bims-ginsta Biomed News
on Genome instability
Issue of 2026–02–15
thirty-six papers selected by
Jinrong Hu, National University of Singapore
  1. Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition.
  2. Spectrin coordinates cell shape and signaling essential for epidermal differentiation.
  3. Leukocyte-epithelial physical contacts mediate interstitial migration in vivo.
  4. Synthetic germ granules reveal a direct role of Vasa/DDX4 in RNA localization and translational activation.
  5. Toll receptors mediate tissue intrinsic surveillance against aberrant cells by detecting cell fate aberrations.
  6. Local PI(4,5)P2 synthesis by septin-associated PIPKIγ isoforms controls centralspindlin association with the midbody during cytokinesis.
  7. Adhesion GPCR-induced ectocytosis mediates intercellular GPCR signal propagation.
  8. Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation.
  9. FANCD2 restrains fork progression and prevents fragility at early origins upon re-replication.
  10. CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response.
  11. Collective Mesoderm and Endoderm Cell Migration during Vertebrate Gastrulation.
  12. Glycocalyx micro- and nanodomains in cell-cell and cell-matrix interactions revealed by enhanced click chemistry.
  13. RAD51 succinylation regulates homologous recombination and contributes to the chemosensitivity in cancer.
  14. Molecular and Cellular Determinants of Human Iron Overload Cardiomyopathy.
  15. STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria.
  16. The human BAF chromatin remodeler processes nucleosomes bound by pioneer transcription factors OCT4-SOX2.
  17. Relocation of Endocytic Leaflet DNA Probes for Asymmetric and Week-Long Lysosomal Labeling.
  18. Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.
  19. Mechanisms and disease relevance of mitochondrial translation in humans.
  20. High-throughput identification of endogenous biomolecular condensates and phase-separating proteins.
  21. ZCWPW1 organizes telomeric architecture to drive meiotic chromosome movements.
  22. A role for condensin-mediator interaction in mitotic chromosome organization.
  23. hnRNPM cooperates with BCAS2 to modulate alternative splicing during oocyte development.
  24. Structural ontogeny of protein-protein interactions.
  25. Overactivation of Cdc42 GTPase Impairs the Cytotoxic Function of NK Cells From Old Individuals Towards Senescent Fibroblasts.
  26. Membrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.
  27. Cell confinement initiates a delayed but heritable loss of chromosomes.
  28. Genetic recording of pancreatic beta cell proliferation.
  29. Volume EM reveals three-dimensional architecture of the desmosome in epithelial cells and tissue models.
  30. Human mitotic spindles as active liquid crystals: From collective behaviors to discrete filaments.
  31. Epigenetic Gatekeeping of Intestinal Stem Cell Transformation.
  32. NCBP1 stress signaling drives alternative S6K1 splicing inhibiting translation.
  33. Direct visualization and tracing of chromatin folding in the Drosophila embryo.
  34. A p63-dependent molecular switch directs epithelial fate to form a specialized seal at the tooth-gingiva interface.
  35. Ribosomal RNA synthesis by RNA polymerase I is subject to premature termination of transcription.
  36. Energy partitioning in the cell cortex.
  1. Cell Stem Cell. 2026 Feb 12. pii: S1934-5909(26)00029-9. [Epub ahead of print]
    Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition.
    Martti Maimets, Mikhail Nikolaev, Cecilia Lövkvist, Fabien Bertillot, Hjalte List Larsen, Raul Bardini Bressan, Antonios Georgantzoglou, Nikolce Gjorevski, Eirini Filidou, Maureen Zøylner, Stine Lind Hansen, Astrid M Baattrup, Isidora Banjac, Jordi Guiu, Sara A Wickström, Matthias P Lutolf, Kim B Jensen.
      During morphogenesis, the intestine undergoes significant structural remodeling, transitioning from a simple tube of immature epithelium into a complex crypt-villus architecture housing mature cell types. However, the relationship between these structural changes and epithelial maturation has remained enigmatic. Using engineered scaffolds that replicate crypt-like geometries, we establish a robust platform for guiding the morphogenesis and differentiation of fetal intestinal cells into mature engineered tissues that mimic their in vivo counterparts. Mechanistically, tissue maturation is driven by cell crowding, leading to reduced YAP1 activation. Modulating YAP signaling in both engineered tissues and the developing mouse intestine alters epithelial lineage specification. These findings uncover a geometry-dependent mechanism that links tissue architecture to cell fate transitions. Our work provides a platform for modeling aspects of intestinal development and offers insights for refining stem cell differentiation protocols and regenerative strategies for intestinal disorders.
    Keywords:  bioengineering; intestine; maturation; state transitions; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2026.01.006
  2. J Cell Biol. 2026 Apr 06. pii: e202502071. [Epub ahead of print]225(4):
    Spectrin coordinates cell shape and signaling essential for epidermal differentiation.
    Arad Soffer, Aishwarya Bhosale, Roohallah Ghodrat, Marc Peskoller, Takeshi Matsui, Carien M Niessen, Chen Luxenburg, Matthias Rübsam.
      Cell shape and fate are tightly linked, yet how the cortical cytoskeleton integrates regulation of shape and fate remains unclear. Using the multilayered epidermis as a paradigm for cell shape-guided changes in differentiation, we identify spectrin as an essential organizer of the actomyosin cortex to integrate transitions in cell shape with spatial organization of signaling. Loss of αII-spectrin (Sptan1) in mouse epidermis altered cell shape in all layers and impaired differentiation and barrier formation. High-resolution imaging and laser ablation revealed that E-cadherin organizes gradients of cortical actin and spectrin into layer-specific submembranous networks with discrete structural and mechanical properties that coordinate cell shape and fate. This layer-specific organization dissipates tension and, in upper layers, retains activated growth factor receptor EGFR and the calcium channel TRPV3 at the membrane to induce terminal differentiation. Together, these findings reveal how polarized organization of the cortical cytoskeleton directs transitions in cell shape and cell fate at the tissue scale necessary to establish epithelial barriers.
    DOI:  https://doi.org/10.1083/jcb.202502071
  3. Res Sq. 2026 Feb 05. pii: rs.3.rs-8594440. [Epub ahead of print]
    Leukocyte-epithelial physical contacts mediate interstitial migration in vivo.
    Anna Huttenlocher, Jonathan Schrope, Tanner Robertson, Adam Horn, Jack Stevens, Clyde Tinnen, Julie Rindy, Yiran Hou, Emilie Rochon, David Beebe.
      Efficient immune cell migration requires physical interactions with surrounding tissues. While tissue matrix mechanics influence leukocyte motility, it is unknown how leukocytes exert pushing and pulling forces to traverse tightly adherent epithelial tissues, which comprise a majority of tissue volume in vivo. Here, we leverage the optical transparency of larval zebrafish to identify how physical interactions with epithelial cells regulate mechanisms of neutrophil force generation to navigate cell-dense tissues. Confining forces from epithelial cells induce a mechanosensitive central actin network, mediated by Cdc42 and WASP, which exerts expansile forces on surrounding cells to dilate a path for migration. In concert, direct cell-to-cell (leukocyte-epithelial) contacts, mediated by integrin ɑE binding to epithelial cadherin, generate tractional forces to enable forward motility. Together, our findings identify how physical interactions with surrounding epithelial cells regulate leukocyte motility through cell-dense tissues in vivo.
