bims-ginsta Biomed News
on Genome instability
Issue of 2026–02–08
47 papers selected by
Jinrong Hu, National University of Singapore
  1. Mitigating xenogeneic barriers to chimerism through Cas13-induced host attenuation.
  2. SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
  3. Injury-induced electrochemical coupling triggers organ growth.
  4. Transient histone deacetylase inhibition induces cellular memory of gene expression and 3D genome folding.
  5. Microtubule depolymerization at kinetochores restricts anaphase spindle elongation.
  6. Zebrafish macrophages convert physical wound signals into rapid vascular permeabilization.
  7. Cellular quiescence uncouples the proteome from the transcriptome in neural stem cells.
  8. Shifting paradigms in tissue stem cell biology: Insights from the intestine.
  9. Single-molecule dynamics of the TRiC chaperonin system in vivo.
  10. M18BP1 valency and a distributed interaction footprint determine epigenetic centromere specification in humans.
  11. Eg5 activity and density-driven bundling organize the human metaphase mitotic spindle independently of spindle bipolarity.
  12. Oriented cell divisions induce basal progenitors and regulate neural expansion across tissues and species.
  13. ER remodelling is a feature of ageing and depends on ER-phagy.
  14. Regulatory grammar in human promoters uncovered by MPRA-based deep learning.
  15. Precise control of transcription condensates across S phase balances linker histone expression with DNA replication, ensuring genome stability.
  16. Bacterial immune activation via supramolecular assembly with phage triggers.
  17. Harnessing glucocorticoid receptor antagonism to enhance the efficacy of cardiac regenerative growth factors and cytokines.
  18. RCC1 depletion drives protein transport defects and rupture in micronuclei.
  19. Interface-Resolved Proteomics of Cell-Cell Membranes Reveals Early Spatial Polarity in a Vertebrate Embryo.
  20. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  21. Asymmetric division in a two-cell-like state rejuvenates embryonic stem cells.
  22. Organizers in a dish: Modeling human CNS morphogenesis.
  23. Proteostasis of organelles in aging and disease.
  24. Regulation of mRNA decay and translation during the mammalian cell cycle.
  25. Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries.
  26. Age-Driven Lipid Remodeling Activates Lysosome-Mediated Plasma Membrane Repair.
  27. Hybrid female sterility due to cohesin protection errors in mouse oocytes.
  28. Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.
  29. The microtubule GTP-tubulin cap size is modulated during cell division.
  30. The desmoglein 2 interactome in primary neonatal cardiomyocytes.
  31. Hypoxia-inducible factor signaling regulates embryonic interneuron development, GRIN2B expression and adult cortical function.
  32. Acute priming using elevated fluid viscosity recovers ' young-like ' single-cell surveillance behaviors in aged human T cells.
  33. Nanog mediated control of TBX3-GATA6 circuitry in primitive endoderm differentiation of mESCs.
  34. Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency.
  35. Regulation of STING activation by phosphoinositide and cholesterol.
  36. Variable partition of non-homogeneous ooplasm sets the stage for divergent potency of 2-cell stage blastomeres.
  37. Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction.
  38. Programmable genome editing in human cells using RNA-guided bridge recombinases.
  39. Fork Reversal Safeguards Epigenetic Inheritance During Replication Stress.
  40. PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling.
  41. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  42. CaMKII nucleates an osmotic protein supercomplex to induce cellular bleb expansion.
  43. Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
  44. CCL3 is produced by aged neutrophils across cancers and promotes tumor growth.
  45. TRPM7 Deficiency Protects Against Myocardial Ischemia-Reperfusion Injury by Regulating Intracellular Zn2+ Homeostasis.
  46. Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity.
  47. A pore-forming antiphage defence is activated by oligomeric phage proteins.
  1. Dev Cell. 2026 Jan 29. pii: S1534-5807(26)00001-8. [Epub ahead of print]
    Mitigating xenogeneic barriers to chimerism through Cas13-induced host attenuation.
    Bingbing He, Shijian Lv, Leijie Li, Lin Zhang, Yingying Hu, Daiji Okamura, Jia Huang, Jun Wu.
      Interspecies chimeras serve as valuable models for studying mammalian development and advancing strategies for organ generation. However, xenogeneic barriers-such as mismatched developmental timing, cell adhesion differences, and intercellular competition-restrict the contribution of human pluripotent stem cells (hPSCs) to non-human embryos. Here, we report that Cas13 collateral RNA cleavage can be harnessed to selectively attenuate host cell proliferation to boost donor cell chimerism. In mouse epiblast stem cells (mEpiSCs), Cas13 activation degraded target RNAs and bystander transcripts, producing a reversible decrease in cell proliferation while preserving pluripotency. In co-culture, selective attenuation of mEpiSCs enhanced the competitiveness and survival of wild-type mEpiSCs and hPSCs in both intra- and interspecies settings. In vivo, blastocysts engineered with inducible Cas13 (iCas13) showed increased donor cell integration in chimeric embryos and adult tissues. Together, these findings demonstrate a generalizable strategy to modulate donor-host dynamics and mitigate xenogeneic barriers to interspecies organogenesis.
    Keywords:  Cas13; blastocyst complementation; cell competition; chimeras; collateral cleavage; embryonic stem cells; induced pluripotent stem cells; xenogeneic barriers
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.001
  2. Nat Metab. 2026 Feb 06.
    SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
    Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.
      Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.
    DOI:  https://doi.org/10.1038/s42255-026-01455-6
  3. Sci Adv. 2026 Feb 06. 12(6): eaec0687
    Injury-induced electrochemical coupling triggers organ growth.
    Jinghui Liu, Elisa Nerli, Charlie Duclut, Amit S Vishen, Naomi Berbee, Sylvia Kaufmann, Cesar Ponce, Aristides B Arrenberg, Frank Jülicher, Rita Mateus.
      Organ injury triggers nonneuronal electric currents essential for regeneration. However, the mechanisms by which electrical signals are generated, sensed, and transmitted upon damage to promote organ growth remain unclear. Here, we uncover that organ repair relies on dynamic electrochemical coupling between membrane potential depolarization and intracellular signaling, essential to activate cell proliferation. By subsecond live imaging of locally injured zebrafish larval fins, we identify events across time and space: a millisecond, long-range, membrane depolarization gradient, followed by second-persistent intracellular calcium responses. In the subsequent hour, voltage sensing phosphatase senses the injury-driven membrane potential change and autonomously translates the electric signal intracellularly, promoting tissue-wide cell proliferation. Connecting these dynamics with an electrodiffusive model showed that ionic fluxes and electric potential become coupled in the fin's interstitial space, enabling organ-wide signal spreading. Our work reveals the coupling between fast electrical signals and slower intracellular signaling, ensuring complete organ recovery.
