bims-ginsta Biomed News
on Genome instability
Issue of 2026–07–05
34 papers selected by
Jinrong Hu, National University of Singapore



  1. Cell. 2026 Jun 30. pii: S0092-8674(26)00696-3. [Epub ahead of print]
      Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet how such heterogeneities are integrated with the mechanochemical state of the tissue and stabilized at the chromatin level into stable, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (YAP1). We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable and self-organized tissue architecture.
    Keywords:  Yap1; epigenetic competence; heterogeneity; image-based phenotyping; intestinal regeneration; mechanics; modeling; multiscale integration; organoids; tissue patterning
    DOI:  https://doi.org/10.1016/j.cell.2026.06.009
  2. Dev Cell. 2026 Jul 01. pii: S1534-5807(26)00226-1. [Epub ahead of print]
      How distinct lineage identities are specified from pluripotent epiblast cells during gastrulation is a longstanding open question. By investigating AXIN, a negative regulator of the WNT/β-catenin pathway, we have uncovered previously unrecognized roles for WNT signaling in the specification of distinct mesoderm identities. Using complementary approaches, including a detailed analysis of Axin1;Axin2 mutant mouse embryos involving single-cell and single-embryo transcriptomics and in vitro pluripotent stem cell differentiation assays, our data revealed two critical layers of regulation. First, WNT initiates differentiation of primitive streak cells into mesoderm progenitors. Next, WNT amplifies and cooperates with bone morphogenetic protein (BMP)/pSMAD1/5/9 or NODAL/pSMAD2/3 to propel differentiating mesoderm progenitors into either posterior or anterior streak identities, respectively. We propose that Axin1 and Axin2 function to prevent precocious differentiation of pluripotent epiblast cells into mesoderm through the spatiotemporal regulation of WNT-signaling levels.
    Keywords:  Axin; BMP; NODAL; WNT; gastrulation; mesoderm; mouse embryo; pluripotency
    DOI:  https://doi.org/10.1016/j.devcel.2026.06.004
  3. Nat Struct Mol Biol. 2026 Jun 30.
      Three-dimensional genomics methods such as Hi-C and Micro-C have uncovered chromatin loops across the genome and linked these loops to gene regulation. However, these methods only measure three-dimensional interaction probabilities on a relative scale. Here we overcome this limitation by using live-imaging data to calibrate Micro-C in mouse embryonic stem cells, thus obtaining absolute looping probabilities for 65,929 Micro-C-identified chromatin loops. We find that the looped state is generally rare, with a mean pairwise looping probability of 1.2% and a maximum of 25% across the quantified loops. On average, CTCF-CTCF loops are stronger than cis-regulatory loops (2.2% versus <1%). Our findings can be extended to human cells with available Micro-C data under certain assumptions. Overall, we establish an approach for genome-wide absolute loop quantification and report that loops occur with low probabilities, generalizing recent live-imaging results to the whole genome.
    DOI:  https://doi.org/10.1038/s41594-026-01819-2
  4. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00686-8. [Epub ahead of print]45(7): 117608
      The spatial organization and dynamics of the endoplasmic reticulum (ER) govern when and where ER tubules engage with other organelles and the plasma membrane. We previously found that ER tubules are closely associated with desmosomes, but the mechanisms of ER recruitment to these adhesive intercellular junctions were unclear. Here, we demonstrate that recruitment of ER tubules to intercellular junctions is dependent upon E-cadherin association with α-catenin. During junction formation, adherens junctions and ER tubules appear nearly simultaneously at nascent cell-cell contacts, followed by desmosome formation. ER recruitment allows the formation of ER-plasma membrane contact sites (ER-PMCSs) and an assembly comprising adherens junctions, ER-PMCS, and desmosomes. Ablating adherens junctions disrupts this tripartite assembly and perturbs global lipid levels. Collectively, our findings identify cadherins as key organizers of ER-PMCS positioning and suggest that the cell-cell adhesion-organelle unit integrates cellular mechanical elements with plasma membrane homeostasis.