    DOI:  https://doi.org/10.21203/rs.3.rs-8594440/v1
  4. bioRxiv. 2026 Feb 03. pii: 2026.02.01.703065. [Epub ahead of print]
    Synthetic germ granules reveal a direct role of Vasa/DDX4 in RNA localization and translational activation.
    Ruoyu Chen, Henoc Zinga, Jay S Goodman, Ruth Lehmann.
      Cytoplasmic RNA granules, including stress granules, P bodies, neuronal RNA granules, and germ granules, are essential for RNA storage and regulation across a wide range of organisms. However, dissecting the contributions of individual factors to granule function is challenging because of the interdependence of components in vivo . This is especially true for DEAD-box helicases, common regulators of mRNA granules, whose specific contributions remain unclear. In this study, we developed a synthetic approach to de novo generate germ granules, enabling us to identify the minimal machinery needed for RNA localization and translational activation. Using a self-assembling PopTag-based scaffold derived from Caulobacter fused to the RNA-binding domain (RBD) of the germplasm organizer Oskar, we found that the recruitment of endogenous germ granule mRNAs ( nanos and pgc ) depended on the DDX4 protein Vasa. By employing orthogonal RNA tethering approaches, we demonstrate that Vasa is both necessary and sufficient for localized mRNA translation. Consistent with these findings, acute depletion of Vasa from endogenous germ granules specifically reduced Nanos translation without affecting mRNA localization, confirming Vasa as a core factor linking RNA recruitment to localized translational activation. These in vivo reconstitution experiments reveal a two-component module in which a scaffold RBD and the Vasa helicase, but not other DEAD-box helicases, enable RNP condensates to accumulate specific RNAs and promote their translation. Overall, our study uncovers previously unrecognized functions of an RNA helicase within ribonucleoprotein condensates and demonstrates the power of synthetic biology to analyze complex biomolecular condensates in living organisms.
    DOI:  https://doi.org/10.64898/2026.02.01.703065
  5. Development. 2026 Feb 09. pii: dev.205006. [Epub ahead of print]
    Toll receptors mediate tissue intrinsic surveillance against aberrant cells by detecting cell fate aberrations.
    Anna Frey, Laurin Ernst, Friedericke Fischer, Lale Alpar, Yohanns Bellaïche, Anne-Kathrin Classen.
      Tissue-intrinsic surveillance systems maintain tissue health by detecting and eliminating aberrant cells. One such mechanism, interface surveillance, is activated by differences in cell fate programs between neighboring cells, leading to actomyosin accumulation, JNK-signaling, and apoptosis at these interfaces. Here, we identify long Toll receptors (Toll-2, Toll-6, Toll-7, Toll-8) as mediators of interface surveillance in Drosophila imaginal discs. Using genetic mosaics and mapping of expression pattern, we show that differences in long Toll receptor levels between adjacent cells are sufficient to induce all hallmarks of interface surveillance. This response relies on the comparison of relative expression levels set by fate-specifying pathways and is thus position-dependent. Specifically, long Toll receptor expression is regulated by multiple patterning pathways, generating a combinatorial cell-surface code that is disrupted in developmentally aberrant or oncogenic cells. Notably, interface surveillance functions independently of NF-κB signaling, rather reflecting a role for long Toll receptors in modulating cell affinity through actomyosin dynamics. Our findings reveal long Toll receptors as integrators of developmental patterning and tissue homeostasis and provide insights into how tissues detect and respond to aberrant or oncogenic mutations.
    Keywords:  Cell competition; Drosophila; Interface surveillance; Ras; Toll; Toll-like receptors
    DOI:  https://doi.org/10.1242/dev.205006
  6. Nat Commun. 2026 Feb 07. 17(1): 1482
    Local PI(4,5)P2 synthesis by septin-associated PIPKIγ isoforms controls centralspindlin association with the midbody during cytokinesis.
    Giulia Russo, Nadja Hümpfer, Nina Jaensch, Steffen Restel, Christopher Schmied, Florian Heyd, Martin Lehmann, Helge Ewers, Volker Haucke, Michael Krauss.
      Cytokinesis critically depends on phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Synthesis of PI(4,5)P2 is crucial for several stages of cytokinesis, including actomyosin ring assembly and constriction, membrane tethering of spindle microtubules, and midbody organization. How these activities of PI(4,5)P2 are spatiotemporally controlled is unknown. Here we unravel a crucial function for local PI(4,5)P2 synthesis at the ingressed cleavage furrow by septin-binding isoforms of PIPKIγ to control midbody formation. We demonstrate that loss of PIPKIγ isoforms perturbs cytokinesis by impairing septin association with microtubules, and anillin and septin deposition at the intercellular bridge and at the midbody. This mechanism requires the ability of PIPKIγ isoforms to synthesize PI(4,5)P2 and to associate with septins. Septins and PIPKIγ further synergize to promote centralspindlin recruitment to the midbody. Our findings establish septin-associated PIPKIγ isoforms as spatiotemporal controllers of midbody organization during cytokinesis that act through generating a local pool of PI4,5P2 at the ingressed cleavage furrow.
    DOI:  https://doi.org/10.1038/s41467-026-69224-3
  7. Nat Chem Biol. 2026 Feb 13.
    Adhesion GPCR-induced ectocytosis mediates intercellular GPCR signal propagation.
    Guobing Huang, Ni Li, Yiyang Chen, Xingrun Li, X Z Shawn Xu, Chanjuan Xu, Jianfeng Liu.
      Cell-cell communications involve signal transmission from sending cells to receiving cells expressing specific receptors. Extracellular vesicles (EVs) mediate this process by transporting diverse biomolecules. G-protein-coupled receptors (GPCRs) are canonical membrane receptors that integrate various extracellular signals into intracellular responses. However, whether and how GPCRs engage in EV-mediated communications remain elusive. Here, we report that adhesion GPCRs (aGPCRs) induce the formation of migrasomes and retractosomes, two newly identified EV subtypes, through their extracellular adhesion-like domains and G12/13-protein signaling. Remarkably, activated receptors undergo ectocytosis into these EVs and are subsequently internalized by receiving cells, eliciting de novo G-protein activation. We further demonstrate that cancer-cell-derived migrasomes transfer aGPCRs such as GPR56 to endothelial cells in vitro and in vivo, thereby enhancing angiogenic potential. Together, our findings uncover that aGPCRs promote migrasome formation and provide a novel mechanism of cell-cell communications through EV-mediated intercellular spread of active GPCRs.
    DOI:  https://doi.org/10.1038/s41589-026-02148-7
  8. Science. 2026 Feb 12. 391(6786): eaea1272
    Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation.
    Mohamed A El-Brolosy, Atharv Oak, An T Hoang, Yassine Damergi, André Fischer, Reuben A Saunders, Jingchuan Luo, Amer Balabaki, Jeremy Guez, Troy W Whitfield, Seth R Goldman, Arash Latifkar, Yuancheng Ryan Lu, Didier Y R Stainier, Konrad J Karczewski, Olivia Corradin, Jonathan S Weissman.
      Transcriptional adaptation (TA) is a genetic robustness mechanism through which mutant messenger RNA (mRNA) decay induces sequence-dependent up-regulation of so-called adapting genes. How cytoplasmically generated mRNA fragments affect nuclear transcription remains poorly understood. Using genome-wide CRISPR screens, we uncover ILF3 as an RNA binding protein connecting cytoplasmic mRNA decay and transcription during TA and show that it is required for a range of TA substrates. ILF3 is enriched at adapting genes' RNAs, and its artificial recruitment through dCas13 promotes gene expression. Using tiling oligonucleotide screens, we identify trigger RNA fragments that activate adapting genes when introduced into cells. Further functional dissection reveals a critical role for homology between trigger and target sequences. These findings enhance our molecular understanding of TA and inform the design of programmable oligonucleotides for gene expression augmentation.
