10.1038/s41588-026-02685-w
  13. Science. 2026 Jul 23. eadw0855
    Spatially resolved single-cell atlas reveals the macroevolutionary trajectory of animal hearts.
    Shanshan Lian, Wei Wang, Yaoxin Liu, Meina Lu, Wentao Han, Jiaxin Luo, Xuejiao Zhang, Yue Pang, Yuru Li, Yufeng Li, Xin Dang, Peiyan Wang, Yating Qin, Ning Tan, Fang Zhang, Jin Zhang, Shuai Gao, Runyi Zhang, Lidong Guo, Lei Jiang, Pengchong Zhang, Yuehuan Zhang, Zhe Qu, Shanshan Pan, Yue Zhang, Naina Hu, Yadong Chen, Yun Cao, Wenbin Li, Xiaomei Chen, Junjie Shi, Shuaiqi Yang, Yiran Li, Qiuyun Song, Lisui Bao, Yuli Li, Xiawei Liu, Jing Wang, Lingling Zhang, Rui Li, Xin Yu, Tao Yang, Jing Chen, Ling Li, Mengqi Zhang, Lei Li, Ruihua Zhang, Hongyan Li, Ying Gu, Xun Xu, Huanming Yang, Zhenmin Bao, C Geoffrey Burns, Caroline E Burns, Robert G Kelly, Jianxun Wang, Yang Zhao, Ying Su, Guangyi Fan, Qun Liu, Shi Wang, Ji-Feng Fei, Silin Pan, Long Zhao.
      Animal hearts display diverse anatomical structures during adaptive evolution. Here, we present a multi-omics atlas of adult hearts from 27 species across chordates, arthropods, and mollusks. Joint analysis indicates that Bilateria hearts share a core gene repertoire, taking a stepwise "add-on" approach as a universal evolutionary strategy. The proto-heart is populated by key cell types, including cardiomyocytes, fibroblasts, endothelial, and neural cells, which maintained core signatures while evolving with shifts in living environments and corresponding adaptations in the cardiovascular system. Additionally, we reveal an evolutionarily conserved cardiomyocyte state dynamic potentially linked to cardiac development and stress responses. Finally, we identify a common molecular program underpinning chamber evolution from a ventricular foundation. Together, this work establishes a resource for understanding the intrinsic mechanisms of heart evolution.
    DOI:  https://doi.org/10.1126/science.adw0855
  14. Nat Aging. 2026 Jul 21.
    Senescent cells cluster CTCF on nuclear speckles to instruct an alternative splicing program.
    Spiros Palikyras, Vassiliki Varamogiani-Mamatsi, Yajie Zhu, Athanasia Mizi, Shyam Ramasamy, Jonas Viken Grini, Isabel Liebermann, Athanasia Stavropoulou, Andrés Penagos Puig, Tuba Sena Ogurlu-Tank, Konstantinos Kydonakis, Ioanna Papadionysiou, Deniz Bartsch, Yulia Kargapolova, Natalia Rosalia Morero, Konstantinos Sofiadis, Christoforos Nikolaou, Franziska Kundel, Leo Kurian, Jan Ellenberg, A Marieke Oudelaar, Mariano Barbieri, Kai Sandvold Beckwith, Argyris Papantonis.
      Senescence, the endpoint of normal cells' replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and functional purpose of SICCs remain unknown. Here we combine three-dimensional genomics, super-resolution imaging, DNA tracing and functional assays with modeling to dissect SICC emergence. We find that, on senescence entry, cells repurpose SRRM2-a key component of nuclear speckles-and BANF1-a 'molecular glue' for chromosomes-to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles helps instruct the senescence splicing program, because disruption of SICCs almost fully reverts alternative splicing patterns and delays senescence onset. We therefore uncover a paradigm whereby human cells translate changes in nuclear biochemistry into architectural changes directing splicing choices to commit to the fate of senescence.
    DOI:  https://doi.org/10.1038/s43587-026-01171-6
  15. Sci Adv. 2026 Jul 24. 12(30): eaef3219
    A genetically encoded sensor of ionic stress links cellular proton dynamics to sleep.
    Zhijian Ji, Bingying Wang, Zhimin Ma, Lina Verbakel, Junqiang Liu, Yanchang Bian, Wenjie Zeng, Chan-I Chung, Shuaian Wei, Jianxiu Zhang, Supeng Yang, Morgane Bourgeois, Laurent Mouchiroud, Xiaokun Shu, Dengke K Ma.
      Although biosensors for specific cellular ions are widely available, real-time monitoring of overall ionic strength in living organisms remains challenging. Here, we present a genetically encoded nuclear translocation ionic sensor (GENTIS) that enables direct visualization of ionic stress in vivo. Using this sensor alongside longitudinal tracking via an automated microfluidic platform, we find that Caenorhabditis elegans larvae experience highly synchronized, rhythmic elevations in intestinal ionic strength during the molt, a stage during which developmentally timed sleep occurs. Cytosolic proton accumulation through inhibition of vacuolar-type adenosine triphosphatases (V-ATPases) triggers GENTIS nuclear translocation and evokes behavioral quiescence, characterized by reduced feeding, locomotion, and activation of sleep-active neurons. Apical membrane V-ATPases naturally undergo disassembly during molting and stress, conditions that cause proton accumulation and sleep. Notably, this proton-linked sleep is suppressed by proton buffering with ammonium. Together, these findings establish GENTIS as a powerful tool for tracking ionic strength dynamics in vivo and reveal that proton ionic rhythms contribute to the regulation of sleep.