    Keywords:  CP: cell biology; ER-plasma membrane contact sites; adherens junctions; desmosomes; endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.celrep.2026.117608
  5. EMBO J. 2026 Jun 29.
      Accurate transition into mitosis driven by cyclin B1-CDK1 activity is essential to avoid chromosome segregation errors and preserve genome integrity. How this activity is spatially controlled to trigger mitotic onset remains unclear. Here, we show that chromosome condensation triggers an increase in nuclear envelope (NE) tension. This increased tension is required for translocation of cyclin B1 into the nucleus and dynein loading on nuclear pore complexes (NPCs), ensuring timely mitotic entry. Micromanipulation experiments further indicate this tension-dependent mechanism requires SUN proteins on the NE. Impairment of chromosome condensation leads to the nuclear accumulation of the G2 checkpoint kinase Wee1 and an inhibition of CDK1 activity, which result in a temporary delay in mitotic entry. This delay can be overridden by increasing tension on the NE, which accelerates the nuclear translocation of cyclin B1 and dynein loading. We propose that mitotic onset is controlled by a chromosome-dependent NE tension mechanism that enables robust spatiotemporal coupling between chromosome condensation and the NE structural changes required for an efficient mitosis.
    DOI:  https://doi.org/10.1038/s44318-026-00835-8
  6. Biophys J. 2026 Jul 03. pii: S0006-3495(26)00480-7. [Epub ahead of print]
      Epithelial tissues are often exposed to cyclic deformations in their physiological environment. Maintenance of mechanical integrity relies on intercellular adhesion proteins which link neighbouring cells and transmit forces across the cellular network. The stability of these intercellular adhesion complexes is therefore critical for tissue strength. Under sustained stress, failure of intercellular adhesion complexes leads to damage accumulation that progressively weakens the material and ultimately causes failure at the tissue scale. Although the collective behaviour of adhesion complexes under static loading has been characterised to some extent, their response to dynamic loading remains largely unknown, despite its physiological importance. Here we combine quantitative experiments on MDCK monolayers with modelling of intercellular adhesion complexes with force dependent detachment rates to investigate tissue resilience under cyclic loading. We find that cyclic loading significantly prolongs tissue lifetime and increases the maximum deformation the tissue can withstand before failure compared to constant tension, thanks to repair occurring during low-tension phases. Our model identifies intrinsic rupture and repair timescales governing adhesion stability, revealing three regimes of tissue behaviour: rupture, slow damage accumulation, and stable equilibrium. Normalizing loading parameters by the intrinsic material timescales collapses experimental and simulated data into universal stability maps. These findings demonstrate that epithelial resilience emerges from stochastic adhesion bond dynamics, providing a predictive framework linking adhesion complex turnover to macroscopic tissue mechanics under physiological cyclic forces.
    Keywords:  Epithelial resilience; cyclic loading; intercellular adhesion; slip-bond kinetics; tissue mechanics
    DOI:  https://doi.org/10.1016/j.bpj.2026.06.038
  7. Nat Mater. 2026 Jul;25(7): 1278-1287
      Topological defects determine the collective properties of anisotropic materials. Nonetheless, it is not fully understood how their configurations are controlled, especially in three dimensions. In living matter, contributions of two-dimensional topological defects to biological functions have been demonstrated, but whether three-dimensional polar defects have any biological relevance is unclear. Here we report a charge-preserving transition between three-dimensional defect configurations driven by boundary geometry and independent of material parameters. Moreover, we find that three-dimensional polar defects in the mouse embryo are the sites where fluid-filled lumina form, essential structures for subsequent development. We validate these findings by experimentally perturbing embryo shape beyond the transition point, which results in the creation of additional lumen initiation sites near predicted defect locations. Overall, our results reveal how boundary geometry controls polar defects, and how embryos use this mechanism for shape-dependent lumen formation. We expect this defect-control principle to apply broadly to systems with orientational order.
    DOI:  https://doi.org/10.1038/s41563-026-02594-7
  8. Science. 2026 Jul 02. 393(6806): eaef0825
      The liver exhibits a marked regenerative capacity organized through distinct zones, yet how tissue mechanics coordinate zonated proliferation remains elusive. We reveal that mechanical cues critically contribute to mouse liver regeneration in a highly region-specific manner through sensing by a subpopulation of mid-lobular hepatocytes, which are characterized by dipeptidyl peptidase-4 (DPP4) expression and represent the key proliferative pool of hepatocytes. PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4+ hepatocytes that integrates biomechanical cues to drive liver regrowth by insulin-like growth factor binding protein 2 (IGFBP2). Genetic disruption of PIEZO1 restrains hepatocyte proliferation and compromises liver regeneration, whereas zonated PIEZO1 gain of function enhances proliferation and accelerates recovery. These findings reveal that DPP4+ mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing, establishing a link between tissue mechanics and liver regeneration.