    DOI:  https://doi.org/10.1126/sciadv.aec0687
  4. Nat Genet. 2026 Feb 04.
    Transient histone deacetylase inhibition induces cellular memory of gene expression and 3D genome folding.
    Flora Paldi, Michael-Florian Szalay, Solène Dufau, Marco Di Stefano, Hadrien Reboul, Daniel Jost, Frédéric Bantignies, Giacomo Cavalli.
      Epigenetic memory enables the propagation of gene expression patterns following transient stimuli. Although three-dimensional chromatin organization is emerging as a key regulator of genome function, it is unknown whether it contributes to cellular memory. Here we establish that acute perturbation of the epigenome can induce cellular memory of gene expression in mouse embryonic stem cells. We uncover how a pulse of histone deacetylase inhibition translates to changes in transcription, histone modifications and genome folding. While most epigenomic and transcriptional changes are initially reversed once the perturbation is removed, some loci remain transcriptionally deregulated and genome architecture partially maintains its perturbed conformation. Consequently, a second pulse of transient hyperacetylation induces stronger memory of transcriptional deregulation. Using ultradeep Micro-C, we associate memory of gene expression with repressive Polycomb-mediated chromatin topology. These results demonstrate how cells can record transient stresses in their genome architecture, thereby enabling an enhanced response to subsequent perturbations.
    DOI:  https://doi.org/10.1038/s41588-025-02489-4
  5. Nat Chem Biol. 2026 Jan 30.
    Microtubule depolymerization at kinetochores restricts anaphase spindle elongation.
    Geng-Yuan Chen, Changfeng Deng, David M Chenoweth, Michael A Lampson.
      Anaphase chromosome segregation depends on forces exerted by spindle microtubules. Current models propose two force-generating mechanisms: kinetochore-microtubule (kMT) depolymerization pulls chromosomes toward spindle poles (anaphase A), while antiparallel microtubule sliding in the central spindle further separates sister chromosomes by elongating the spindle (anaphase B). Experimental evidence in cells supports the sliding mechanism but contributions of the depolymerization mechanism remain unclear. We show that kMT depolymerization limits spindle elongation rather than moving chromosomes apart. We developed a chemical optogenetic approach to recruit microtubule depolymerases to kinetochores at anaphase onset, thereby increasing kMT depolymerization rates without perturbing earlier stages of mitosis. We find that increased depolymerization slows the velocity at which spindle poles move apart without changing kinetochore separation velocities. Our findings support a model in which kinetochores selectively couple to central spindle microtubules parallel to their kMTs, such that antiparallel sliding drives chromosome segregation while kMT depolymerization pulls poles inward.
    DOI:  https://doi.org/10.1038/s41589-026-02143-y
  6. Nat Commun. 2026 Feb 06.
    Zebrafish macrophages convert physical wound signals into rapid vascular permeabilization.
    Zaza Gelashvili, Zhouyang Shen, Yanan Ma, Mark Jelcic, Philipp Niethammer.
      Blood vessels near injury sites rapidly dilate, become permeable, and release serum and leukocytes into the wounded tissue to support healing and regeneration. How the vasculature senses distant homeostatic tissue perturbations within seconds-to-minutes remains incompletely understood. Using high-speed imaging of live zebrafish larvae, we monitor two hallmark vascular responses to injury: vessel dilation and serum exudation. By genetic, pharmacologic, and osmotic perturbation along with leukocyte depletion, we show that the cPla2 nuclear membrane mechanotransduction pathway converts a ~ 50 μm/s osmotic wound signal into rapid vessel-permeabilization via perivascular macrophages, 5-lipoxygenase (Alox5a), and leukotriene A4 hydrolase (Lta4h). By revealing a previously undescribed physiological function of nuclear membrane mechanotransduction, we provide real-time insights into the long-range communication of wounds and blood vessels in intact tissue.
    DOI:  https://doi.org/10.1038/s41467-026-68520-2
  7. EMBO J. 2026 Feb 05.
    Cellular quiescence uncouples the proteome from the transcriptome in neural stem cells.
    Alice Rossi, Antoine Coum, Manon Madelenat, Lachlan Harris, Stephanie Strohbuecker, Andrea Chai, Hania Fiaz, Rita Chaouni, Peter Faull, Neve Costello Heaven, William Grey, Dominique Bonnet, Fursham Hamid, Eugene V Makeyev, Ambrosius P Snijders, Gavin Kelly, François Guillemot, Rita Sousa-Nunes.
      Quiescence is a cellular state defined by reversible cell-cycle arrest and diminished biosynthesis, particularly of nucleic acids and proteins. These features protect stem cells from proliferation-induced mutations, self-renewal exhaustion, and environmental insults. Despite relevance to development, tissue homeostasis and cancer, we lack understanding about many aspects of quiescence regulation and unique molecular markers for this state. Here, we employ Drosophila and mammalian neural stem cells to reveal that a mechanism for inhibiting translation in quiescence is selective nuclear enrichment of transcripts from more than 2000 genes, resulting in uncoupling between transcriptome and proteome. Three-quarters of these transcripts become increasingly nuclear as quiescence deepens, and nuclear bias predicts protein downregulation for the large majority of targets. We find that a large fraction of nuclear-biased transcripts present GA-rich multivalency and relocalise to nuclear speckles with increased SR-protein enrichment, which we propose promotes their nuclear retention. Finally, our evidence for differing degrees of transcript processing in steady-state quiescence suggests regulated sequential deployment of factors towards cell-cycle reentry. In brief, we present a previously unappreciated layer of post-transcriptional control of quiescence.
    Keywords:  Neural Stem Cells; Nucleocytoplasmic Partitioning; Nucleoporins; Quiescence; RNA Localisation
    DOI:  https://doi.org/10.1038/s44318-026-00693-4
  8. Cell. 2026 Feb 05. pii: S0092-8674(25)01438-2. [Epub ahead of print]189(3): 706-724
    Shifting paradigms in tissue stem cell biology: Insights from the intestine.
    Hans Clevers.
      The small intestinal epithelium represents the most rapidly self-renewing adult mammalian tissue, with a turnover time of 1-2 weeks. It contains ∼12 easily recognizable cell types with a wide diversity of functions, including nutrient absorption, mucus production, antimicrobial defense, and the regulation of metabolism by incretins like Glp1. The simple and repetitive crypt-villus architecture allows for easily interpretable experimentation in transgenic mice in vivo, while the human stem cell hierarchy is experimentally accessible in epithelial organoids in vitro. This review aims to comprehensively describe the design, the cellular constituents, and the molecular regulation of crypt-villus epithelial self-renewal. More generally, it highlights deviations from commonly held views on tissue stem cell biology: gut stem cells divide continually and symmetrically. They can be expanded indefinitely in vitro, while the plasticity of daughter cells can recreate stem cells during regeneration.