    DOI:  https://doi.org/10.1126/sciadv.aef3219
  16. J Cell Biol. 2026 Sep 07. pii: e202604036. [Epub ahead of print]225(9):
    GCL pruning of PIP3 establishes the soma-germline boundary.
    Mariyah Saiduddin, Juhee Pae, Asier M Vidal, Martin L Alani, Ruth Lehmann.
      Primordial germ cells (PGCs) are the first cells specified in the Drosophila embryo and are precursors to the germline. Their formation requires suppression of somatic fates, achieved by degrading the receptor tyrosine kinase Torso at the posterior pole through the ubiquitin ligase adaptor germ cell-less (GCL). Although Torso is known to antagonize PGC formation, the underlying mechanisms remained unclear. Here, we combine optogenetic Ras activation and Ras effector loop mutants to show that Ras suppresses PGC formation independently of the canonical Raf/MEK/ERK pathway. We identify an unexpected early role for Torso in activating phosphoinositide 3-kinase (PI3K), generating membrane domains enriched in phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Elevated PI3K activity disrupts PGC formation, while reduced PI3K activity creates ectopic PGCs. We demonstrate that GCL remodels the posterior pole membrane by suppressing Torso-dependent PI3K activation. Clearing PIP3 enables myosin II enrichment, allowing for PGC formation. Together, our findings reveal how antagonistic Torso and GCL activities establish the soma-germline boundary by organizing cortical lipids.
    DOI:  https://doi.org/10.1083/jcb.202604036
  17. Cell. 2026 Jul 22. pii: S0092-8674(26)00804-4. [Epub ahead of print]
    Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development.
    Tao Zhang, Xiufeng Li, Wei Zhou, Zhao-Lu Li, Jundong Bi, Xin Ma, Xiang Li, Yiming Fan, Yaqiang Hong, Shiqi Wang, Yankun Wang, Le Yang, Yongxing Chen, Wei Qin, Haifeng Wang, Qiaoran Xi, Songhai Shi, Nian Liu.
      Genes that define cell identity are often highly transcribed, but how their activity is regulated to prevent pathological dysregulation remains elusive. Using a two-tiered genetic screen, we identify a network of genes regulating hypertranscribed loci, which is notably enriched for genes mutated in developmental disorders. Among these, ANKRD11, a chromatin regulator haploinsufficient in KBG syndrome, exerts progressively stronger repression on more highly transcribed genes. ANKRD11 enriches around hypertranscribed loci and forms biomolecular condensates via charge-block-patterned intrinsically disordered regions. These condensates spatially sequester elongation factors away from RNA polymerase II, thereby restricting transcription elongation. In mice, Ankrd11 loss abrogates this restriction, causing aberrant developmental gene activation, disrupted organogenesis, and embryonic lethality. Critically, KBG patient cells with ANKRD11 mutations show defective condensate formation and consequent overactivation of hypertranscribed genes. These results uncover a condensate-mediated mechanism that restricts hypertranscribed genes and suggest its disruption underlies developmental disorders such as KBG syndrome.
    Keywords:  ANKRD11; KBG syndrome; LTR retrotransposon; biomolecular condensate; developmental disorders; genetic screen; hypertranscription; self-limiting control; transcription elongation
    DOI:  https://doi.org/10.1016/j.cell.2026.07.006
  18. J Cell Biol. 2026 Sep 07. pii: e202510024. [Epub ahead of print]225(9):
    PAK4 promotes vertex remodeling to maintain epithelial integrity and barrier function.
    Babli Adhikary, Alexander Chang, Atsuko Y Higashi, Hideki Chiba, Ann L Miller, Tomohito Higashi.
      Cell-cell junctions are essential for epithelial integrity and barrier function, but the mechanisms regulating their remodeling remain unclear. Here, we investigated the role of the junctional kinase PAK4 in vertex remodeling. PAK4 accumulated at multicellular vertices in MDCK cells and Xenopus embryos. Inhibition or knockout (KO) of PAK4 increased the number of higher-order vertices, caused junctional discontinuities, and impaired barrier function in MDCK cells. PAK4 recruitment required the scaffolding protein Afadin. Severe junctional defects and reduced barrier function in Afdn-KO cells were partially rescued by artificial PAK4 targeting. In Xenopus embryos, PAK4 showed dynamic accumulation at remodeling vertices, and PAK4 inhibition hindered vertex remodeling. Expression of an amino-terminal fragment (PAK4-NT) impaired remodeling, induced cytokinetic failure, and caused barrier leakage at multicellular vertices. In both systems, PAK4-deficient cells exhibited abnormal accumulation of junctional myosin II, likely due to reduced myosin phosphatase activity. These findings indicate that PAK4 and Afadin cooperate to maintain epithelial integrity and barrier function by promoting vertex remodeling.