    DOI:  https://doi.org/10.1126/science.aef0825
  9. Curr Biol. 2026 Jul 01. pii: S0960-9822(26)00724-4. [Epub ahead of print]
      Nuclei and mitotic spindles are actively positioned at defined locations within cells to regulate cell polarity, division, and multicellular morphogenesis.1,2,3,4 Forces generated by cytoskeleton networks regulate the positioning of these organelles and are commonly influenced by extrinsic cues, such as cell geometry or polarity.5,6,7,8,9,10,11,12 To date, however, most studies have investigated this problem in one given cell type, hampering our understanding of how mechanical systems that position nuclei and spindles may scale during multicellular development. We tracked the spatiotemporal behavior of centrosomes, nuclei, and spindles in early sea urchin embryos from the 1-cell to the ∼1,000-cell blastula stage. We found that they are initially located at cell centers, but that they undergo a progressive decentration toward the embryo apical surface, as cells become smaller during development. This apical shift is mediated by microtubule (MT) pulling forces, which are influenced by both cell shapes and apical polarity domains. Using 3D mathematical models and embryo dissections, we propose that apical cortical polarity MT decentering forces progressively take over centering forces during development as a consequence of cell size reduction and resulting increase in surface-to-volume ratio. Our results support a self-organized scenario in which polarity cues progressively outcompete cell geometry to modulate the overall balance of MT forces and pattern nuclear and spindle positioning throughout early embryo development.
    DOI:  https://doi.org/10.1016/j.cub.2026.06.013
  10. Nat Methods. 2026 Jun 29.
      Spatially resolved lineage tracing is essential for understanding how clonal relationships shape tissue architecture. However, such an approach has not been established in mice across different tissues. Here we present Spatio-DARLIN, a versatile method that integrates the high-diversity DARLIN lineage-tracing mouse with sequencing-based spatial transcriptomics. Through a dedicated computational pipeline, Spatio-DARLIN achieves accurate clonal mapping at single-cell resolution and recovers reliable lineage information from ~25-50% of cells in the intestine and brain. Spatio-DARLIN identified stereotyped clonal patterns in the intestinal epithelium and revealed clonal dynamics that were consistent with stem-cell neutral drift. In the brain, we uncovered greater clonal expansion of radial glial cells in the cortex and hippocampus during development than in other regions. Moreover, our data strongly suggested that neuronal progenitors across different nuclei in the hypothalamus were already spatially prepatterned by embryonic day E10. Spatio-DARLIN enables high-resolution study of clonal architecture, expansion and migration across diverse tissues in situ.
    DOI:  https://doi.org/10.1038/s41592-026-03151-5
  11. Nat Commun. 2026 Jul 04.
      Cutaneous development is initiated by crosstalk between non-neural ectodermal epithelium and underlying mesenchymal cells. Recent studies have shown that some mesenchymal cells contribute to keratinocyte regeneration in injured skin. However, whether mesenchymal cells contribute to keratinocyte formation in physiologically normal skin remains unclear. Here we show, using lineage tracing, single-cell transcriptome and epigenome analyses of mouse skin, that the interfollicular epidermis consists largely of mesenchymal-lineage cells. Further lineage-tracing and live-imaging analysis of mouse embryos indicate that these mesenchymal-lineage epidermal progenitor cells arise from ectomesenchyme and contribute to the surface ectoderm through a mesenchymal-to-epithelial transition-like process between embryonic days 8.5 and 9.5. We also establish human induced pluripotent stem cell-derived ectomesenchyme and demonstrate that it generates p63-expressing keratinocytes. These data reveal a previously unappreciated contribution of ectomesenchyme to cutaneous development and provide insight into skin diseases involving epidermal mosaicism.
    DOI:  https://doi.org/10.1038/s41467-026-75278-0
  12. Science. 2026 Jul 02. eaeh1348
      Ribosomal RNA (rRNA) transcription rates vary during development, and their dysregulation is linked to diseases such as cancer and ribosomopathies. Owing to their high abundance and genomic redundancy, the functional significance of rRNA-levels remains unclear. Here, we developed TAPIR (Targeted Activation of Protein Translation), a CRISPR-based approach to elevate rRNA-levels by inducing 47S rDNA transcription. TAPIR increased nucleolar size and enhanced protein synthesis, even in rapidly proliferating cells. In neural stem cells, elevated translation promoted self-renewal and proliferation in vitro and in vivo. Furthermore, TAPIR enabled the modeling and partial rescue of associated disease phenotypes. Our findings revealed that rRNA-levels directly regulate translational output and that protein synthesis capacity can act as a key determinant of mammalian stem cell behavior.