    DOI:  https://doi.org/10.1016/j.cell.2025.12.025
  9. Nature. 2026 Feb 04.
    Single-molecule dynamics of the TRiC chaperonin system in vivo.
    Rongqin Li, Niko Dalheimer, Martin B D Müller, F Ulrich Hartl.
      The essential chaperonin T-complex protein ring complex (TRiC) (also known as chaperonin containing TCP-1 (CCT)) mediates protein folding in cooperation with the co-chaperone prefoldin (PFD)1-5. In vitro experiments have shown that the cylindrical TRiC complex facilitates folding through ATP-regulated client protein encapsulation6-9. However, the functional dynamics of the chaperonin system in vivo remain unexplored. Here we developed single-particle tracking in human cells to monitor the interactions of TRiC-PFD with newly synthesized proteins. Both chaperones engaged nascent polypeptides repeatedly in brief probing events typically lasting around one second, with PFD recruiting TRiC. As shown with the chaperonin client actin8, the co-translational interactions of PFD and TRiC increased in frequency and lifetime during chain elongation. Close to translation termination, PFD bound for several seconds, facilitating TRiC recruitment for post-translational folding involving multiple reaction cycles of around 2.5 s. Notably, the lifetimes of TRiC interactions with a folding-defective actin mutant were markedly prolonged, indicating that client conformational properties modulate TRiC function. Mutant actin continued cycling on TRiC until it was targeted for degradation. TRiC often remained confined near its client protein between successive binding cycles, suggesting that the chaperonin machinery operates within a localized 'protective zone' in which free diffusion is restricted. Together, these findings offer detailed insight into the single-molecule dynamics and supramolecular organization of the chaperonin system in the cellular environment.
    DOI:  https://doi.org/10.1038/s41586-025-10073-3
  10. EMBO J. 2026 Feb 02.
    M18BP1 valency and a distributed interaction footprint determine epigenetic centromere specification in humans.
    Kai Walstein, Louisa Hill, Doro Vogt, Lina Oberste-Lehn, Petra Janning, Ingrid R Vetter, Dongqing Pan, Andrea Musacchio.
      The histone H3 variant CENP-A is considered an epigenetic landmark of centromeres. Its deposition reflects cell-cycle-regulated assembly of M18BP1, HJURP, and PLK1 on a divalent MIS18α/β scaffold. The localization determinants of this machinery remain poorly characterized. Here, we report that in human cells, artificial M18BP1 dimerization bypasses MIS18α/β, allowing the identification of at least four determinants of M18BP1 centromere localization. These include the SANTA domain, of which we report the first structure, as well as linear motifs in disordered neighboring regions, of which we characterize the interaction footprint on the CENP-A-associated 16-subunit constitutive centromere-associated network (CCAN). Our observations imply that M18BP1, after dimerization, is necessary and sufficient for centromere localization. Its cell-cycle-dependent dimerization on MIS18α/β promotes initial recognition of a multivalent centromeric assembly of old CENP-A and associated proteins, followed by cooption of PLK1 and HJURP and new CENP-A deposition. Our results shed new light on the determinants of centromere epigenetic inheritance in humans.
    Keywords:  CENP-A Loading; Cell Cycle; Centromere; Kinetochore; M18BP1
    DOI:  https://doi.org/10.1038/s44318-026-00698-z
  11. bioRxiv. 2026 Jan 16. pii: 2026.01.16.699769. [Epub ahead of print]
    Eg5 activity and density-driven bundling organize the human metaphase mitotic spindle independently of spindle bipolarity.
    William Conway, Daija Bobe, Vitaly Zimyanin, Gunar Fabig, Alex de Marco, Stefanie Redemann.
      The mitotic spindle segregates chromosomes through the coordinated actions of microtubules and molecular motors. Classic models propose that microtubules nucleate at spindle poles and grow inward to capture chromosomes; however, recent structural studies show that spindles contain short microtubules that do not span the distance between poles and chromosomes. It is unclear how these short microtubules assemble a bipolar spindle. Using cryo-electron tomography to map microtubule polarity in human metaphase spindles, we find that microtubules form locally antiparallel bundles with consistent 8 nm wall-to-wall spacing. We utilized motor perturbations and centriole depletion, which generated motor-active monopolar spindles, to reveal that the kinesin-5 motor Eg5 organizes local antiparallel overlap independently of spindle bipolarity. We found that bundles are organized by density-driven steric interactions rather than motor-mediated crosslinking. These findings support a self-organized, bottom-up model in which local microtubule-motor interactions within dense bundles generate forces that build the bipolar spindle, challenging pole-centric models.
    KEY FINDINGS: Microtubules in metaphase spindles organize in locally antiparallel bundles with consistent 8 nm wall-to-wall spacing.The Eg5 motor generates antiparallel microtubule overlap independently of spindle bipolarity.Microtubule spacing scales with density through steric interactions, not direct motor crosslinking.Dynein regulates microtubule density to control bundle architecture; balanced Eg5-dynein density regulation maintains spindle bipolarity.
    DOI:  https://doi.org/10.64898/2026.01.16.699769
  12. Sci Adv. 2026 Feb 06. 12(6): eadz6827
    Oriented cell divisions induce basal progenitors and regulate neural expansion across tissues and species.
    Benoit Boulan, Marine Lacomme, Amin Benadjal, Miranda Krueger, Ko Currie, Anna La Torre, Alain Chédotal, Michel Cayouette.
      Nervous system expansion relies on progenitor proliferation, yet its regional and evolutionary regulation is incompletely understood. While basally dividing progenitors are implicated in neocortical growth, their developmental origins and relevance beyond the cortex remain unclear. We show here that double inactivation of spindle orientation regulators GPSM2 and SAPCD2 in mice completely reorients progenitor divisions in both the neocortex and retina. This shift increases basal progenitors over sixfold in the neocortex and induces their ectopic emergence in the retina, resulting in extra cell layers and ~30% tissue enlargement. Single-cell RNA sequencing reveals that the induced basal progenitors in the cortex resemble human outer radial glia, and both cortical and retinal progenitors show altered Hippo signaling. Last, macaque and human retinas display twice as many reoriented divisions as the mouse and naturally contain basal progenitors. These findings show that division orientation is critical for regulating neural progenitor output and scaling tissue growth.
    DOI:  https://doi.org/10.1126/sciadv.adz6827
  13. Nat Cell Biol. 2026 Feb 02.
    ER remodelling is a feature of ageing and depends on ER-phagy.