    DOI:  https://doi.org/10.1083/jcb.202510024
  19. Nat Struct Mol Biol. 2026 Jul 22.
    PLA2G2F suppresses ferroptosis through phospholipid remodeling.
    Yingying Hu, Joleen Csuka, Presha Rajbhandari, Penghsuan Huang, Nicholas Carbone, Deguang Liang, Wei Gu, Alban Ordureau, Brent R Stockwell, Xuejun Jiang.
      Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation, and it has emerged as a potential therapeutic vulnerability of cancer. Here we identify the secretory phospholipase PLA2G2F (phospholipase A2 group IIF) as a ferroptosis suppressor in bladder cancer and elucidate its regulation and mechanism of action. PLA2G2F functions through an intracellular mechanism by localizing to the endoplasmic reticulum to inhibit ferroptosis. Our genetic and pharmacological analyses reveal that peroxisome proliferator-activated receptor γ (PPARG), a nuclear hormone receptor and transcription factor previously implicated in ferroptosis regulation, upregulates PLA2G2F and that PPARG-mediated ferroptosis resistance is largely dependent on PLA2G2F in bladder cancer. Further, lipidomic profiling suggests that PLA2G2F preferentially acts on ether-linked phospholipids containing polyunsaturated fatty acids, thereby reducing the pool of peroxidation-prone polyunsaturated fatty acid-containing phospholipids. Together, our findings establish PLA2G2F as an endoplasmic reticulum-resident ferroptosis suppressor regulated by PPARG and show that inhibiting PPARG signaling or PLA2G2F activity can sensitize bladder cancer cells to ferroptosis induction.
    DOI:  https://doi.org/10.1038/s41594-026-01830-7
  20. Genomics Proteomics Bioinformatics. 2026 Jul 23. pii: qzag068. [Epub ahead of print]
    Integrated Single-cell Proteomic and Transcriptomic Landscape of Mouse Folliculogenesis.
    Hongchao Li, Xinshuai Zhang, Huimin Kang, Yun Yang, Xinyu Xiao, Yan Wang, Bin Fu, Jie Chen, Xinwen Dong, Yuanjun Zhai, Jing Yang, Jianming Ying, Fuchu He, Yang Li, Xiaowen Wang.
      Folliculogenesis is a complex process essential to female fertility, characterized by multifaceted communication between oocytes and granulosa cells (GCs). While transcriptional regulation during folliculogenesis has been extensively studied, the proteomic landscape remains largely unexplored. Here, we profiled both the proteomic and transcriptomic landscapes of single oocytes and their surrounding mini-bulk GCs across four consecutive stages, from secondary to preovulatory follicles. Integrated dual-omics analysis provided a high-resolution characterization of cell type-specific transcriptional and proteomic changes. Proteomic profiling revealed coordinated metabolic programs, in which oocytes shift toward lipid storage while GCs enhance energy production and steroidogenic metabolism to support oocyte maturation. These metabolic changes in oocytes were accompanied by dynamic remodeling of mitochondrial organization. In addition, we identified novel transcription factors involved in regulating folliculogenesis, as well as a SATB1-centered regulatory network that may reflect preparatory chromatin remodeling preceding zygotic genome activation. Furthermore, GDF9-BMPR2 signaling progressively increased from the secondary stage to the preovulatory stage, indicating strengthened intercellular communication between oocytes and GCs. Together, these findings provide mechanistic insights into oocyte development and follicle growth, with potential implications for novel fertility treatments and diagnostic strategies.
    Keywords:  Folliculogenesis; Intercellular communication; Single-cell proteome; Single-cell transcriptome; Transcription factor regulatory network
    DOI:  https://doi.org/10.1093/gpbjnl/qzag068
  21. Semin Cell Dev Biol. 2026 Jul 21. pii: S1084-9521(26)00020-0. [Epub ahead of print]184 103686
    Multiscale biophysical control of epithelial shape transitions during animal development.
    Jianyi Mai, Abhirami Anil Gayathry, David M Richards, Stefan Harmansa.
      The regulation of epithelial cell shape is fundamental to development, homeostasis and disease, and is intricately linked to tissue function. Epithelial morphology emerges from integration of biochemical and mechanical cues across multiple scales, from intrinsic cellular factors to tissue-wide forces. In this review we focus on the mechanical aspects of cell shape control and highlight the multi-scale regulation of epithelial cell shape that links (i) cell-intrinsic factors, such as cytoskeletal organization, contractility and growth, (ii) the local mechanical environment, including cell-matrix interactions and (iii) tissue-scale mechanics governing global morphogenesis. At the cellular level, contractility and growth generate stresses that interact with the surrounding microenvironment, shaped by the extracellular matrix. At the tissue level, large-scale stresses and boundary constraints from neighbouring tissues, bones or cuticles further shape epithelial morphology. Feedback across scales ensures robustness and adaptability of epithelial architecture. In this review, we synthesis recent insights into the mechanical control of epithelial cell-shape transitions and how intrinsic and extrinsic stresses integrate to drive morphogenesis. We also highlight how theoretical modelling frameworks are increasingly essential for disentangling the multiscale interplay of forces that govern epithelial architecture. This review aims to provide perspectives on how epithelial mechanics are coordinated by multiscale regulation and how they contribute to development, homeostasis and disease.