    DOI:  https://doi.org/10.1126/science.aeh1348
  13. Cell. 2026 Jul 01. pii: S0092-8674(26)00700-2. [Epub ahead of print]
      Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.
    Keywords:  Alzheimer’s disease; DNA damage; DNA strand breaks; amyotrophic lateral sclerosis; frontotemporal dementia; genomic instability; mutation signature; ribonucleotide excision repair; somatic mutation; topoisomerase 1
    DOI:  https://doi.org/10.1016/j.cell.2026.06.013
  14. Nat Struct Mol Biol. 2026 Jun 30.
      Mutations in the ATRX chromatin remodeler confer a predisposition to a developmental genetic disorder and cancer, but how ATRX safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX-deficient cells. ATRX-CST synthetic lethality manifests following accumulation of telomeric G-rich single-stranded DNA (ssDNA), which results in telomere loss and cell death. Conversely, we attribute ATRX-9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show that ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable, requiring its ATPase activity and PIP-box, respectively. We also show that such roles protecting genome stability are largely independent of the ATRX-DAXX interaction. Collectively, our data show that functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.
    DOI:  https://doi.org/10.1038/s41594-026-01827-2
  15. Science. 2026 Jul 02. eaeh2300
      Mammalian cells frequently enter mitosis before DNA replication has finished, necessitating the rapid processing of unreplicated loci to facilitate chromosome segregation. The TRAIP ubiquitin ligase induces replisome disassembly during mitosis, triggering the cleavage of DNA replication forks. Until now, the mechanisms that regulate TRAIP and process cleaved DNA replication forks were unclear. Here we show that the TTF2 ATPase is a new type of phospho-receptor that binds a conserved phosphorylation site on TRAIP during mitosis. TTF2 couples phosphorylated TRAIP to DNA polymerase epsilon (Pol ε) in the replisome, leading TRAIP to ubiquitylate the CDC45-MCM-GINS (CMG) helicase. This triggers mitotic replisome disassembly, and a repair pathway that produces sister-chromatid exchanges, supporting a model for how fork cleavage promotes the segregation of under-replicated loci in mammalian cells.
    DOI:  https://doi.org/10.1126/science.aeh2300
  16. Nat Aging. 2026 Jul 02.
      Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11ra1 reduces the proportion of activated fibroblasts. Furthermore, administration of siIl11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging.
    DOI:  https://doi.org/10.1038/s43587-026-01159-2
  17. Cell Chem Biol. 2026 Jun 30. pii: S2451-9456(26)00194-7. [Epub ahead of print]
      Mitochondrial lipid peroxidation is a major component of oxidative damage and is also thought to contribute to ferroptosis. Lipid peroxidation is generally assessed from the accumulation of oxidized end products, such as 4-hydroxynonenal (HNE). However, these report on damage throughout the cell and are affected by changes in how oxidized phospholipids are turned over. To overcome these constraints, we developed MitoLiPOX, a mitochondria-targeted mass spectrometry probe. Mitochondria targeting and detection sensitivity were achieved by incorporating a lipophilic triphenylphosphonium cation. Responsiveness to lipid peroxidation was brought about by building in a bis-allylic carbon-hydrogen bond mimic that, upon oxidation and processing, generated a single product, MitoLiPOX-OH. LC-MS/MS quantification of MitoLiPOX-OH followed by normalization to the amount of MitoLiPOX present enabled ratiometric quantification of mitochondrial lipid peroxidation. We then used MitoLiPOX to assess mitochondrial lipid peroxidation during ferroptosis in vitro and in zebrafish in vivo.