    Eric K F Donahue, Nathaniel L Hepowit, Elizabeth M Ruark, Alexandra G Mulligan, Brennen Keuchel, Nicholas D Urban, Li Peng, Stedman Stephens, Derek J Johnson, Natalie S Wallace, Lauren P Jackson, Mark H Ellisman, Rafael Arrojo E Drigo, Andrew W Folkmann, Matthias C Truttmann, Jason A MacGurn, Kristopher Burkewitz.
      The endoplasmic reticulum (ER) comprises an array of subdomains, each defined by a characteristic structure and function. Although altered ER processes are linked to age-onset pathogenesis, it is unclear whether shifts in ER structure or dynamics underlie these functional changes. Here we establish ER structural and functional remodelling as a conserved feature of ageing across yeast, Caenorhabditis elegans and mammals. Focusing on C. elegans as the exemplar of metazoan ageing, we reveal striking age-related reductions in ER volume across diverse tissues and a morphological shift from rough sheets to tubular ER. This morphological transition corresponds with large-scale shifts in ER proteome composition from protein synthesis to lipid metabolism, a phenomenon conserved in mammalian tissues. We show that Atg8 and ULK1-dependent ER-phagy drives age-associated ER remodelling through tissue-specific factors, including the previously uncharacterized ER-phagy regulator TMEM-131 and the IRE-1-XBP-1 branch of the unfolded protein response. Providing support for a model where ER remodelling is adaptive, diverse lifespan-extending paradigms downscale and remodel ER morphology throughout life. Furthermore, mTOR-dependent lifespan extension in yeast and worms requires ER-phagy, indicating that ER remodelling is a proactive and protective response during ageing. These results reveal ER-phagy and ER dynamics as pronounced, underappreciated mechanisms of both normal ageing and age-delaying interventions.
    DOI:  https://doi.org/10.1038/s41556-025-01860-1
  14. Nature. 2026 Feb 04.
    Regulatory grammar in human promoters uncovered by MPRA-based deep learning.
    Lucía Barbadilla-Martínez, Noud Klaassen, Vinícius H Franceschini-Santos, Jérémie Breda, Hatice Yücel, Miguel Hernández-Quiles, Tijs van Lieshout, Carlos G Urzua Traslaviña, Minh Chau Luong Boi, Maryam Akbarzadeh, Celia Hermana-Garcia-Agullo, Sebastian Gregoricchio, Marcel de Haas, Roy Straver, Sarah Derks, Wilbert Zwart, Emile Voest, Lude Franke, Michiel Vermeulen, Jeroen de Ridder, Bas van Steensel.
      Promoters are the core regulatory elements of all genes. Their activity ensures the correct transcription level of each individual gene, which is essential for cellular homeostasis and responses to a wide range of signals. One of the major challenges in genomics is to build computational models that accurately predict genome-wide gene expression from the sequences of regulatory elements1. Here we present promoter activity regulatory model (PARM), a cell-type-specific deep-learning model trained on specially designed massively parallel reporter assays (MPRAs) that query human promoter sequences. PARM is experimentally and computationally lightweight so that cell-type-specific and condition-specific models can be generated that reliably predict autonomous promoter activity across the genome from the DNA sequence alone. PARM can also design purely synthetic strong promoters. We leveraged PARM to systematically identify binding sites of transcription factors that probably contribute to the activity of each natural human promoter and to detect the rewiring of these regulatory interactions after various stimuli to the cells. We also uncovered and experimentally confirmed substantial positional preferences of transcription factors that differ between activating and repressive regulatory functions and a complex grammar of motif-motif interactions. Our approach provides a highly economic strategy towards a deeper understanding of the dynamic regulation of human promoters by transcription factors.
    DOI:  https://doi.org/10.1038/s41586-025-10093-z
  15. Mol Cell. 2026 Feb 04. pii: S1097-2765(26)00025-0. [Epub ahead of print]
    Precise control of transcription condensates across S phase balances linker histone expression with DNA replication, ensuring genome stability.
    Carlos Origel Marmolejo, Celina Sanchez, Erin Helms, Melissa J McEvoy, Juyoung Lee, Marcel Werner, Paige Roberts, Stephan Hamperl, Joshua C Saldivar.
      Transcription condensates are liquid-like compartments where transcription factors, co-activators, and RNA polymerases are selectively enriched and regulate transcription initiation of associated genes. While the principles governing the enrichment of proteins within transcription condensates are being elucidated, mechanisms that coordinate condensate dynamics with other nuclear processes, such as DNA replication, have not been identified. We show in human cells that at the G1/S cell-cycle transition, large transcription condensates form at histone locus bodies (HLBs) in a cyclin-dependent kinase 1 and 2 (CDK1/2)-dependent manner. By mid-S phase, ataxia-telangiectasia and Rad3-related kinase (ATR) accumulates within HLBs and dissolves the associated condensates via its downstream effector, CHK1. Failure to dissolve condensates results in overexpression of linker H1 histones and nucleus-wide DNA damage. Moreover, an imbalance in the different linker histones accentuates DNA damage in ATR-CHK1-deficient cells. Our work reveals how transcription condensates are precisely controlled in the S phase to fine-tune gene activation and safeguard genome stability.
    Keywords:  ATR; DNA damage; MED1; genome stability; histone locus body; linker histones; transcription condensates
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.005
  16. Nature. 2026 Feb 04.
    Bacterial immune activation via supramolecular assembly with phage triggers.
    Tong Zhang, Yifei Lyu, Christina R Beck, Naseer Iqbal, Renee Barbosa, Alireza Ghanbarpour, Michael T Laub.
      Bacteria use diverse mechanisms to protect themselves against phages1-6. Many antiphage systems form large oligomeric complexes, but how oligomerization is regulated during phage infection remains mostly unknown7-12. Here we demonstrate that the bacterial immunity protein ring-activated zinc-finger RNase (RAZR) assembles into an active, 24-meric ring around the circumference of large ring structures formed by two unrelated phage proteins: a putative recombinase and a portal protein. Each multi-layered, megadalton-scale complex enables RAZR to cleave RNA nonspecifically to inhibit translation and restrict phage propagation. The recognition of unrelated phage proteins that form rings with similar diameters indicates that these proteins not only bind to RAZR but also enforce a geometry crucial to activation. The lack of large ring structures in the host probably prevents auto-immunity and RAZR activation before infection. The infection-triggered oligomerization of RAZR mirrors pathogen-induced oligomerization in eukaryotic innate immune complexes13, underscoring a common principle of immunity across biology.