    Keywords:  Biophysics; Boundary constraints; Cell & tissue mechanics; Cell-matrix interaction; Cytoskeletal regulation; Epithelial morphogenesis; Mathematical and computational modelling; Mechanical feedback
    DOI:  https://doi.org/10.1016/j.semcdb.2026.103686
  22. Nat Struct Mol Biol. 2026 Jul 23.
    Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.
    Buren Li, Ayat Yaseen, Nikola P Pavletich.
      The ATR protein kinase preserves genomic integrity during DNA replication by controlling checkpoints needed for the orderly progression of S phase and for the responses to replication stress. ATR, with its obligate partner ATRIP, is activated by the TOPBP1 and ETAA1 proteins, which control different branches of ATR signaling. TOPBP1 is essential for induction of the S phase checkpoint in response to stalled replication forks, while ETAA1 is required for timely progression to mitosis from an unperturbed S phase. TOPBP1 and ETAA1 contain ATR-activating domains (AADs) of limited homology, but how they activate ATR has not yet been fully elucidated. Here we present the 3.0-Å cryo-EM structure of the human ATR-ATRIP complex bound to the TOPBP1 AAD, showing that TOPBP1 activates ATR by inducing a global conformational change that allosterically realigns active site residues in the kinase domain ~70 Å away. We also present the 3.3-Å structure of the ATR-ATRIP-ETAA1 AAD complex, which reveals a binding mode distinct from TOPBP1. Our data suggest that the distinct binding modes of TOPBP1 and ETAA1 contribute to the different cellular contexts and outcomes of ATR-ATRIP activation.
    DOI:  https://doi.org/10.1038/s41594-026-01844-1
  23. Nat Commun. 2026 07 20. pii: 6674. [Epub ahead of print]17(1):
    Leiomodin 2 is a processive pointed-end elongator of actin filaments.
    Sudipta Biswas, Tania M Larrinaga, Sandeep Choubey, Carol C Gregorio, Shashank Shekhar.
      The actin cytoskeleton drives essential processes like cell migration and muscle contraction. While barbed-end polymerization is well-established, pointed-end elongation was long considered impossible in vivo. Here, we demonstrate that Leiomodin 2 (Lmod2), which localizes to thin-filament pointed ends in striated muscle cells, functions as an actin polymerase for pointed-end elongation. Single-molecule and single-filament imaging reveal that Lmod2 remains processively bound to pointed ends in vitro, enabling elongation even in the presence of high profilin concentrations found in the cytoplasm that otherwise would cause depolymerization of free pointed ends. Kinetic analysis indicates that Lmod2-mediated elongation proceeds through a linked two-step mechanism, in which monomer addition is followed by a first-order transition at the Lmod2-bound pointed end that limits elongation at high actin concentrations. Lmod2's activity also persists in the presence of tropomyosin, underscoring its physiological relevance. Both processivity and elongation rate of Lmod2 are dependent on its WH2 domain. Remarkably, human dilated cardiomyopathy-associated mutations in Lmod2 greatly reduce Lmod2's pointed-end elongation activity, providing a potential mechanism for disease progression and supporting a role for Lmod2-mediated polymerization in the formation and maintenance of muscle sarcomeres.
    DOI:  https://doi.org/10.1038/s41467-026-74809-z
  24. Genes Dev. 2026 Jul 23.
    Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.
    Aleksandra S Anisimova, Sabina Omerbegovic, Milica Mihailovic, Sascha Gratzl, Harald Hornegger, Irmgard Fischer, Gijs A Versteeg, Stefan L Ameres, G Elif Karagöz.
      Misfolded protein accumulation in the endoplasmic reticulum (ER) perturbs cellular homeostasis, causing pathological ER stress. While a transcriptional response is paramount for the unfolded protein response (UPR), which counters ER protein stress, multiple UPR-linked mRNAs are posttranscriptionally regulated. However, the mechanisms mediating this regulation remain unclear. Here, we reveal specific interactions between the conserved RNA-binding protein IGF2BP3 and transcripts encoding UPR effectors. During ER stress, IGF2BP3 destabilizes many of its target transcripts, including UPR effectors. Mechanistically, ER stress enhances IGF2BP3's association with the mRNA decapping complex and the ER stress sensor RNase IRE1, which correlates with a shift toward mRNA destabilization. Unexpectedly, prolonged depletion of IGF2BP3 inhibits the UPR via decreased transcription of UPR target genes. Together, our findings suggest that IGF2BP3 contributes to proteostasis during ER stress through a dual mechanism: directly promoting mRNA degradation to reduce translation and folding burden and indirectly supporting transcriptional activation of the UPR.