    Keywords:  exomarker; lipid peroxidation, ferroptosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.chembiol.2026.05.015
  18. Curr Biol. 2026 Jul 01. pii: S0960-9822(26)00723-2. [Epub ahead of print]
      The actomyosin cortex displays diverse dynamic behaviors that drive essential cellular processes. Myosin dynamics are often modulated by small GTPases and their regulators, including GAPs and GEFs, which provide spatio-temporal control for myosin activity. Drosophila neural stem cells, known as neuroblasts, polarize and divide asymmetrically to generate a large self-renewing stem cell and a smaller differentiating progenitor. During the neuroblast cell cycle, pulsatile contractions followed by a series of actomyosin flows occur at highly specific times and subcellular locations. The regulation and physiological relevance of the contractions and many of these flows remain incompletely understood. Here, we systematically analyze the localization of RhoGAPs and RhoGEFs throughout the neuroblast cell cycle and identify a dual role for the ARHGAP19 homolog RhoGAP54D in regulating myosin dynamics. First, during interphase and metaphase, cytoplasmic RhoGAP54D suppresses pulsatile cortical contractions. These contractions are transiently permitted during prophase, when RhoGAP54D is sequestered through nucleoporin-mediated nuclear import. RhoGAP54D also promotes daughter cell size asymmetry, likely through its anaphase-specific cortical recruitment at the apical pole (unique among thus far known polarized proteins in neuroblasts), where it locally depletes myosin and promotes membrane expansion. We further show that PsGEF functions in neuroblasts, likely as a scaffold rather than as a canonical GEF, to mediate anaphase-specific recruitment of RhoGAP54D. PsGEF itself is recruited downstream of the polarity proteins Par3 and Pins, linking cortical polarity to local RhoGAP54D activity and thereby promoting daughter cell size asymmetry during asymmetric neuroblast division.
    Keywords:  Pins; RhoGAPs; RhoGEFs; asymmetric cell division; cell polarity; cell size asymmetry; flows; myosin; pulsatile contraction; stem cells
    DOI:  https://doi.org/10.1016/j.cub.2026.06.012
  19. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2612800123
      The NLRP3 inflammasome is central to host defense and sterile inflammation and forms condensates at the microtubule-organizing center (also known as the centrosome), although the mechanisms regulating this process remain unclear. Here we define a functional relationship among microtubule transport, the centrosomal kinase NEK7, priming, and NLRP3 abundance. We show that microtubule-dependent transport is required for NEK7-dependent NLRP3 activation and promotes NEK7 to the pericentriolar material (PCM). Microtubules, priming, and NEK7 synergistically converge on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and inflammasome assembly. Elevated NLRP3 expression compensates for limited PCM abundance, rendering K+ efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. By contrast, NLRP3 overexpression only partially bypasses NEK7 dependence in response to the K+ efflux-independent stimulus imiquimod, likely due to its activation of a non-trans-Golgi network pool of NLRP3 that is quantitatively limited. Together, these findings define a conserved spatial mechanism in which microtubule transport, NEK7 localization, priming, and NLRP3 abundance integrate at the PCM to establish the activation threshold and magnitude of NLRP3 inflammasome signaling across species and stimuli.
    Keywords:  MTOC; NEK7; NLRP3 inflammasome; innate immunity; pericentriolar material
    DOI:  https://doi.org/10.1073/pnas.2612800123
  20. J Cell Biol. 2026 Aug 03. pii: e202509039. [Epub ahead of print]225(8):
      Actin's transition from monomers (G-actin) to polymers (F-actin) and then into bundled and branched networks underlies many cellular and system functions. Yet, how these networks are dynamically assembled and disassembled is incompletely understood-including why F-actin is often simultaneously and redundantly bundled by different proteins. Here, we focus on fascin and espin, two bundlers that often coexist and robustly bundle F-actin. We find that they synergistically bundle F-actin compared to equal amounts of each one alone. However, we show that bundles containing these two proteins are robustly destabilized by a synergism between Mical and cofilin, indicating mechanisms of how complex bundles are disassembled and remodeled. Yet, our results also reveal that together fascin and espin protect F-actin from this disassembly more effectively than each one alone-including to regulate F-actin disassembly and cellular remodeling in vivo. These findings reveal mechanisms for assembling and disassembling complex networks of bundled F-actin, including a synergism between different bundlers and disassemblers in these processes.
    DOI:  https://doi.org/10.1083/jcb.202509039
  21. Nature. 2026 Jul 01.
      Replication stress poses a major threat to genome integrity, yet how higher-order chromatin organization contributes to replication fork protection remains unclear1,2. Here we show that replication stress induces the formation of transient chromatin loops that enclose de novo heterochromatin-enriched stalled replication forks3. Stressed forks preferentially stall at convergent CTCF motifs, triggering stress-dependent CTCF enrichment that constrains loop extrusion and stabilizes these structures. Loop stabilization requires both CTCF anchoring and G9a-dependent heterochromatin (trimethylation of Lys9 of histone H3 (H3K9me3)) deposition on nascent DNA within the loop body. These loops function as protective scaffolds that shield stalled and reversed forks from degradation by multiple nucleases. By contrast, combined loss of stress-induced heterochromatin and CTCF enrichment destabilizes the loop scaffold, exposing multiple entry points for nucleolytic attack and resulting in extensive nascent-strand degradation through mechanisms distinct from classical fork-reversal-dependent pathways. This protective architecture is similarly critical in BRCA2-deficient cells, in which replication-stress-associated loops predominantly safeguard replication initiation zones, while nascent DNA outside these loops undergoes massive degradation and remains highly susceptible to mutations. Our study elucidates the fundamental role of replication-stress-induced three-dimensional genome reorganization in preserving replication fork stability, thereby mitigating mutagenesis and genomic instability.