    DOI:  https://doi.org/10.1126/science.aea1272
  9. Nat Commun. 2026 Feb 07.
    FANCD2 restrains fork progression and prevents fragility at early origins upon re-replication.
    Nibal Badra-Fajardo, Elena Karydi, Aleix Bayona-Feliu, Belén Gómez-González, Ourania Preza, Marina Arbi, Argyro Kalogeropoulou, Juha K Rantala, Stavros Taraviras, Andrés Aguilera, Zoi Lygerou.
      DNA replication is tightly regulated to ensure a single round of chromosome duplication per cell division. DNA licensing restricts origin firing to once-per-cell-cycle while aberrant licensing promotes re-replication and genome instability. Here, we investigate the mechanisms that protect genome integrity following re-replication induced by depletion of the licensing inhibitor Geminin. We find that re-replicating cells require FANCD2 to prevent genome instability. FANCD2 is rapidly recruited to chromatin upon Geminin loss, where it limits unrestrained fork progression and prevents single strand DNA gap accumulation and fork breakage. Genome-wide analyses reveal that upon re-replication, FANCD2 localizes to early origins within highly transcribed regions prone to accumulate R-loops and enriched in early replicating fragile sites. Importantly, reducing transcription and R-loops alleviates re-replication-induced genome fragility, whereas PARP inhibition exacerbates it. Our study uncovers a role for FANCD2 in safeguarding genome integrity during re-replication, offering avenues for selective targeting of cancer cells.
    DOI:  https://doi.org/10.1038/s41467-026-68966-4
  10. Cell. 2026 Feb 11. pii: S0092-8674(25)01491-6. [Epub ahead of print]
    CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response.
    Yinghua Wang, Weiwei Hu, Rui Xia, Xianfa Yang, Yange Gu, Zihan Ning, Tiange Yang, Chune Yu, Lulu Zhang, Dun Li, Yitian Jin, Jianhua Li, Feifei Zhang, Yaochen Xu, Chenqi Xu, Zhengxin Wang, Naihe Jing, Luonan Chen, Guangchuan Wang.
      The tumor microenvironment (TME) poses a major barrier to effective immunotherapy, yet high-throughput perturbation-mapping approaches to dissect TME spatial complexity and its contextual immune modulators remain lacking. Here, we introduce CRISPR-laser-captured microdissection (LCM) integration mapping of the tumor-immune microenvironment (CLIM-TIME), a scalable platform that integrates CRISPR screening with LCM of metastatic tumors for transcriptomic, deconvolution, and immunofluorescence analyses. CLIM-TIME enables spatially resolved mapping of how tumor suppressor gene (TSG) loss reshapes the TME and modulates immune responses. We identified seven distinct TME subtypes, revealing that DNA repair and Polycomb repressive complex (PRC) TSG loss is linked to immune-infiltrated TMEs sensitive to T cell therapy. In contrast, knockouts of TSGs in the Hippo pathway promoted immune evasion and therapy resistance by fostering myeloid-enriched but T cell-excluded TMEs with elevated extracellular matrix (ECM). Targeting the ECM-crosslinking enzyme LOXL2 effectively remodeled the metastatic TME, enhancing T cell infiltration and improving therapeutic efficacy in lung metastases across multiple cancers.
    Keywords:  Hippo pathway; LOXL2; T cell infiltration; T cell therapy; extracellular matrix; immunotherapy; metastasis; spatial CRISPR; tumor microenvironment; tumor suppressor gene
    DOI:  https://doi.org/10.1016/j.cell.2025.12.042
  11. Cold Spring Harb Perspect Biol. 2026 Feb 09. pii: a041793. [Epub ahead of print]
    Collective Mesoderm and Endoderm Cell Migration during Vertebrate Gastrulation.
    Cornelis J Weijer.
      Collective migration is a key mechanism during embryonic development, particularly during gastrulation when the basic three-dimensional body plan is established. During this critical phase, mesoderm and endoderm tissues internalize from the surface to form the embryo's inner structures through species-specific processes. This internalization involves extensive collective migration of large cohorts of mesenchymal cells along characteristic routes inside the embryo. Despite decades of research, the mechanisms that control and guide the movement of these cells to their destinations remain largely unresolved. Understanding these complex interactions remains a central challenge in developmental biology. This review examines complementary insights obtained through the study of multiple vertebrate model systems-frogs, fish, chick, mouse-as well as embryonic stem cell-derived gastruloids. The evidence points to key roles for chemotactic movement and guidance mechanisms operating in concert with dynamic changes in cell-cell and cell-substrate adhesion. Recent studies have increasingly revealed critical roles for cell- and tissue-generated mechanical stresses and mechanosensing in executing and coordinating motion. Furthermore, dynamic feedback between signaling and motion generates emergent properties that enable large-scale coordination of collective migration.
    DOI:  https://doi.org/10.1101/cshperspect.a041793
  12. Nat Commun. 2026 Feb 12.
    Glycocalyx micro- and nanodomains in cell-cell and cell-matrix interactions revealed by enhanced click chemistry.
    Daan Smits, Johannes A M Damen, Tianfu Li, Floris L van Delft, Bauke Albada, Peter Friedl.
      The glycocalyx consists of glycoproteins, glycolipids and extracellular polysaccharides at the cell surface which mediate viscoelastic and electrostatic barrier function. In molecular interactions, the glycocalyx is thought to segregate locally to facilitate receptor-ligand binding, yet high-resolution maps of glycocalyx domains in cell-cell and cell-matrix interactions are lacking. We here apply TMTH-sulfoximine (THS)-based biorthogonal chemistry in live-cell culture and demonstrate enhanced glycocalyx detection, compared to established dibenzocyclooctyne-based labeling. Using superresolution microscopy in cancer cells, we identify micron-scale diminished glycocalyx in cell-cell contacts and depletion in protrusions at the leading and trailing edges and membrane blebs when cells invade 3D fibrillar matrix. At contacts to collagen fibrils, focal integrin clusters segregate ~350 nm outward from the glycocalyx level, forming adhesion sites of low glycocalyx content. Thus, we identify micro- and nanodomains with altered glycocalyx density using THS-based bioorthogonal labeling of live cells, implicating local glycocalyx downregulation in functional cell-cell and cell-matrix interactions.
    DOI:  https://doi.org/10.1038/s41467-026-69242-1
  13. Mol Cell. 2026 Feb 11. pii: S1097-2765(26)00062-6. [Epub ahead of print]
    RAD51 succinylation regulates homologous recombination and contributes to the chemosensitivity in cancer.
    Zhe Wang, Mingpeng Jin, Linhui Zhai, Bingsong Huang, Xuan Jin, Xuanhe Wang, Ala Eddine Boudemia, Xiaoning Yang, Zhiting Wei, Yiming He, Jie Yang, Yunxuan Li, Xin Ding, Rui Li, Xuan Zhou, Wen Zheng, Yaobing Ouyang, Qianwen Wang, Yifei Song, Zhikai Zeng, Yu Li, Lu Lu, Jiaqi Liu, Yunhui Li, Lei Li, Ke Li, Chun-Long Chen, Zhenkun Lou, Minjia Tan, Jinhuan Wu, Yuping Chen, Jian Yuan.