    Keywords:  IGF2BP3; IRE1; RNA-binding proteins; endoplasmic reticulum; mRNA decapping complex; posttranscriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1101/gad.353291.125
  25. Elife. 2026 Jul 21. pii: RP108559. [Epub ahead of print]14
    Quantitative computerized analysis demonstrates strongly compartmentalized tissue deformation patterns underlying mammalian heart tube formation.
    Morena Raiola, Miquel Sendra Sendra, Jorge N Domínguez, Miguel Torres.
      The quantitative analysis of tissue deformation at cellular resolution remains an important challenge in mammalian organogenesis. Here, we developed a new computational workflow to extract regional and temporal patterns of tissue deformation, and applied it to a collection of live microscopy datasets from mouse cardiogenesis. We devised a method to track tissue deformation directly from time-lapse raw images and experimentally validated the method by comparison with actual cell tracks. We then used a machine-learning approach to temporally and spatially align different specimens and reconstruct a single statistical model of tissue motion, deducing maps of strain, anisotropy, and tissue growth. We also implemented a virtual fate mapping tool that allows tracking any initial position in the cardiac primordium onto the linear heart tube (HT). Our study reveals predominant local cellular coherence during the deformation of the cardiac tissue, whereas strong compartmentalization of tissue deformation patterns transforms the bilateral cardiac primordium into a 3D longitudinal HT. At the future outer curvature of the primitive tube, the ventricular chamber forms by expansion of the tissue in a hemi-barrel shape with two harnessing belts: one that constrains tissue expansion at the arterial pole and one that constrains the expansion at the venous pole. Our study provides a new approach to understanding heart morphogenesis and proposes a new model of primitive HT formation.
    Keywords:  computational biology; developmental biology; embryogenesis; heart development; morphogenesis; mouse; systems biology; video microscopy
    DOI:  https://doi.org/10.7554/eLife.108559
  26. EMBO J. 2026 Jul 23.
    RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability.
    Ruofei Liu, Jiachen Xuan, Carmelo Cerra, Nyree Stojnic, Junqi Pan, Shalini S Chelliah, Shannon Mendez, Rhynelle Dmello, Karla J Cowley, Yangyi Zhang, Kezia Gitareja, Matthew Wakefield, Andrew Deans, Clare L Scott, Keefe T Chan, Kaylene J Simpson, Jian Kang, Elaine Sanij.
      The nucleolus is organized around actively transcribed ribosomal RNA genes (rDNA), where high RNA polymerase I (Pol I) activity creates intrinsic susceptibility to replication stress and DNA damage. Here, we identify the DNA translocase RAD54L as a critical regulator of the nucleolar DNA damage response (nDDR) to rDNA double-strand breaks (DSBs) and replication stress. We show that RAD54L localizes to the nucleolus under basal conditions and is recruited to nucleolar caps following CRISPR-Cas9-induced rDNA-DSBs to promote repair. RAD54L loss results in persistent RAD51 foci, increased nucleolar γH2AX, and micronuclei formation, indicating defective resolution of rDNA lesions and genome instability. Under baseline conditions and replication stress induced by the Pol I transcription inhibitor CX-5461, RAD54L limits the accumulation of ssDNA and coordinates nDDR signaling. We further show that rDNA-DSBs induce RNA polymerase II-dependent RNA-DNA hybrids (R-loops) at intergenic rDNA regions, which facilitate nucleolar reorganization and cap formation and repair factor recruitment. Together, these findings establish RAD54L as a key regulator that coordinates replication stress response and rDNA repair, maintaining rDNA stability and genome integrity.
    DOI:  https://doi.org/10.1038/s44318-026-00864-3
  27. Cell. 2026 Jul 21. pii: S0092-8674(26)00756-7. [Epub ahead of print]
    Localized PD-1 CAR T therapy reprograms neuroinflammation.
    Rotem Shalita, Maya Ben Yehuda, Chamutal Gur, Yasmin Frid, Sarah McGrath, Roni Suhler, Lihi Bolokan, Vasyl Eisenberg, Reut Sharet Eshed, Shir Shlomi-Loubaton, Adin Tofield, Karin Vardy, Mor Zada, Anna Kurilovich, Eyal David, Diego Jaitin, Kfir Mazuz, Roberto Avellino, Reut Tzemach, Yuri Kuznetsov, Liat Fellus-Alyagor, Adva Levy-Barda, Sarah Mundt, Rina Rosenzweig, Bettina Schreiner, Anneli Peters, Christine Stadelmann, Pascale Zwicky, Adi Wilf Yarkoni, Florian Ingelfinger, Ido Amit.
      B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.
    Keywords:  CAR T cells; IL-10; PD-1; autoimmunity; deep probabilistic modeling; enhancer-driven regulatory circuits; follicular Th cells; immunotherapy; multiple sclerosis; single-cell genomics
    DOI:  https://doi.org/10.1016/j.cell.2026.06.036
  28. Nature. 2026 Jul 22.
    Genetic background sets the trajectory of experimental cancer evolution.