    DOI:  https://doi.org/10.1038/s41586-026-10695-1
  22. Nat Commun. 2026 Jul 03. pii: 5844. [Epub ahead of print]17(1):
      In eukaryotes, meters of DNA are packaged into micrometer scale nuclei. Nucleosomes, as the major organizational unit, have been extensively studied in vitro, yet the elaborate 3D structure of chromatin inside cells and its distinct oligo-nucleosome arrangements remain poorly resolved. Here, we combine cryo-electron tomography with template matching, subtomogram averaging and molecular simulations to visualize nucleosomes and chromatin structure inside human cells. We confidently assign individual nucleosomes and report their in-situ structure at secondary structure resolution. By predicting the paths of linker DNA, we identify oligo-nucleosome arrangements and uncover higher-order chromatin structures in situ, including a 37-nm wide, elongated but non-fibrous arrangement. In situ structural biology thus reveals the molecular chromatin organization inside cells and sets the stage for 3D genomics.
    DOI:  https://doi.org/10.1038/s41467-026-75087-5
  23. Cell Rep. 2026 Jul 02. pii: S2211-1247(26)00715-1. [Epub ahead of print]45(7): 117637
      Human placental development is essential for pregnancy but remains mechanistically obscure because early post-implantation tissues are inaccessible. Here, we establish a rotational trophoblast organoid platform that recapitulates selected morphogenetic features shared with early trophoblast development, including spontaneous syncytiotrophoblast (STB) differentiation and progressive fusion of lacuna-like cavities. Integrated multi-omic analyses associate this architecture with a biomechanical balance between attenuated YAP activity and peripheral CREB activation, with GCM1 stabilizing trophoblast chromatin state and POLQ supporting genome maintenance in rapidly expanding progenitors. The organoids display autonomous endocrine activity, induce an endometrial epithelial state consistent with metabolic activation, and can generate extravillous trophoblasts that directionally engage endothelial networks. This platform provides a framework for studying placental morphogenesis and tissue interactions relevant to pregnancy complications.
    Keywords:  CP: developmental biology; CP: stem cell research; biomechanics; extravillous trophoblast; maternal-fetal interface; placental morphogenesis; syncytiotrophoblast; trophoblast organoids
    DOI:  https://doi.org/10.1016/j.celrep.2026.117637
  24. Nat Commun. 2026 Jun 30.
      Centriole biogenesis is viewed as a template-free physical transformation where a cartwheel scaffold emerges to guide centriole growth and subsequently disassembles; however, the mechanism underlying cartwheel dynamics remains obscure. Here, we identify the intrinsically disordered protein (IDP) ALMS1 as an external cofactor that causes a seed for cartwheel formation without itself incorporating into the seed structure. The cartwheel seed (CS) forms during interphase as dense composites of CEP152/CEP63 complexes, adopting a nanoscale ring from which the cartwheel grows. Upon mitotic entry, CSs undergo disassembly involving ALMS1, correlating with cartwheel disassembly. Hypomorph ALMS1 mutations trigger aberrant cartwheel expansion-shedding from its own grown centriole, in turn forming ectopic centrioles, leading to perpetual reciprocal amplification. ALMS1 depletion aborts CS assembly, whereas reintroducing ALMS1 initializes biogenesis anew, creating diverse yet heritable centriole architectures that evolve through selection, instead of generating a single canonical form. These findings suggest that centriole biogenesis relies on adaptable transformation cues extrinsic to constituents, propagating via IDP-mediated CS assembly-disassembly cycles, we conjecture, involving memory.