      Genomic instability and metabolic reprogramming are core hallmarks of cancer, yet how they are mechanistically interconnected remains unclear. Here, we demonstrate that succinyl-coenzyme A (CoA), a tricarboxylic acid (TCA) cycle metabolite and protein succinylation donor, modulates homologous recombination (HR) by regulating RAD51 succinylation. OXCT1 succinylates RAD51 at K285, whereas HDAC11 removes this modification. RAD51 succinylation disrupts BRCA2 interaction, impairs RAD51 foci formation, and suppresses HR. Upon DNA damage, ATM-dependent phosphorylation of HDAC11 enhances the interaction with RAD51, promoting RAD51 desuccinylation and inhibiting HR. In breast cancer models, elevated RAD51 succinylation correlates with reduced HR capacity and increased sensitivity to the PARP inhibitor olaparib, whereas diminished succinylation confers resistance. Moreover, a cell-penetrating peptide that disrupts the RAD51-HDAC11 interaction increases RAD51 succinylation and synergizes with chemotherapy. Collectively, our findings uncover a metabolic-epigenetic mechanism linking protein succinylation to HR and genomic stability and identify RAD51 succinylation as a predictive biomarker and therapeutic target in cancer.
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.020
  14. bioRxiv. 2026 Feb 04. pii: 2026.02.02.703307. [Epub ahead of print]
    Molecular and Cellular Determinants of Human Iron Overload Cardiomyopathy.
    Sayli S Modak, Lina Greenberg, W Tom Stump, Akiva E Greenberg, Nathaniel Huebsch, Michael J Greenberg.
      Iron overload cardiomyopathy (IOC) is a serious heart condition that is caused by elevated levels of systemic iron. IOC is characterized by both systolic and diastolic dysfunction as well as arrhythmias. It has been challenging to isolate the cardiac-specific cellular and molecular mechanisms driving IOC because the disease affects multiple interconnected organ systems. Here, we leverage stem cell technologies, cardiac tissue engineering, and protein reconstitution assays to model key aspects of human IOC in vitro and to probe the cellular and molecular mechanisms driving cardiac dysfunction. We demonstrate that human engineered heart tissues consisting of both cardiomyocytes and cardiac fibroblasts faithfully recapitulate key aspects of the human disease, including reduced systolic function, impaired diastolic function, and increased prevalence of arrhythmogenic events. We demonstrate that while both cardiomyocytes and cardiac fibroblasts show increased intracellular iron levels, leading to reduced viability, cardiomyocytes show higher levels of iron accumulation and higher levels of reactive oxygen species production. Moreover, we show that in a tissue, iron overload has little effect on the action potential kinetics; however, it directly impacts the amplitude and kinetics of the calcium transient, potentially driving arrhythmogenesis. Finally, we demonstrate that iron overload decreases force production, in part, through oxidative damage of sarcomeric proteins and direct iron-based inhibition of myosin. In summary, our results reveal new insights into the cellular and molecular mechanisms of human IOC pathogenesis, and they establish new in vitro models that can be harnessed to faithfully recapitulate key aspects of the human disease phenotype.
    Highlights: Contractile aspects of iron overload cardiomyopathy have been difficult to study in vitro.We developed engineered heart tissues to model key aspects of the human disease.In vitro iron overload reduces contractility and induces arrhythmogenesis.Iron differentially affects cardiomyocytes and cardiac fibroblasts.Iron overload directly impacts the actomyosin contractile apparatus.
    DOI:  https://doi.org/10.64898/2026.02.02.703307
  15. EMBO J. 2026 Feb 11.
    STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria.
    Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Carlos Pascual-Caro, Patricia Gómez-Suaga, Estela Area-Gomez, Eulalia Pozo-Guisado, Jorge Montesinos, Francisco Javier Martin-Romero.
      STIM1 is a transmembrane protein localized in the endoplasmic reticulum (ER), where it acts as a calcium ion sensor, activating store-operated Ca2+ entry upon ER Ca2+ depletion. Via cellular calcium influx, STIM1 is thought to indirectly affect mitochondrial calcium content. Here we show that STIM1 also interacts with mitochondrial proteins such as PTPIP51 and GRP75, suggesting its presence in mitochondria-associated ER membranes (MAMs), which are specialized ER regions that facilitate ER-mitochondria communication. Lowering STIM1 expression disrupts ER-to-mitochondria Ca2+ transfer, reduces basal mitochondrial Ca2+ levels, impairs maximal mitochondrial respiration, and reduces ATP production. The STIM1-GRP75 interaction depends on STIM1's Ca2+-sensing ability. ER Ca2+ depletion or the constitutive-open R429C mutation both reduce STIM1 binding to GRP75, suggesting that conformational changes in STIM1 play a role in this interaction. Deletion analysis revealed that the STIM1 (551-611) segment is crucial for GRP75 binding, as the peptide STIM1(551-611) binds GRP75, while STIM1(Δ551-611) shows reduced binding. These findings reveal a previously unrecognized role of STIM1 in direct inter-organelle communication.
    Keywords:  Calcium; GRP75; MAM; Mitochondria; STIM1
    DOI:  https://doi.org/10.1038/s44318-026-00700-8
  16. Mol Cell. 2026 Feb 11. pii: S1097-2765(26)00063-8. [Epub ahead of print]
    The human BAF chromatin remodeler processes nucleosomes bound by pioneer transcription factors OCT4-SOX2.
    Joscha Weiss, Luca Vecchia, David Domjan, Simone Cavadini, Anton Sabantsev, Georg Kempf, Ganesh R Pathare, Klaus Brackmann, Alicia K Michael, Lukas Kater, Eric Hietter-Pfeiffer, Mina Haddawi, Urja P Kuber, Sandra Mühlhäusser, Ralph S Grand, Michael B Stadler, Sebastian Deindl, Nicolas H Thomä.
      Chromatin remodeling complexes mobilize nucleosomes and promote transcription factor (TF) binding. Using ensemble and single-molecule assays combined with cryo-electron microscopy (cryo-EM), we studied the interaction between pioneer TFs OCT4-SOX2 and the human BRG1/BRM-associated factor (BAF) complex on nucleosomes. BAF engages TF-bound substrates in two orientations, placing OCT4-SOX2 at either the remodeler ENTRY or EXIT site. At the ENTRY site, OCT4-SOX2 initially coexists with BAF without structural interference. However, continued DNA translocation is expected to cause collisions with bound TFs, which can trigger remodeling direction reversals or may induce TF dissociation. To accommodate TFs at the EXIT site, BAF undergoes structural rearrangements, and ensemble assays reveal a nucleosome subpopulation translocating away from TF-binding sites. Moreover, single-molecule experiments show that nucleosome-bound BAF frequently changes remodeling direction, and we identify an ADP-bound remodeler conformation as a potential intermediate. Together, these findings reveal key aspects of the conformational dynamics and remodeling outcomes underlying BAF processing of TF-bound nucleosomes.
    Keywords:  BAF; OCT4; SOX2; SWI/SNF; chromatin remodelers; cryo-EM; gene regulation; nucleosome; pioneer TFs; single-molecule FRET
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.021
  17. J Am Chem Soc. 2026 Feb 10.
    Relocation of Endocytic Leaflet DNA Probes for Asymmetric and Week-Long Lysosomal Labeling.
    An Yan, Yuhan Kong, Yuxing Shang, Yifan Ge, Hang Xing, Di Li.