    Liver Cancer Evolution Consortium
      Human cancers are heterogeneous1. Dissecting how germline genetic variation and environmental factors shape tumour evolution using human datasets is limited by inherent diversity in genetic backgrounds2 and environmental exposures3-5. Here, to overcome these limitations, we re-ran early tumour evolution hundreds of times in diverged inbred mouse strains, generating matched histology and whole-genome and transcriptome sequences. The sex, environment and carcinogenic exposures were all controlled, and the study design allowed us to capture genetic variation comparable with that observed across human populations while exploiting the nested hierarchical structure of strain-litter-animal-tumour relationships. Our analyses reveal that epistatic interactions between genetic background and acquired somatic mutations result in population-specific disease progression, including choice of driver mutations, occurrence of whole-genome duplication and subclonal selection dynamics that mirror both cancer susceptibility and tumour growth rate. Even modest genetic divergence, comparable with that found across human ancestry groups, can strikingly alter selection pressures during cancer development to shape both cancer risk and the trajectory of tumour evolution.
    DOI:  https://doi.org/10.1038/s41586-026-10821-z
  29. Science. 2026 Jul 23. 393(6809): eadw4243
    A 3D genome atlas of human tonsil and the role of loop extrusion in B cell somatic hypermutation.
    Yubao Cheng, Jianshu Wang, Yuan Zhang, Anurupa Devi Yadavalli, Miao Liu, Shengyan Jin, Grace Buddle, Ann Haberman, David G Schatz, Siyuan Wang.
      B cell maturation within the germinal center tissue microenvironment involves immunoglobulin gene diversification by somatic hypermutation (SHM). How three-dimensional (3D) genome architecture influences SHM is not fully understood. We leveraged sequencing-based and image-based 3D genomics and transcriptomics to map single-cell 3D genome organization and gene expression across cell types and states in human tonsils and in B cell lymphoma cell lines. These analyses revealed trajectories of compartment, looping, and nuclear position changes during the B cell immune response and activation of SHM. Targeted protein degradation of cohesin component RAD21 revealed its contribution to enabling SHM. Our results provide a single-cell 3D genome atlas of human tonsil cells and outline the links between the chromatin loop extrusion machinery and SHM.
    DOI:  https://doi.org/10.1126/science.adw4243
  30. Stem Cell Reports. 2026 Jul 23. pii: S2213-6711(26)00230-4. [Epub ahead of print] 103019
    High and intermittent hydrostatic pressure promotes maturation of engineered cardiac tissues derived from human pluripotent stem cells.
    Wusiman Maihemuti, Kozue Murata, Takahiro Jimba, Jun Iida, Keisuke Hakamada, Akane Sakaguchi, Mosha Abulaiti, Yuichi Saito, Laura Yuriko González-Teshima, Satoshi Takatori, Takahiro Kenmotsu, Kenichi Yoshikawa, Kenji Minatoya, Seitaro Nomura, Wataru Kimura, Hidetoshi Masumoto.
      The immaturity of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and engineered cardiac tissues (ECTs) limits their use in regenerative therapies. Ventricular loading pressure plays a vital role in cardiac repair, prompting the hypothesis that hydrostatic pressure could enhance ECT maturation. ECTs were created by co-culturing hPSC-derived cardiovascular cells with extracellular matrix proteins and subjecting them to intermittent hydrostatic pressure (1 h/day at 50 kPa for 3 days after 2 weeks of pre-culture). This protocol improved cardiomyocyte alignment, mitochondrial content, and metabolic and functional maturation, evidenced by enhanced contractility, calcium flux, and single-cell RNA sequencing. Endothelial cells were critical for these effects, as their absence prevented maturation. Hydrostatic pressure combined with dynamic culture also promoted vascular network formation. Transplanted trained ECTs significantly improved ejection fraction in a rat myocardial infarction model. These findings demonstrate the potential of hydrostatic pressure training to advance ECT maturation and therapeutic application.
    Keywords:  cardiac maturation; cardiac regeneration; cardiomyocytes; endothelial cells; engineered cardiac tissues; human pluripotent stem cells; hydrostatic pressure; mechanotransduction
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103019
  31. EMBO J. 2026 Jul 18.
    Reactive oxygen species stimulate Paneth cell plasticity and diminish antimicrobial function.
    Jiaxing Yang, Sheila Bandyopadhyay, Dahui Wang, Edward Gonzalez, Yeqing Chen, Jagannatham Naidu Bhupana, Oscar Pellon-Cardenas, Helen Park, Iyshwarya Balasubramanian, Jared Bianchi-Smak, Xiao Zhang, Zhi Wei, Edward M Bonder, Michael P Verzi, Jean-Pierre Etchegaray, Nan Gao.