    DOI:  https://doi.org/10.1038/s41467-026-74821-3
  25. Res Sq. 2026 Jun 25. pii: rs.3.rs-10046174. [Epub ahead of print]
      A general puzzle in stem-cell and ageing biology is why a few cellular clones come to dominate an ageing tissue while otherwise similar neighbours do not, a fate that the average transcriptional state of a cell predicts poorly. Here we ask whether the variability between sister cells of a clone, rather than their transcriptional state, is the property that predicts ageing-associated clonal selection, using the haematopoietic stem cell (HSC) as a tractable test case. We combine heritable lineage tracing with single-cell RNA sequencing across heterochronic and homochronic transplantation models to link early transcriptional states of individual HSC clones to their long-term functional output in vivo. To quantify transcriptional heterogeneity at clonal resolution, we developed a computational framework (scCloneVar) that estimates mean-adjusted gene expression variance and identifies differentially variable genes (DVG). We found that ageing increases transcriptional heterogeneity at both the cellular and clonal levels, reflected by elevated variability in gene expression programs that regulate stem cell activity. We observe polyclonal expansion of HSC independently of the age of the host or the donor mice; however, individual clones in heterochronic transplantations show reduced self-renewal and fitness compared to sister clones in homochronic transplantations, indicating better adaptation of HSC clones in age-matched microenvironments. Strikingly, transcriptional features measured prior to transplantation predict clonal self-renewal at later time points, with transcriptional variability, captured by DVG, providing predictive power beyond that captured by mean expression differences. DVG-associated programs are conserved across mouse and human HSC, are established by middle age, and are enriched in pathways relevant to clonal haematopoiesis and myeloid malignancy risk. Together, our findings support a model in which ageing expands transcriptional heterogeneity that tracks with subsequent clonal selection, rendering clonal fate partially predictable from early cellular states.
    DOI:  https://doi.org/10.21203/rs.3.rs-10046174/v1
  26. Nat Commun. 2026 Jul 01.
      Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.
    DOI:  https://doi.org/10.1038/s41467-026-74786-3
  27. Nat Genet. 2026 Jun 30.
      The developmental history of a cell fundamentally defines its identity and function. Recent advances in cell lineage tracing now enable high-resolution reconstruction of cellular ancestries in vivo, illuminating how lineage dictates fate in health and disease. This Review highlights recently developed tools, ranging from refined recombinase systems to advanced synthetic and natural barcoding approaches, that facilitate the investigation of pathological lineage programs in cancer, cardiovascular disease and aging. Moving forward, integrating permanent lineage records with single-cell multi-omics promises to provide a unified framework to decode how a cell's past shapes its present state and future potential, heralding a new era for precision medicine.
    DOI:  https://doi.org/10.1038/s41588-026-02628-5
  28. Nat Commun. 2026 Jul 01.
      Transposable elements (TEs) are DNA sequences able to create copies of themselves within the genome. TEs have been shown to act as cis-regulatory elements and be co-opted in the human genome. Thus, their impact might come from their relationship with the epigenome. However, a systematic analysis that relates TEs with chromatin histone marks across human cell types remains lacking. Here we leverage a dataset from the International Human Epigenome Consortium featuring 4867 uniformly processed ChIP-seq experiments for 6 histone marks across 47 cell types and show that TEs have drastically different enrichments levels across histone marks. We find that TEs are generally depleted but enriched in select contexts such as L1s in H3K9me3 histone mark. Notably, we identify 456 cell type-histone-TE triplets with strong cell-type specific enrichments and show that many of these triplets are associated with relevant biological processes.
    DOI:  https://doi.org/10.1038/s41467-026-74920-1
  29. Science. 2026 Jul 02. 393(6806): eadr3817
      Developing therapies and vaccines against integral membrane proteins is hindered by their extensive hydrophobic surfaces, which complicate production and structural analysis. Here, we describe a general deep learning-based design approach for solubilizing native membrane proteins while preserving their sequence, fold, active-site, and ligand-binding properties. Genetically encoded de novo protein WRAPs [water-soluble RFdiffused amphipathic proteins] surround the lipid-interacting hydrophobic surfaces, rendering them thermostable and water-soluble without the need for detergents. We design WRAPs for both monomeric and oligomeric beta-barrel outer membrane proteins and helical multipass transmembrane proteins. A 2.95-angstrom-resolution cryo-electron microscopy structure of WRAPed mycobacterial porin demonstrates that WRAPs can be used for the structural determination of membrane proteins in solution. As a step toward syphilis vaccine development, we generated soluble versions of Treponema pallidum antigens.