      Visualization of lysosomes in living cells is essential for understanding their physiological functions; yet, most probes that target the lysosomal interior often disrupt luminal chemistry, exhibit signal leakage, and fail to support long-term imaging. To address these challenges, we developed RELAY (Relocation of Endocytic Leaflet tAg to modifY organelles), a topology-preserving labeling strategy to transfer the inner-leaflet tags on the plasma membrane to the cytosol-facing outer leaflet of lysosomes. RELAY employs liposome-cell membrane fusion to anchor fluorescent DNA probes with phosphorothioate (PS) backbones on the cytoplasmic inner leaflet of the plasma membrane, followed by endocytic trafficking that preserves the membrane topology and relocates the probes onto the lysosomal outer surface. Because this labeling occurs on the lysosomal exterior that is protected from luminal degradation and the PS backbone resists nuclease degradation, RELAY enables highly stable asymmetric labeling that sustains week-long lysosome imaging in living cells. Using this approach, we visualized lysosomal dynamics during cellular senescence and discovered random, unidirectional, intercellular lysosomal transfer in cell-cell communications via tunnelling nanotubes. Holding the capability for prolonged, high-fidelity visualization of lysosomes, RELAY facilitates the exploration of their biological functions.
    DOI:  https://doi.org/10.1021/jacs.5c21974
  18. Nat Genet. 2026 Feb 13.
    Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types.
    Andrew Everall, Avraam Tapinos, Aliah Hawari, Alex J Cornish, Amit Sud, Daniel Chubb, Ben Kinnersley, Anna Frangou, Miguel Barquin, Josephine Jung, David N Church, Ludmil B Alexandrov, Richard S Houlston, Andreas J Gruber, David C Wedge.
      Whole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potentially targetable pathway defects. Here alongside single-base substitution, doublet-base substitution, small insertion and deletion and copy number aberration signatures previously covered by the Catalogue of Somatic Mutations in Cancer (COSMIC), we report signatures from an additional mutation type, structural variations (SVs), extracted de novo from WGS in 10,983 patients across 16 tumor types recruited to the 100,000 Genomes Project. Across the five mutation classes, we report 134 signatures, 26 of which are new to COSMIC, including an SV signature reference set. By relating signatures to genomic features and clinical phenotypes, we provide further insights into mutagenic processes and the application of signature analysis to precision oncology.
    DOI:  https://doi.org/10.1038/s41588-025-02474-x
  19. Nat Rev Mol Cell Biol. 2026 Feb 13.
    Mechanisms and disease relevance of mitochondrial translation in humans.
    Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.
      Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41580-026-00948-2
  20. Nat Protoc. 2026 Feb 12.
    High-throughput identification of endogenous biomolecular condensates and phase-separating proteins.
    Pengjie Li, Fukang Qi, Wenjie Zhu, Jiashuo Li, Jinyun Shi, Xinyu Tu, Mengran Wang, Peng Chen, Bi-Feng Liu, Yiwei Li.
      Biomolecular condensates formed through liquid-liquid phase separation regulate cellular processes, and their dysregulation causes disease. Current methods for identifying endogenous phase-separating proteins have low throughput and cannot capture dynamic responses to stimuli. Here we present a protocol combining osmotic compression or transforming growth factor-β (TGF-β) treatment to induce condensation with sucrose density gradient centrifugation and quantitative mass spectrometry to enable systematic, high-throughput identification of endogenous condensates and phase-separating proteins. The method exploits the density changes that occur when phase-separating proteins undergo oligomerization during condensate formation. In H1975 cells, we identified over 1,500 phase-separating proteins under osmotic compression or TGF-β treatment; 538 of these candidates were not present in PhaSepDB, a database that compiles in vivo, in vitro and omics-derived proteins. The approach detects constitutive condensates and proteins that dynamically phase-separate in response to osmotic stress or TGF-β signaling. This protocol provides proteome-wide analysis of fractions of proteins having different densities and enables temporal resolution of phase-separation events. The procedure takes ~9 d and requires expertise in cell culture, biochemistry and mass spectrometry. This method enables systematic study of biomolecular condensates and disease-associated phase-separation mechanisms.
    DOI:  https://doi.org/10.1038/s41596-025-01327-5
  21. bioRxiv. 2026 Feb 02. pii: 2026.01.30.702899. [Epub ahead of print]
    ZCWPW1 organizes telomeric architecture to drive meiotic chromosome movements.
    Wenxin Xie, Manjunath Gowder, Dominic Bazzano, Adrienne Niederriter Shami, Aastha Pandey, Melissa Frasca, Lakshmi Paniker, Luciana Previato de Almeida, Binod Kumar Bharati, Jing Liang, Attila Tóth, Morgan DeSantis, Jayakrishnan Nandakumar, Evgeny Nudler, Shyamal Mosalaganti, Roberto Pezza, Francesca Cole, Saher Sue Hammoud.
      Meiotic homolog pairing relies on programmed DNA recombination and large-scale chromosome movements, yet, how these genetic and mechanical events are coordinated remains unclear. ZCWPW1 is a histone reader that recognizes PRDM9-deposited chromatin marks. We identify an unexpected role for ZCWPW1 as a regulator of rapid prophase movements (RPMs). Using super-resolution imaging, we show that ZCWPW1 is strongly enriched at subtelomeric regions of mouse spermatocytes, where it stabilizes TRF1, LINC complex components, dynein, and meiosis-specific cohesin (STAG3). Loss of ZCWPW1 disrupts telomere architecture, weakens telomere-LINC- motor coupling, and abolishes chromosome movement, leading to defective synapsis and pairing, and persistence of DSBs. These defects are more severe than, and mechanistically independent of, those observed in Prdm9 - / - spermatocytes. Together, our findings reveal that ZCWPW1 acts independently of PRDM9 as a chromatin-based intranuclear regulator of telomere architecture and telomere-led chromosome movements, thereby linking telomeric chromatin state to nuclear force transmission required for faithful meiotic progression.
    Significance Statement: Meiotic pairing requires recombination and telomere-led chromosome movements, yet no chromatin factor has been shown to regulate both. We identify ZCWPW1 as the first chromatin-based regulator of rapid prophase movements. ZCWPW1 organizes telomeric chromatin and promotes cohesin and motor assembly at telomeres that for force transmission across the nuclear envelope. Loss of ZCWPW1 disrupts the telomere-nuclear envelope mechanical coupling, impairing motion and altering recombination. This function doesn't rely on PRDM9 despite their co-evolution and co-expression, challenging the prevailing view that ZCWPW1 only acts downstream of PRDM9 in DNA repair. Our findings show that chromatin readers can function as structural regulators of genome organization, revealing a conserved mechanism integrating chromosome structure, motion, and repair to ensure proper pairing and fertility.
    DOI:  https://doi.org/10.64898/2026.01.30.702899
  22. Nat Commun. 2026 Feb 08.
    A role for condensin-mediator interaction in mitotic chromosome organization.
    Osamu Iwasaki, Sanki Tashiro, Claire Yik-Lok Chung, Tomomi Hayashi, Hideki Tanizawa, Xuebing Wang, Shinya Ohta, Yuko Fujioka, Joseph Han, Gabrielle Tabor, Mikihiro Kawagoe, Ronen Marmorstein, Nobuo N Noda, Ken-Ichi Noma.