      The gut epithelium faces constant environmental oxidative stresses. How it responds to pathological reactive oxygen species (ROS) is not fully understood. Using Paneth cell (PC) lineage reporters and genetic tracing, we show that as PC progenitors mature, a decline in their oxidative phosphorylation (OXPHOS) activity coincides with an increased capacity to produce antimicrobial peptides (AMPs). Direct stimulation by elevated extracellular ROS, often found during gut infection and inflammation, can drive a subset of PCs into mitotic cell division. Increasing mitochondrial superoxide production via impairment or uncoupling of the respiratory electron transport chain similarly stimulated PC cell-cycle entry and dedifferentiation into various intestinal epithelial cell types. Using gain- and loss-of-function approaches, we found that the Rho-GTPase CDC42 in PCs regulates the balance of ROS and antimicrobial peptide production, influencing the outcome of pathogenic infection. CDC42 deficiency impairs mitochondrial respiration in PCs, elevating cellular ROS, plasticity, and inflammation. Together, ROS directly suppress the mature PC phenotypes, contributing to the widely observed PC pathology in inflammatory diseases. Our findings suggest that molecular defects affecting OXPHOS balance and antimicrobial peptide production in PCs will likely impair innate defense and drive inflammatory progression in the intestine.
    DOI:  https://doi.org/10.1038/s44318-026-00869-y
  32. Science. 2026 Jul 23. 393(6809): eady6893
    Single-cell multiomics and chromatin structure reveal gene-regulatory dynamics in heart failure.
    Yang Xie, Luca Tucciarone, Elie N Farah, Lei Chang, Qian Yang, Thirupura S Shankar, Weston Elison, Shaina Tran, Jovina Djulamsah, Audrey Lie, Timothy Loe, Alyssa R Holman, Sierra Corban, Justin Buchanan, Sainath Mamde, Haowen Zhou, Ruth M Elgamal, Eleni Tseliou, Vincent Huang, Zhaoning Wang, Jeffrey Huey-Chuan Chiu, Rebecca Melton, Emily Griffin, Qingquan Zhang, Jacinta Lucero, Sutip Navankasattusas, Daofeng Li, Chanrung Seng, Eugin Destici, Craig H Selzman, Agnieszka D'Antonio-Chronowska, Ting Wang, Allen Wang, Stavros G Drakos, Kyle J Gaulton, Bing Ren, Neil C Chi.
      Heart failure is a leading cause of morbidity and mortality, yet gene-regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications, and chromatin organization of 13 nonfailing and 23 failing human hearts across all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene-regulatory programs, and chromatin organization, particularly in cardiomyocytes and fibroblasts. Mapping cell type-specific enhancer-gene interactions from these analyses enabled the illumination of likely causal genetic contributors to heart failure from genetic association data. Together, these findings provide multimodal gene-regulatory maps of the human heart in health and disease, offering a framework for designing precise, cell type-targeted therapies for treating heart failure.
    DOI:  https://doi.org/10.1126/science.ady6893
  33. Cell Rep. 2026 Jul 18. pii: S2211-1247(26)00775-8. [Epub ahead of print]45(7): 117697
    PRKCI-ECT2 copy number gain promotes developmental reprogramming and metastatic competence in lung adenocarcinoma.
    Duy T Nguyen, Kayleah M Meneses, Cheng Zhang, Luis I Prieto, Capella Weems, Lee Jamieson, Hu Li, Darren J Baker, Andras Khoor, Nicole R Murray, Verline Justilien, Alan P Fields.
      Lung adenocarcinoma (LUAD) shows extensive lineage plasticity and early metastatic dissemination, but the oncogenic events that actively drive these processes remain poorly defined. Here, we identify coordinated PRKCI and ECT2 copy number gain, present in approximately 30% of human LUADs, as a driver of developmental reprogramming and metastasis. Using a genetically engineered mouse model that recapitulates PRKCI-ECT2 gain in Kras/Trp53-driven LUAD, we show that elevated PKCι-ECT2 signaling rewires tumor trajectory in a cell-of-origin-dependent manner. Alveolar type II cell-derived tumors dedifferentiate into a distal SOX9high progenitor-like state associated with aggressive growth and liver metastasis, whereas club cell-derived tumors transition into a foregut SOX2high progenitor-like state that supports lineage infidelity and histological transformation. Human LUAD analyses support these progenitor programs as clinically relevant features of PRKCI-ECT2 gain.
    Keywords:  CP: Cancer; CP: Developmental biology; ECT2; PRKCI; SOX2; SOX9; copy number gain; developmental reprogramming; lineage plasticity; lung adenocarcinoma; metastasis; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117697
  34. Sci Adv. 2026 Jul 24. 12(30): eaeb0060
    Single-cell chromatin state transitions during epigenetic memory formation.
    Taihei Fujimori, Abby R Thurm, Simon Gaudin, Carolina Rios-Martinez, Benjamin R Doughty, Michaela M Hinks, Joydeb Sinha, Derek Le, Antonina Hafner, William J Greenleaf, Alistair N Boettiger, Lacramioara Bintu.
      Repressive chromatin modifications compact chromatin and mediate heritable gene silencing, but how structural changes quantitatively relate to epigenetic memory remains unclear. Using targeted recruitment of the KRAB repressor to induce H3K9me3 at a reporter gene, combined with single-molecule 3D chromatin imaging, we show that irreversible silencing is associated with large-scale chromatin compaction across tens of kilobases. In contrast, histone deacetylation produces reversible silencing without such compaction. Despite substantial single-cell heterogeneity, average compaction at the end of silencing quantitatively predicts epigenetic memory weeks after KRAB removal. Here, memory arises not through stable H3K9me3 domains but rather through a dynamic handoff in which H3K9me3 is gradually lost and replaced by DNA methylation. Stochastic simulations recapitulating these dynamics suggest that compaction enhances read-write feedback to promote this transition. Similar compaction is observed at endogenous loci during differentiation and fate commitment, suggesting that spatial organization may be predictive of epigenetic memory in other systems.