    DOI:  https://doi.org/10.1038/s41586-025-10060-8
  17. Nat Cardiovasc Res. 2026 Feb 06.
    Harnessing glucocorticoid receptor antagonism to enhance the efficacy of cardiac regenerative growth factors and cytokines.
    Silvia Da Pra, Stefano Boriati, Carmen Miano, Francesca Sacchi, Christopher Batho, Chiara Bongiovanni, Irene Del Bono, Alla Aharonov, Nicola Pianca, Riccardo Tassinari, Rowda Dahir, Carlo Ventura, Mattia Lauriola, Eldad Tzahor, Catherine H Wilson, Gabriele D'Uva.
      Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.
    DOI:  https://doi.org/10.1038/s44161-026-00776-9
  18. J Cell Biol. 2026 Apr 06. pii: e202510133. [Epub ahead of print]225(4):
    RCC1 depletion drives protein transport defects and rupture in micronuclei.
    Molly G Zych, Maya Contreras, Anna E Mammel, Emily M Hatch.
      Micronuclei (MN), a hallmark of chromosome instability, frequently rupture, leading to protumorigenic consequences. MN rupture requires nuclear lamina defects, yet their underlying causes remain unclear. Here, we demonstrate that MN lamina gaps are linked to excessive MN growth resulting from impaired protein export. This export defect arises from reduced levels of the transport protein RCC1 in MN. Overexpressing RCC1 increases protein export and protects MN from rupture. Differences in RCC1 levels linked to chromatin state also explain why high euchromatin content increases the stability of small MN. Additional RCC1 loss in euchromatic MN results in impaired protein import. For these MN, increasing RCC1, directly or through increasing histone methylation, accelerates rupture. Our findings define a new model of MN rupture, where defects in protein export drives continuous MN growth causing nuclear lamina gaps that predispose MN to membrane rupture and where chromatin-specific features can alter rupture of small MN by further impairing nuclear transport.
    DOI:  https://doi.org/10.1083/jcb.202510133
  19. bioRxiv. 2026 Jan 12. pii: 2026.01.10.698819. [Epub ahead of print]
    Interface-Resolved Proteomics of Cell-Cell Membranes Reveals Early Spatial Polarity in a Vertebrate Embryo.
    Fei Zhou, Peter Nemes.
      Cell-cell membrane interfaces are central sites of adhesion, signaling, and polarity establishment, yet they have remained inaccessible to proteome-wide analysis as discrete analytical units. Here, we report an interface-resolved proteomics workflow that isolates intact intercellular membrane segments from single, identified blastomeres and quantitatively profiles their protein composition. Using a microdissection-enabled strategy combined with optimized mild-detergent extraction and high-sensitivity high-resolution mass spectrometry, we achieve deep coverage of low-input membrane samples, identifying ∼3,000 proteins per interface type, including over 100 annotated plasma-membrane proteins. Applying this approach to defined dorsal-dorsal, dorsal-ventral, and ventral-ventral cell-cell interfaces in a 16-cell chordate embryo model, Xenopus laevis , reveals reproducible, interface-specific proteomic signatures that distinguish neighboring membrane contacts along the primary body axis. Region-enriched proteins include regulators of membrane trafficking, signaling, cytoskeletal organization, and metabolic pathways linked to early dorsal-ventral patterning. These results demonstrate that intercellular membrane interfaces exhibit molecular polarity at early developmental stages and establish interface-resolved proteomics as a general strategy for mapping spatially organized biochemical activities at cell-cell contacts.
    DOI:  https://doi.org/10.64898/2026.01.10.698819
  20. Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.
    Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
  21. Cell Res. 2026 Feb 03.
    Asymmetric division in a two-cell-like state rejuvenates embryonic stem cells.
    Xinyi Wang, Hong Fu, Qingyang Sun, Boyan Huang, Zhe Xu, Xuzhao Zhai, Chuncao Deng, Laru Peng, Mengdan Zhang, Tianran Peng, An Gong, Jiasui Liu, Zhengzhi Zou, Guangjin Pan, Jiekai Chen, Guangming Wu, Man Zhang, Mingwei Min.
      A fundamental question in biology is whether all cells age. Embryonic stem cells (ESCs) defy the norm as rare normal cells capable of indefinite in vitro passage. However, the mechanisms underlying ESC lineage immortality remain unresolved. Using long-term live-cell imaging to follow the fates of single ESCs, we show that ESC lineage renewal is achieved through sporadic entry into a state characterized by the expression of two-cell embryo-specific markers. During this state, cells undergo asymmetric fate divisions, enriching accumulated DNA damage into one daughter lineage that is destined for elimination, while producing a second lineage that reverts to the pluripotent state. Importantly, the latter lineage exhibits signs of rejuvenation, including reduced DNA damage and enhanced chimeric efficiency. These findings underscore the crucial role of asymmetric cell division in maintaining the long-term health of the ESC lineage against mounting damage within individual cells and provide a potential model for studying cellular aging and rejuvenation in mammalian cells.
    DOI:  https://doi.org/10.1038/s41422-026-01221-z
  22. Dev Cell. 2026 Feb 04. pii: S1534-5807(26)00026-2. [Epub ahead of print]
    Organizers in a dish: Modeling human CNS morphogenesis.
    Georgina Miller, Daniel J Lloyd-Davies Sánchez, José González Martínez, Alexander W Justin, Madeline A Lancaster, Luca Guglielmi.
      The human brain stands out for the scale of cellular and morphological complexity across anterior-posterior domains. Modeling the entire neuraxis is therefore essential to comprehend human neural development and disease. Brain organoids commonly recapitulate anterior regions due to the propensity of neural progenitors to acquire telencephalic identities and self-organize into cortical layers. In the embryo, posterior brain patterning is orchestrated by organizers, signaling centers positioned at anterior-posterior locations that are rarely induced in vitro. Several strategies have been developed to reproduce organizer signals, employing small molecules and recombinant morphogens, thereby expanding the in vitro repertoire of human neural identities. Despite this, posterior models do not yet reproduce the morphological complexity of their in vivo counterparts. In this review, we discuss how this discrepancy may stem from the inability to recapitulate the spatiotemporal dynamics of organizer activity and how recent technologies can balance guided differentiation and self-organization, enhancing the fidelity of human brain organoid models.
    Keywords:  assembloids; bioengineering; gastruloids; neurodevelopment; organizers; organoids; patterning
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.003
  23. FEBS J. 2026 Feb 04.
    Proteostasis of organelles in aging and disease.
    Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.
      To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.
    Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules
    DOI:  https://doi.org/10.1111/febs.70439
  24. RNA. 2026 Feb 05. pii: rna.080910.125. [Epub ahead of print]
    Regulation of mRNA decay and translation during the mammalian cell cycle.