      Condensin organizes eukaryotic genomes into three-dimensional (3D) chromosome architectures that support accurate chromosome segregation during mitosis. However, the molecular mechanisms underlying this organization remain unclear. Here, we identify a previously unrecognized interaction between the condensin subunit Cnd1 and the mediator subunit Pmc4 in fission yeast, Schizosaccharomyces pombe. We characterize a condensin mutation, cnd1-K658E, which disrupts this interaction and observe that it impairs the formation of condensin-mediated chromatin domains during mitosis, resulting in chromosome segregation defects. This condensin-mediator interaction facilitates condensin recruitment to highly transcribed genes and mitotically activated genes, the latter of which demarcate condensin-mediated domains. Moreover, 1,6-hexanediol treatment and Pmc4 mediator depletion impair expression of mitotically activated genes, diminish condensin enrichment at those boundary genes, and disrupt domain boundaries, suggesting that mediator contributes to mitotic gene expression and chromosome architecture via phase separation. Together, these results reveal a mechanism by which mitotic gene expression patterns shape condensin-mediated chromosome architecture to ensure faithful chromosome segregation.
    DOI:  https://doi.org/10.1038/s41467-026-69270-x
  23. Nat Commun. 2026 Feb 12.
    hnRNPM cooperates with BCAS2 to modulate alternative splicing during oocyte development.
    Shumin Zhou, Dalin Liu, Shiming Gan, Ziqi Yu, Ruibao Su, Hao Zhou, Jiaqi Zhang, Haoran Xu, Yifan Zhao, Hua Zhang, Zuoqi Deng, Xuan Wu, Chunhai Luo, Yunlong Liu, Shuiqiao Yuan, Heng-Yu Fan, Fei Sun.
      Growing oocytes accumulate maternal mRNA to support subsequent meiotic maturation and maternal-to-zygotic transition. However, the regulatory mechanisms governing the fate of these maternal mRNAs remain largely unknown. Here, we identified heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a critical regulator of pre-mRNA alternative splicing during mouse oocyte development. Genetic ablation of hnRNPM leads to severe cytoplasmic defects, meiotic arrest, and complete female infertility. Using SCAN-seq, we uncovered novel transcript isoforms and systematically characterized hnRNPM-regulated alternative splicing events. Furthermore, LACE-seq revealed hnRNPM-binding sites at single-nucleotide resolution in oocytes, linking its RNA-binding activity to splicing fidelity. Additionally, hnRNPM interacts with BCAS2, a known splicing factor critical for oocyte development, and modulates its binding to pre-mRNA loci to precisely control the alternative splicing. Overall, our study not only uncover an essential role of hnRNPM in mammalian oocyte development and female fertility but also unveils a critical regulatory network governing alternative splicing during oocyte development.
    DOI:  https://doi.org/10.1038/s41467-026-69176-8
  24. Science. 2026 Feb 12. 391(6786): eadx6931
    Structural ontogeny of protein-protein interactions.
    Aerin Yang, Hanlun Jiang, Kevin M Jude, Deniz Akpinaroglu, Stephan Allenspach, Alex Jie Li, James Bowden, Carla Patricia Perez, Liu Liu, Po-Ssu Huang, Tanja Kortemme, Jennifer Listgarten, K Christopher Garcia.
      Understanding how protein binding sites evolve interactions with other proteins could hold clues to targeting "undruggable" surfaces. We used synthetic coevolution to engineer new interactions between naïve surfaces, simulating the de novo formation of protein complexes. We isolated seven distinct structural families of protein Z-domain complexes and found that synthetic complexes explore multiple shallow energy wells through ratchet-like docking modes, whereas complexes formed by natural binding sites converged in a deep energy well with a relatively fixed geometry. Epistasis analysis of a machine learning-estimated fitness landscape revealed "seed" contacts between binding partners that anchored the earliest stages of encounter complex formation. Our results suggest that "silent" surfaces have a shallower energy landscape than natural binding sites, disfavoring tight binding, likely owing to evolutionary counterselection.
    DOI:  https://doi.org/10.1126/science.adx6931
  25. Aging Cell. 2026 Feb;25(2): e70398
    Overactivation of Cdc42 GTPase Impairs the Cytotoxic Function of NK Cells From Old Individuals Towards Senescent Fibroblasts.
    Albert Kallon Koroma, Karmveer Singh, Yongfang Wang, Linda Krug, Philipp Haas, Meinhard Wlaschek, Vadim Sakk, Tanja Schuster, Daniel Fürst, Hubert Schrezenmeier, Rashmi Priyadharshini Dheenadayalan, Stephan Stilgenbauer, Lutz Walter, Hartmut Geiger, Karin Scharffetter-Kochanek, Pallab Maity.
      Senescent fibroblasts accumulate in the connective tissue of all organs and promote organ aging and aging-related diseases. The underlying mechanisms for the accumulation of senescent fibroblasts are poorly understood. Natural killer (NK) cells of innate immunity play a critical role in the removal of tissue resident senescent cells. We here show that NK cells from old adults and old mice fail to efficiently remove senescent fibroblasts. This is due to severely reduced perforin and granzyme B release from aged NK cells where perforin is responsible for inducing holes in the membrane of senescent fibroblasts through which granzyme B enters enforcing cell death of senescent fibroblasts. We demonstrate elevated activation of the small Cdc42 Rho GTPase in aged NK cells to be responsible for the disruption of the microtubular organization which is essential for the proper release of perforin and granzyme B and for energy homeostasis. Attenuation of the elevated activity of Cdc42 in aged human NK cells with CASIN, a small molecule Cdc42 inhibitor, rebalances Cdc42 activity to a young level. Rebalancing of Cdc42 restores proper perforin and granzyme B release and attenuates reduced ATP levels in aged NK cells resulting in an attenuated "youthful" cytotoxicity of aged NK cells against senescent cells. Collectively, we identified a previously unreported molecular mechanism underlying functional impairment of NK cells from older adults. In perspective, our data hold promise to develop novel strategies against age-related disorders driven by tissue-resident senescent fibroblasts.
    Keywords:  CASIN; Cdc42; NK cell; aging; granzyme B; malignant lymphoma cells; perforin; senescent fibroblasts
    DOI:  https://doi.org/10.1111/acel.70398
  26. Sci Adv. 2026 Feb 13. 12(7): eaeb0803
    Membrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.
    Jinyu Fei, Yuanmin Zheng, Caden LaLonde, Yuan Tao, Ruobo Zhou.
      Endocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane-associated periodic skeleton (MPS), an actin spectrin-based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways-CME, caveolin-, flotillin-, and fast endophilin-mediated endocytosis-are spatially gated by the MPS and occur exclusively within MPS-free "clearing" zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular signal-regulated kinase signaling, promoting protease-mediated spectrin cleavage and MPS disruption, which in turn facilitates further endocytosis. Furthermore, the MPS limits amyloid precursor protein endocytosis, thereby suppressing Aβ42 production and linking MPS integrity to neurodegeneration. Our findings establish the MPS as a dynamic, signal-responsive modulator coupling membrane trafficking with cortical cytoskeletal organization and neuronal health.
    DOI:  https://doi.org/10.1126/sciadv.aeb0803
  27. bioRxiv. 2026 Feb 03. pii: 2026.02.03.703566. [Epub ahead of print]
    Cell confinement initiates a delayed but heritable loss of chromosomes.
    Steven H Phan, Mai Wang, Kayla R Snare, Jonah Kandell, Jeneille S Deans, Panteleimon Rompolas, Guilherme P F Nader, Dennis E Discher.