    DOI:  https://doi.org/10.1126/sciadv.aeb0060
  35. Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00472-7. [Epub ahead of print]
    Biomolecular condensates can function as inherent catalysts.
    Michael W Chen, Xiao Guo, Mina Farag, Naixin Qian, Xiaowei Song, Anton Ni, Vicky Liu, Yu Xia, Yuefeng Ma, Leshan Yang, Wen Yu, Matthew R King, Joonho Lee, Richard N Zare, Wei Min, Rohit V Pappu, Yifan Dai.
      Biomolecular condensates possess distinct solvent environments. This has been postulated to affect biochemical activities. Here, we report the discovery of inherent catalytic functions of condensates formed by intrinsically disordered proteins. The proteins themselves lack any catalytic activities. The catalytic functions of condensates emerge as a consequence of phase separation-dependent mesoscale electrochemical microenvironments. Condensates can mediate the hydrolysis of diverse types of biologically relevant substrates. Through sequence design that enriches selective residues at condensate interfaces, interfacial electrochemical properties, such as interfacial electric field and water activity, are shown to control catalytic behaviors. Synthetic condensates in live cells exhibit hydrolytic activity, reshaping transcription profiles and activating gene circuits that depend on hydrolytic products. Together, these findings support a model that biomolecular condensates function as "condenzymes," contributing emergent biochemical functions in cells.
    Keywords:  biological water; biomolecular condensates; condensate chemistry; condensate microenvironment; condenzymes; electrochemistry; inherent catalytic function; interface; non-enzymatic chemistry; phase transition
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.008
  36. Nat Rev Cardiol. 2026 Jul 23.
    The cardiac 4D nucleome: nuclear and chromatin dynamics across development, disease and ageing.
    Yinuo Wang, Gergana Dobreva.
      The nucleus is a highly organized and dynamic organelle, with hierarchical layers ranging from nucleosome positioning to chromatin domains and higher-order 3D genome topology. Viewed over time as the 4D nucleome, this organization enables precise and context-dependent transcriptional control. In the heart, dynamic nuclear architecture orchestrates precise transcriptional programmes that control lineage commitment and the establishment of cardiac cell types crucial not only for heart development, but also for postnatal function and adaptive responses. Correspondingly, transitions between developmental and disease states are accompanied by coordinated changes in genome organization, chromatin accessibility and transcription factor occupancy. These architectural programmes are modulated by mechanical and metabolic inputs, which further shape chromatin organization, nuclear positioning and epigenetic state. Deciphering the 4D nucleome of the heart can potentially provide new insights into disease mechanisms, regenerative strategies and precision cardiovascular medicine. In this Review, we highlight studies that define the fundamental principles of nuclear organization; explore nuclear and chromatin reorganization during cardiac development, disease and ageing; and discuss emerging methods to interrogate nuclear architecture. We also consider how mechanical and metabolic signals shape the 4D epigenome and examine their therapeutic and translational implications for cardiovascular health and disease.
    DOI:  https://doi.org/10.1038/s41569-026-01322-7
  37. J Cell Biol. 2026 Sep 07. pii: e202509110. [Epub ahead of print]225(9):
    The missing link: Piccolino is essential for tethering synaptic vesicles to rod photoreceptor ribbons.
    Kaspar Gierke, Michalina Gadomska, Julia Breuer, Julius N Bahr, Tanja M Müller, Hanna Ehnis, Sina Zobel, Nancy Mejia Villagran, Sonja A Kirsch, Alexandra Skrzypek, Renato Frischknecht, Anna Fejtová, Rainer A Böckmann, Carolin Wichmann, Hanna Regus-Leidig, Johann Helmut Brandstätter.
      Retinal photoreceptors transmit light signals to their postsynaptic neurons with high precision, speed and without fatigue. This high-throughput neurotransmission relies on a sophisticated molecular machinery centered on a presynaptic organelle, the synaptic ribbon (SR). A hallmark of SRs is the recruitment of synaptic vesicles (SVs) from the cytoplasmic SV pool via "tethering". However, the identity of the tether and the mechanism underlying SV tethering are unknown. Here, we show that cell-specific deletion of the SR-associated protein Piccolino from rod photoreceptors disrupts SR morphology and ablates SV tethering. Nanoscale epitope mapping suggests that Piccolino acts as an SV tether by extending its N terminus away from the SR into the SV-filled terminal cytoplasm. With in silico modeling and protein lipid-binding assays, we demonstrate that an amphipathic liquid packing sensor motif (ALPS) at the N terminus of Piccolino binds SV-like liposomes, implicating this interaction as the mechanism underlying SV tethering. Together, our findings identified Piccolino as the molecular link between the SR and SVs.
    DOI:  https://doi.org/10.1083/jcb.202509110
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