    Jimmy Ly, Ekaterina Khalizeva, Yi Fei Tao, Iain M Cheeseman.
      Cell cycle progression requires cells to continually remodel their gene expression programs as they transition through distinct functional states. Although transcriptional and post-translational mechanisms have long dominated our understanding of this regulation, recent work additionally highlights the essential contribution of cell cycle-specific mRNA decay and translational control. Across G1, S, G2, and mitosis, cells dynamically modulate global and transcript-specific mRNA stability and translation to coordinate processes including DNA replication, growth, checkpoint signaling, and chromosome segregation. Mitosis presents a particularly striking challenge: transcription is silenced, necessitating that cells rely on post-transcriptional mechanisms to sustain mitotic functions and preserve viability. In this review, we highlight how these coordinated layers of post-transcriptional regulation collectively contribute to cell cycle control.
    Keywords:  Cell cycle; Gene expression; Mitosis; Translation; mRNA decay
    DOI:  https://doi.org/10.1261/rna.080910.125
  25. Science. 2026 Feb 05. eads0960
    Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries.
    Yick Hin Ling, Chloe Liang, Sixiang Wang, Carl Wu.
      Eukaryotic gene expression is orchestrated by RNA polymerases (RNAPI, II, and III) and associated factors, yet their real-time dynamics remain obscure. Using single-molecule tracking in living yeast, we quantified the kinetics of 58 proteins encompassing three RNAP machineries. RNAPI and RNAPIII pre-initiation complexes (PICs) engage in long-lived chromatin interactions, contrasting with transient RNAPII PIC. We further report kinetics of RNAPII-associated factors for elongation, histone modification, C-terminal domain (CTD) modification, RNA processing, and termination. Many elongation factors show brief rather than persistent association, suggesting dynamic interactions with factor exchange, allowing a potential repertoire of regulatory events. CTD truncation reduces U1 snRNP residence time and intron retention in ribosomal protein genes, providing insights into co-transcriptional splicing. Our findings establish a framework of dynamic interactions of RNAP machineries.
    DOI:  https://doi.org/10.1126/science.ads0960
  26. Res Sq. 2026 Jan 20. pii: rs.3.rs-8607320. [Epub ahead of print]
    Age-Driven Lipid Remodeling Activates Lysosome-Mediated Plasma Membrane Repair.
    Dorota Skowronska-Krawczyk, Emily Tom, Fangyuan Gao, Carolina Franco, Adrian Wong, Nathan Kemmerer, Zichen Wang, Qianlan Xu, Yinyin Zhuang, Samuel Du, Grazyna Palczewska, Krzysztof Palczewski, Itay Budin, Xiaoyu Shi, Vera Bonilha, Johannes Schöneberg, Karl Wahlin, Lauren Albrecht.
      The abundance and stoichiometry of membrane lipid species vary across a cell's lifespan and metabolic state. In the retinal pigment epithelium (RPE), age-related alterations in lipid composition contribute to vision loss and diseases such as age-related macular degeneration (AMD), yet the molecular drivers of these changes remain unclear. Here, we show that age-dependent remodeling of the composition and biophysical properties of the plasma membrane compromises membrane integrity and function. Remarkably, rather than undergoing cell death, affected cells activate a lysosome-dependent plasma membrane repair program to preserve barrier integrity. While this adaptive response may protect RPE structure under metabolic stress, it also drives spatially polarized release of lysosomal contents that potentially can contribute to extracellular matrix remodeling and sub-RPE deposit formation during aging and AMD. Finally, we demonstrate that supplementation with the direct product of the aging-associated lipid elongase ELOVL2 alleviates these phenotypes, providing direct evidence for a critical role of ELOVL2-mediated PUFA elongation in healthy aging. Taken together, our results propose a model in which age-dependent decline in PUFA elongation disrupts the balance between membrane flexibility and stability, initiating a compensatory cycle of membrane stress and repair.
    DOI:  https://doi.org/10.21203/rs.3.rs-8607320/v1
  27. Sci Adv. 2026 Feb 06. 12(6): eadx9729
    Hybrid female sterility due to cohesin protection errors in mouse oocytes.
    Warif El Yakoubi, Bo Pan, Takashi Akera.
      Hybrid incompatibility can lead to lethality and sterility of F1 hybrids, promoting speciation. The cell biological basis underlying hybrid incompatibility remains largely unknown, especially in mammals. Here, we found that female hybrids between Mus musculus domesticus and Mus spicilegus mice are sterile due to the failure of homologous-chromosome separation in oocyte meiosis, producing aneuploid eggs. This nondisjunction phenotype was driven by the mislocalization of the cohesin protector, SGO2, along the chromosome arms instead of its typical centromeric enrichment, resulting in cohesin overprotection. The upstream kinase, BUB1, showed a higher activity in hybrid oocytes, explaining SGO2 mistargeting. Higher BUB1 activity was not observed in mitosis, consistent with viable hybrid mice. Cohesion defects were also evident in hybrid mice from another genus, Peromyscus, wherein cohesin protection is weakened. Defective cohesion in oocytes is a leading cause of reduced fertility. Our work provides evidence that a major cause of human infertility may play a positive role in mammalian speciation.
    DOI:  https://doi.org/10.1126/sciadv.adx9729
  28. Nature. 2026 Feb 04.
    Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.
    Xin Li, Cynthia Lebeaupin, Aikaterini Kadianaki, Clementine Druelle-Cedano, Niklas Vesper, Charlotte Rennert, Júlia Huguet-Pradell, Borja Gomez Ramos, Chaofan Fan, Robert Stefan Piecyk, Laimdota Zizmare, Pierluigi Ramadori, Luqing Li, Lukas Frick, Menjie Qiu, Cangang Zhang, Luiza Martins Nascentes Melo, Vikas Prakash Ranvir, Peng Shen, Johannes Hanselmann, Jan Kosla, Mirian Fernández-Vaquero, Mihael Vucur, Praveen Baskaran, Xuanwen Bao, Olivia I Coleman, Yingyue Tang, Miray Cetin, Zhouji Chen, Insook Jang, Stefania Del Prete, Mohammad Rahbari, Peng Zhang, Timothy V Pham, Yushan Hou, Aihua Sun, Li Gu, Laura C Kim, Ulrike Rothermel, Danijela Heide, Adnan Ali, Suchira Gallage, Nana Talvard-Balland, Marta Piqué-Gili, Albert Gris-Oliver, Alessio Bevilacqua, Lisa Schlicker, Alec Duffey, Kristian Unger, Marta Szydlowska, Jenny Hetzer, Duncan T Odom, Tim Machauer, Daniele Bucci, Pooja Sant, Jun-Hoe Lee, Jonas Rösler, Sven W Meckelmann, Johannes Schreck, Sue Murray, M Celeste Simon, Sven Nahnsen, Almut Schulze, Ping-Chih Ho, Manfred Jugold, Kai Breuhahn, Jan-Philipp Mallm, Peter Schirmacher, Susanne Roth, Nuh Rahbari, Darjus F Tschaharganeh, Stephanie Roessler, Benjamin Goeppert, Bertram Bengsch, Geoffroy Andrieux, Melanie Boerries, Nisar P Malek, Marco Prinz, Achim Weber, Robert Zeiser, Pablo Tamayo, Peter Bronsert, Konrad Kurowski, Robert Thimme, Detian Yuan, Rafael Carretero, Tom Luedde, Roser Pinyol, Felix J Hartmann, Michael Karin, Alpaslan Tasdogan, Christoph Trautwein, Moritz Mall, Maike Hofmann, Josep M Llovet, Dirk Haller, Randal J Kaufman, Mathias Heikenwälder.
      Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear2. Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.
    DOI:  https://doi.org/10.1038/s41586-025-10036-8
  29. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699367. [Epub ahead of print]
    The microtubule GTP-tubulin cap size is modulated during cell division.
    Anna C Cassidy, Dylan T Burnette, Marija Zanic.
      Microtubule dynamics change during cell division to enable rapid microtubule network remodeling. The switching from microtubule growth to shrinkage is attributed to the loss of a stabilizing GTP-cap structure at the growing microtubule end. The size of the GTP-cap is a result of a balance between GTP-tubulin addition to the microtubule end and subsequent GTP-hydrolysis in the microtubule lattice. Whether the cell-cycle-dependent changes in microtubule dynamics are supported by concurrent modulation of the stabilizing GTP-cap size is not known. Here, we use high spatiotemporal resolution live-cell imaging of EB1, an established marker for the GTP-cap, to directly determine the relationship between GTP-cap size and microtubule growth rate throughout the cell cycle. Our data reveal that GTP-cap size for matching growth rates is reduced during mitosis. Comparison of EB1 comets on astral versus spindle microtubules reveals that the scaling between the GTP-cap size and microtubule growth rate is not spatially regulated in mitosis. We find that these regulatory patterns are conserved across epithelial cells from two different species. Taken together, our findings reveal modulation of GTP-cap size as a cell-cycle-regulated mechanism for tuning microtubule stability.
    Significance Statement: Microtubule dynamics are altered during the cell cycle to enable rapid microtubule network remodeling and accurate chromosome segregation. By comparing EB1 comets on microtubule ends during different cell cycle stages, the authors find that microtubule GTP-cap size is subject to global differential regulation during specific cell cycle stages. These results identify modulation of microtubule stabilizing GTP-cap size as a previously underappreciated, cell-cycle-regulated mechanism for tuning microtubule stability throughout the cell cycle.
    DOI:  https://doi.org/10.64898/2026.01.13.699367
  30. J Cell Sci. 2026 Feb 01. pii: jcs264213. [Epub ahead of print]139(3):
    The desmoglein 2 interactome in primary neonatal cardiomyocytes.
    Yang Li, Alexandra P Campbell, Sahana Balasubramanian, Xuemei Zeng, Emma Porter, Pamela S Cantrell, Mai Sun, Alexa L Mattheyses, Adam V Kwiatkowski.
      Mechanical coupling and chemical communication between cardiomyocytes are facilitated through a specialized adhesive structure called the intercalated disc (ICD). The ICD is essential for heart organization and contraction. Yet, the network of adhesion, adaptor and signaling proteins that form the ICD remains poorly defined. Here, we combined proximity labeling and quantitative mass spectrometry to identify proteins associated with the desmosomal cadherin desmoglein 2 (DSG2), in cultured neonatal cardiomyocytes. We identified over 300 proteins in the DSG2 interactome, half of which are shared with the N-cadherin (CDH2) interactome in cardiomyocytes. Proteins unique to DSG2 include connexin 43 and the plakin family of cytolinker proteins. Comparison of the cardiomyocyte DSG2 interactome with the interactomes of desmosomal proteins from epithelia revealed few shared proteins. In cardiomyocytes, plakoglobin and plakophilin 2 (PKP2) were the most abundant shared proteins between the DSG2 and CDH2 interactomes. We show that PKP2 is a dynamic protein whose membrane recruitment in cardiomyocytes is dependent on tension. Our analysis of the DSG2 interactome provides a crucial new dimension to the proteomic atlas of the essential molecular complexes required for cardiomyocyte adhesion.
    Keywords:  Cardiomyocyte; Cell–cell adhesion; Desmoglein 2; Desmosome interactome; Intercalated disc; Plakophilin 2
    DOI:  https://doi.org/10.1242/jcs.264213
  31. Dev Cell. 2026 Feb 05. pii: S1534-5807(26)00030-4. [Epub ahead of print]
    Hypoxia-inducible factor signaling regulates embryonic interneuron development, GRIN2B expression and adult cortical function.
    I-Ling Lu, Mengyi Song, Cinthia Rangel-Sandoval, Juan Moriano Palacios, JaeYeon Kim, Eric J Huang, Arturo Alvarez-Buylla, Arnold Kriegstein, Mercedes F Paredes, David H Rowitch.
      Although hypoxia-inducible factors (HIFs) are central regulators of cellular adaptation to oxygen and metabolic fluctuations in the mammalian brain, potential roles for HIF regulation during inhibitory neuron development are poorly understood. Here, we report that Nkx2.1-cre-driven conditional deletion of Hif1/2a in the medial ganglionic eminence (MGE) leads to reduced proliferation of Lhx6-positive interneuron precursors, whereas loss of von Hippel-Lindau (vHL), required for HIF degradation, drives increased precursor proliferation. Integrating single-cell transcriptomics, we identified HIF targets regulating proliferation and synaptogenesis. We also show that HIF1A directly activates glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), encoding glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) subunit 2B. In the adult HIF1 conditional knockout (cKO) cortex, we observed decreased numbers of parvalbumin (PV) interneurons and fewer GABAergic synapses and GRIN2B/Bassoon puncta on layer 2/3 excitatory neurons, resulting in attenuated long-term potentiation. These findings identify non-canonical roles for HIF signaling that are essential for PV interneuron production, GRIN2B expression, and cortical circuit maturation and function.
    Keywords:  GRIN2B; Hif1a; Lhx6; Nkx2.1; embryonic brain; hyperoxia; hypoxia-inducible factor; interneuron; parvalbumin; preterm infant brain injury
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.007
  32. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699374. [Epub ahead of print]
    Acute priming using elevated fluid viscosity recovers ' young-like ' single-cell surveillance behaviors in aged human T cells.