      Heritable genetic changes continually arise in cancer, especially in solid tumors where cells sometimes appear compressed. Rare heritable losses of chromosomes in live cells are quantified here with chromosome reporters (ChReporters) that reveal similar levels of loss after imposing a threshold level of confinement. Compression to ∼60% of interphase height ruptures few nuclei compared to deeper compression but perturbs mitotic spindles and prolongs pro/metaphase. Chromosome mis-segregation into micronuclei is discovered only after release from modest confinement, but arrest and death predominate. All such effects are phenocopied by Nocodazole washout that generates a 'memory' of prolonged mitosis, and effects differ from the rapid induction of micronuclei by a spindle assembly checkpoint inhibitor and by a clinical CDK4/6-inhibitor of cell cycle entry. Single-cell-RNA-sequencing confirms chromosome loss days after confinement and reveals persistence of chromosome segregation pathways. Chromosome losses as mitotic memories of confinement ultimately address knowledge gaps in mechanobiology and cancer evolution.
    DOI:  https://doi.org/10.64898/2026.02.03.703566
  28. Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2507877123
    Genetic recording of pancreatic beta cell proliferation.
    Huan Zhao, Hui Chen, Zhixin Kang, Xiuzhen Huang, Jingting Zhu, Zixin Liu, Xiuxiu Liu, Ximeng Han, Jie Lu, Bin Zhou.
      Pancreatic beta cell generation and proliferation primarily rely on the self renewal of preexisting beta cells, making precise quantification of beta cell proliferation essential for understanding pancreatic homeostasis and pathogenesis. However, previous methods had limitations and were unable to trace beta cell proliferation in vivo over extended periods. Here, we developed beta cell ProTracer, a genetic system that uses dual recombinase technology to enable continuous and cell type-specific recording of beta cell proliferation in mice. The beta cell ProTracer system allows for the quantification of the proliferation rate of adult pancreatic beta cells during homeostasis and in response to injury or drug treatment. Clonal analysis of the proliferated beta cell population reveals a uniform proliferative capacity among these cells. Our findings enhance the understanding of beta cell proliferation dynamics in homeostasis, repair, and regeneration.
    Keywords:  diabetes; dual recombinases; lineage tracing; pancreatic beta cell proliferation
    DOI:  https://doi.org/10.1073/pnas.2507877123
  29. bioRxiv. 2026 Jan 30. pii: 2026.01.27.702185. [Epub ahead of print]
    Volume EM reveals three-dimensional architecture of the desmosome in epithelial cells and tissue models.
    Navaneetha Krishnan Bharathan, William Giang, Eunice Chen, Stephanie E Zimmer, Sonam Lhamo, Danielle M Jorgens, Jamie L Inman, Vito Mennella, Manfred Auer, Andrew P Kowalczyk.
      Desmosomes are a type of cell-cell adhesive junction present in cardiac tissue and epithelial tissues such as the epidermis. These intercellular junctions anchor to the intermediate filament cytoskeleton, providing mechanical integrity to the tissues in which they reside. Our understanding of desmosome architecture has largely been influenced by observations of two-dimensional images obtained through conventional electron microscopy. Here, using focused ion beam scanning electron microscopy, we report the three-dimensional ultrastructure of desmosomes in A431 and S1 human mammary epithelial cells. We also reveal differences in desmosome ultrastructure at homo- and heterotypic junctions of human nasal airway epithelial cells. Quantitative analyses of these volume EM datasets reveal variations in desmosome size, shape, and organization. Importantly, we report the presence of discontinuities or "holes" within the desmosome outer dense plaque, a novel feature that is observed in either one or both halves of a desmosome. This study provides the first comprehensive description of the epithelial desmosome as a three-dimensional structure, and emphasizes the need to investigate the effects of dynamic morphogenetic processes and disease states on desmosome ultrastructure.
    DOI:  https://doi.org/10.64898/2026.01.27.702185
  30. Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2520490123
    Human mitotic spindles as active liquid crystals: From collective behaviors to discrete filaments.
    Suryanarayana Maddu, Colm P Kelleher, Mustafa Basaran, Thomas Müller-Reichert, Michael J Shelley, Daniel J Needleman.
      How thousands of microtubules (MTs) and molecular motors self-organize into spindles remains poorly understood. By combining static, nanometer-resolution, large-scale electron tomography reconstructions and dynamic, optical-resolution, polarized light microscopy, we test an active liquid crystal continuum theory of mitotic spindles in human tissue culture cells. At micron length scales, probed by optical microscopy, the continuum theory accurately captures spindle morphology and fluctuation spectra, indicating that local interactions-polymerization, alignment, diffusion, and polar transport-govern the collective behaviors of MTs in human mitotic spindles. Electron tomography data enables tests of the continuum theory at submicron scales, revealing that chromosome-attached kinetochore microtubules (KMTs) show distinctive lateral organization not explained by the coarse-grained theory, while the non-KMTs that make up the bulk of the spindle follow the theory down to ∼300 nm length scales. At length scales below ∼300 nm, fluctuations arising from the intrinsic discreteness of the microtubule ensemble dominate over the collective correlations predicted from the continuum theory. Taken together, these findings show that an active liquid-crystal theory can quantitatively capture the self-organization of human mitotic spindles on long length scales and provides a means to measure the spindle's material properties, while also pointing to the existence of additional processes contributing to the behaviors of KMTs.
    Keywords:  active matter; electron tomography; microtubules and motors; self-organization; spindle assembly
    DOI:  https://doi.org/10.1073/pnas.2520490123
  31. bioRxiv. 2026 Feb 03. pii: 2026.01.31.702974. [Epub ahead of print]
    Epigenetic Gatekeeping of Intestinal Stem Cell Transformation.
    Alireza Lorzadeh, Sweta Sharma, Geroge Ye, Sabrina Rabaya, Yun Jee Kang, Ramesh A Shivdasani, Unmesh Jadhav.
      Widespread cell plasticity recognized in fetal intestinal epithelium is preserved in limited fashion in Wnt-responsive adult stem cells and contributes to tumor initiation, progression, and relapse. 1, 2, 3 It is unclear which epigenetic features maintain stem-cell properties, restrict adult expression of fetal genes 4 , and are attenuated in tumors, allowing non-stem cells to replenish targeted tumor stem cells 5 . Here we show that reversible stemness in normal adult intestinal crypt cells hinges on a dynamic balance between activating H3K27ac and repressive H3K27me3 marks. Cells that leave the Wnt-rich stem-cell niche normally acquire H3K27me3 at thousands of stemness-associated enhancers. Constitutive tumorigenic Wnt activity transforms Apc ‒/‒ intestinal stem cells by gradual erosion of H3K27me3 at select enhancers and extends stem-like properties beyond usual anatomic confines; continued depletion of H3K27me3 reactivates enhancers that control growth and expression of a wider swath of fetal genes than appreciated previously. Subsequent focal DNA demethylation at expanded superenhancer domains is associated with tumor growth. Human colorectal cancers also carry evidence of this epigenetic rewiring. Accelerated H3K27me3 loss in mice hastens, and its preservation delays, activation of stemness-related enhancers, superenhancers, and tumor progression. During transformation, H3K27me3 loss at enhancers erases a crucial distinction between stem and non-stem populations, endowing the latter with stemness and providing an explanation for tumor resistance to cancer stem cell targeting. Thus, H3K27me3 at Wnt-responsive enhancers is an intrinsic barrier to intestinal tumorigenesis and aberrant reactivation of hundreds of fetal genes.