    DOI:  https://doi.org/10.1126/science.adr3817
  30. Nature. 2026 Jul 01.
      Synthetic mRNA therapeutics offer a versatile platform for treating diverse conditions, including cancer and infectious diseases. For delivery into cells, these mRNAs are encapsulated in lipid nanoparticles and commonly incorporate modified ribonucleotides to improve stability, enhance translation and mitigate immune recognition1. N1-Methylpseudouridine (m1Ψ) has become the industry standard for synthetic mRNAs owing to its effectiveness in promoting translation and reducing immunogenicity2. However, recent studies have shown that m1Ψ can compromise translational fidelity, leading to errors such as premature termination and ribosomal frameshifting3-5. Here we reveal N4-acetylcytidine (ac4C) as a functionally distinct alternative to m1Ψ. Across cultured cell lines, primary human monocyte-derived dendritic cells and mouse liver, ac4C suppressed inflammatory responses as effectively as m1Ψ while driving higher protein yields. Single-molecule imaging of translation revealed broadly similar ribosome densities per mRNA for ac4C-modified and m1Ψ-modified transcripts. However, translation elongation with m1Ψ-modified mRNA was nearly twofold slower than with ac4C, which resulted in reduced protein output and increased ribosome collisions that further limited protein production through the engagement of quality-control pathways and +1 frameshifting. These findings underscore the importance of context in designing therapeutic mRNAs and position the translation elongation rate as a key determinant of the efficacy of modified ribonucleotides.
    DOI:  https://doi.org/10.1038/s41586-026-10729-8
  31. Science. 2026 Jul 02. eaeh1834
      Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: the ATPase TTF2 is recruited to the replisome, where its noncatalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.
    DOI:  https://doi.org/10.1126/science.aeh1834
  32. Nat Cell Biol. 2026 Jul 02.
      Lipid-binding domains, traditionally isolated from natural proteins, are essential tools for probing membrane lipid dynamics and specialized cellular compartments. Despite diverse applications, a general strategy for their engineering remains elusive. Here we present a robust and high-throughput method for monitoring protein-lipid interactions, named the cell surface liposome binding (CLiB) assay. Using the assay, we conducted directed evolution of the PX domain from SnxA, isolating high-affinity variants specific for phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Combining the CLiB assay with next-generation sequencing enabled parallel analysis of >6,000 clones, comprehensively identifying key residues critical for lipid binding. An engineered variant, PX-SnxAGV, functioned as a lipid biosensor in yeast and mammalian cells, visualizing PI(3,5)P2-enriched membrane subdomains upon hyperosmotic shock and during microautophagy, thereby suggesting localized PI(3,5)P2 synthesis within spatially restricted regions. This study provides a framework for on-demand generation of lipid-binding probes, facilitating the discovery of membrane compartments characterized by unique lipid compositions.
    DOI:  https://doi.org/10.1038/s41556-026-01996-8
  33. Nat Chem Biol. 2026 Jun 29.
      The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.
    DOI:  https://doi.org/10.1038/s41589-026-02256-4
  34. Nature. 2026 Jul 01.
      Cells must rapidly counteract heat stress-induced hyperfluidization of the plasma membrane to prevent membrane damage1,2, yet how cells achieve such early protection remains unknown. Here we show that in rice (Oryza sativa), the P4-ATPase OsALA5, together with its β-subunit OsALIS2, mediates a heat-responsive flipping of saturated phosphatidylcholines that rapidly stabilizes plasma membrane fluidity. Using leaflet-resolved lipidomics and complementary transport assays, we demonstrate that heat exposure induces a minute-timescale shift in OsALA5 transport activity that leads to selective enrichment of saturated phosphatidylcholines in the cytoplasmic plasma membrane leaflet. This OsALA5-mediated saturated phosphatidylcholine flipping prevents plasma membrane hyperfluidization upon heat stress, thus mitigating ion leakage and cell death. Our analyses of OsALA5 orthologues in Arabidopsis thaliana and yeast support functional conservation of a rapid heat-associated response within a subset of plasma membrane-localized, phosphatidylcholine-transporting P4-ATPases. We identified a rare haplotype of OsALA5 that confers both heat tolerance and yield stability in multi-year, multi-location field trials. Thus, beyond identifying this P4-ATPase-mediated flipping of saturated phosphatidylcholines in response to heat stress and providing genetic resources to advance breeding of heat-tolerant crops, our study reveals how cells counteract heat stress-driven plasma membrane hyperfluidization at an earlier stage than the previously known transcription-dependent lipid remodelling response.
    DOI:  https://doi.org/10.1038/s41586-026-10726-x