    DOI:  https://doi.org/10.64898/2026.01.31.702974
  32. Nat Chem Biol. 2026 Feb 10.
    NCBP1 stress signaling drives alternative S6K1 splicing inhibiting translation.
    Dalu Chang, Mahdi Assari, Chananya Suwathep, Khomkrit Sappakhaw, Chayasith Uttamapinant, Marcus J C Long, Yimon Aye.
      Subcellular stress profoundly influences protein synthesis. However, both the nature of spatiotemporally restricted chemical cues and local protein responders to these cues remain elusive. Unlocking these mechanisms requires the ability to functionally map in living systems locale-specific stress responder proteins and interrogate how chemical modification of each responder impacts proteome synthesis. We resolved this problem by integrating precision localized electrophile generation and genetic code expansion tools. Upon examination of four distinct subcellular locales, only nuclear-targeted electrophile stress stalled translation. We discovered that NCBP1-a nuclear-resident protein with multifaceted roles in eukaryotic mRNA biogenesis-propagated this nuclear stress signal through a single cysteine (C436) from among its 19 conserved cysteines. This NCBP1(C436)-specific modification elicited alternative splicing of more than 250 genes. Mechanistically, global protein synthesis stall was choreographed by impaired association between electrophile-modified NCBP1(C436) and SF3A1, an essential component of spliceosome, triggering the production of alternatively spliced S6 kinase, whose expression was sufficient to dominantly inhibit protein translation.
    DOI:  https://doi.org/10.1038/s41589-025-02135-4
  33. EMBO J. 2026 Feb 09.
    Direct visualization and tracing of chromatin folding in the Drosophila embryo.
    Fadwa Fatmaoui, Pascal Carrivain, Fatima Taiki, Amina Iusupova, Diana Grewe, Wim Hagen, Burkhard Jakob, Jean-Marc Victor, Amélie Leforestier, Mikhail Eltsov.
      Chromatin organization, through the assembly of DNA with histones and the folding of nucleosome chains, regulates DNA accessibility for transcription, DNA replication and repair. Although models derived from in vitro studies have proposed distinct nucleosome chain geometries, the organization of chromatin within the crowded cell nucleus remains elusive. Using cryo-electron tomography of thin vitreous sections, we directly observed the path of nucleosomal and linker DNA in situ from a flash-frozen organism - Drosophila embryos. We quantified linker length and curvature, characterizing an irregular zig-zag chromatin-folding motif, with a low degree of linker bending. Nucleosome conformations could be identified on individual particles in favorable orientations without structure averaging. Additionally, we observed particles that accommodate a number of DNA gyres ranging from less than one to up to three, which resemble previously proposed non-octameric nucleosomal particles with variable DNA wrapping.
    Keywords:  Chromatin Fiber; In Situ Cryo-Electron Tomography; Linker DNA; Nucleosome; Sub-Nucleosomal Particles
    DOI:  https://doi.org/10.1038/s44318-026-00701-7
  34. Cell Rep. 2026 Feb 12. pii: S2211-1247(26)00059-8. [Epub ahead of print]45(2): 116981
    A p63-dependent molecular switch directs epithelial fate to form a specialized seal at the tooth-gingiva interface.
    Yu Liang, Jie Gao, Litian Han, Yao Zhou, Qianqian Li, Fei Pei, Zhi Chen, Peng Fei, Yufeng Zhang, Huan Liu.
      Failure to maintain the epithelial seal at the tooth-gingiva interface drives periodontitis. This specialized junctional epithelium (JE) is critical for immune homeostasis, yet mechanisms for its regeneration are poorly understood. Using murine gingivectomy, single-cell transcriptomics, lineage tracing, and clinical data, we delineate requirements for JE repair. We identify ODAM as a specific JE marker derived from Krt5+ basal progenitors. We show these cells migrate from distal sites, explaining the superior outcomes of progenitor-preserving single flap surgery. Genetic deletion of p63 blocks JE regeneration and disrupts cellular organization. We define an essential p63-RUNX1-ODAM axis for JE specification, distinct from the p63-KLF4-loricrin pathway driving keratinization-a feature of pathological repair. These findings reveal a fundamental molecular switch controlling epithelial fate, offering a roadmap to therapeutically promote tissue sealing at inflammation-prone interfaces.
    Keywords:  CP: developmental biology; cell fate; junctional epithelium; periodontium; wound healing
    DOI:  https://doi.org/10.1016/j.celrep.2026.116981
  35. Elife. 2026 Feb 12. pii: RP106503. [Epub ahead of print]14
    Ribosomal RNA synthesis by RNA polymerase I is subject to premature termination of transcription.
    Chaïma Azouzi, Katrin Schwank, Sophie Queille, Marta Kwapisz, Marion Aguirrebengoa, Anthony Henras, Simon Lebaron, Herbert Tschochner, Annick Lesne, Frederic Beckouët, Olivier Gadal, Christophe Dez.
      The RNA polymerase I (Pol I) enzyme that synthesizes large rRNA precursors exhibits a high rate of pauses during elongation, indicative of a discontinuous process. We show here that premature termination of transcription (PTT) by Pol I in yeast Saccharomyces cerevisiae is a critical regulatory step limiting rRNA production in vivo. The Pol I mutant, SuperPol (RPA135-F301S), produces 1.5-fold more rRNA than the wild type (WT). Combined CRAC and rRNA analysis link increased rRNA production in SuperPol to reduced PTT, resulting in shifting polymerase distribution toward the 3' end of rDNA genes. In vitro, SuperPol shows reduced nascent transcript cleavage, associated with more efficient transcript elongation after pauses, to the detriment of transcriptional fidelity. Notably, SuperPol is resistant to BMH-21, a drug impairing Pol I elongation and inducing proteasome-mediated degradation of Pol I subunits. Compared to WT, SuperPol maintains subunit stability and sustains high transcription levels upon BMH-21 treatment. These comparative results show that PTT is alleviated in SuperPol while it is stimulated by BMH-21 in WT Pol I.
    Keywords:  BMH-21; RNA polymerase I; S. cerevisiae; genetics; genomics; premature termination of transcription; rDNA transcription
    DOI:  https://doi.org/10.7554/eLife.106503
  36. Nat Phys. 2024 Nov;20(11): 1824-1832
    Energy partitioning in the cell cortex.
    Sheng Chen, Daniel S Seara, Ani Michaud, Songeun Kim, William M Bement, Michael P Murrell.
      Living systems are driven far from thermodynamic equilibrium through the continuous consumption of ambient energy. In the cell cortex, this energy is invested in the formation of diverse patterns in chemical and mechanical activities, whose spatial and temporal dynamics determine the cell phenotypes and behaviours. How cells partition internal energy between these activities is unknown. Here we measured the entropy production rate of both chemical and mechanical subsystems of the cell cortex across a variety of patterns as the system is driven further from equilibrium. We do this by manipulating the Rho GTPase pathway, which controls the cortical actin filaments and myosin-II. At lower levels of GTPase-activating protein expression, which produce pulses or choppy Rho and actin filament waves, energy is proportionally partitioned between the two subsystems and is subject to the constraint of Onsager reciprocity. Within the range of reciprocity, the entropy production rate is maximized in choppy waves. As the cortex is driven into labyrinthine or spiral travelling waves, reciprocity is broken, marking an increasingly differential partitioning of energy and an uncoupling of chemical and mechanical activities. We further demonstrate that energy partitioning and reciprocity are determined by the competing timescales between chemical reaction and mechanical relaxation.
    DOI:  https://doi.org/10.1038/s41567-024-02626-6
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