    Yoseph W Dance, Alice Amitrano, Annaka M Saffron, Chanhong Min, Ladaisha T Thompson, Zhuoxu Ge, Ian M Smith, Nicolas C Macaluso, Charles Ezenwanne, Nicholas Milcik, Abigail Fennell, Kendall A Pyndell, Kimberly M Stroka, Jeremy D Walston, Sean X Sun, Konstantinos Konstantopoulos, Jude M Phillip.
      Aging is a complex biological process, often characterized by increased vulnerability to disease, infection, and death. This increased vulnerability is mechanistically linked to a progressive and functional decline of the immune system. In humans, aged lymphocytes lose their capacity to effectively surveil within diverse microenvironments, decreasing their capability for clearing infections and maintaining physiological homeostasis. However, specific mechanisms by which aged lymphocytes, specifically T cells, lose this capacity to surveil remain unclear. We profiled three core characteristics of T cell surveillance at single-cell resolution, specifically migration, deformability, and sensing. While aged T cells retained their capacity for spontaneous migration, they exhibited impaired cellular deformability and deficiencies in sensing local signaling cues. To modulate this surveillance defect, we performed mechanical reprogramming using elevated fluid viscosity. Results showed that acute priming of aged T cells with elevated fluid viscosity recovered a transient young-like surveillance phenotype, which was mechanistically linked to membrane tension, cortical F-actin, and Arp3 expression. These findings reveal a key source of surveillance defects in aged T cells and provide an effective mechanical approach to tuning their single-cell behaviors.
    Teaser: Recovery of 'young-like' surveillance phenotypes in aging human T cells via viscosity priming.
    DOI:  https://doi.org/10.64898/2026.01.13.699374
  33. EMBO Rep. 2026 Feb 02.
    Nanog mediated control of TBX3-GATA6 circuitry in primitive endoderm differentiation of mESCs.
    Hao Wu, Ying Ye, Hongxia Dai, Peixin Chen, Tenghui Yang, Zhifang Li, Li Li, Chirag Parsania, Junjun Ding, Man Zhang, Erwei Zuo, Ulf Schmitz, Xi Chen, Zhexin Zhu, Wensheng Zhang.
      Cell fate decisions in the early embryo rely on reciprocal transcriptional networks that balance pluripotency with lineage commitment. NANOG is essential for directing the epiblast-primitive endoderm (PrE) fate choice, but the molecular mechanisms underlying its repressive activity remain incompletely understood. Here we show that NANOG partners with TBX3 and the PRC2 complex to maintain embryonic stem cell (ESC) identity by silencing PrE genes through newly identified distal enhancers. Loss of Nanog reduces PRC2-mediated repression of Gata6, initiating its expression independently of TBX3. Subsequent TBX3 upregulation enables its association with GATA6, driving a feed-forward programme that activates Gata6, Gata4 and Sox17 and promotes PrE differentiation. Thus, NANOG suppresses PrE fate not only by direct repression but also by preventing TBX3 from switching partners. These findings define a Nanog-Tbx3-Gata6 regulatory axis that integrates enhancer control, chromatin regulation and transcription factor redeployment to couple ESC maintenance with lineage commitment.
    Keywords:  Embryonic Stem Cells; Nanog; PRC2 Complex; Primitive Endoderm
    DOI:  https://doi.org/10.1038/s44319-026-00707-6
  34. Cell Stem Cell. 2026 Feb 05. pii: S1934-5909(26)00034-2. [Epub ahead of print]
    Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency.
    Shangtao Cao, Shengyong Yu, Dongwei Li, Jing Ye, Xuejie Yang, Chen Li, Xiaoshan Wang, Yuanbang Mai, Yue Qin, Jian Wu, Jiangping He, Chunhua Zhou, He Liu, Bentian Zhao, Xiaodong Shu, Chuman Wu, Ruiping Chen, Waiyee Chan, Guangjin Pan, Jiekai Chen, Jing Liu, Duanqing Pei.
      
    DOI:  https://doi.org/10.1016/j.stem.2026.01.011
  35. Nature. 2026 Feb 04.
    Regulation of STING activation by phosphoinositide and cholesterol.
    Jie Li, Jay Xiaojun Tan, Zhijian J Chen, Xuewu Zhang, Xiao-Chen Bai.
      Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway1. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS)2-5. cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation6-11. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear12-17. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2 and PtdIns(4,5)P2, and by PtdIns4P to a lesser extent. Our cryo-electron microscopy structures reveal that PtdInsPs together with cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PtdInsPs. Mutational and biochemical analyses confirm the binding modes of PtdInsPs and cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING mediated by specific lipids, which may underlie the role of intracellular trafficking in dictating STING signalling.
    DOI:  https://doi.org/10.1038/s41586-025-10076-0
  36. Mol Hum Reprod. 2026 Feb 04. pii: gaag004. [Epub ahead of print]
    Variable partition of non-homogeneous ooplasm sets the stage for divergent potency of 2-cell stage blastomeres.
    Thomas Nolte, Reza Halabian, Steffen Israel, Yutaka Suzuki, Hannes C A Drexler, Wojciech Makalowski, Georg Fuellen, Michele Boiani.
      Following fertilization in mice and humans, the first two blastomeres are not equivalent, but one produces more epiblast than the other (imbalance), therefore, they do not feature equal totipotency. Research into the causes has overlooked that the epiblast imbalance is preceded by a fertilization imbalance, since in nature, the spermatozoon fertilizes the oocyte preferentially in the animal hemisphere near the animal-vegetal midline (equator). We conceived a hypothesis that the two imbalances are linked to each other, and broke it down into testable predictions. If the two imbalances were interdependent, then changing the site of sperm entry into the oocyte should change the extent of the epiblast imbalance. Thus, we evened out the fertilization imbalance, using ICSI to fertilize mouse oocytes also in the vegetal hemisphere and the equator. Resultant embryos were split at the 2-cell stage, and the twin blastocysts originating from the sister blastomeres were analyzed. Against the similarity in mRNA levels of epiblast genes, twin blastocysts differed in epiblast function, as measured by NANOG protein expression and derivation of embryonic stem cells, and the epiblast imbalance was greater after oocyte fertilization at the equator. There is no simple way to explain the positional effect other than through differences in the molecular composition of the ooplasm, which, moreover, should also be apportioned variably at the first zygotic division. We tested these predictions by measuring the orientation of the first zygotic division regarding the ICSI site, and the composition of bisected oocytes' hemispheres using half-cell proteomics. Since we found that the hemispheres have different compositions depending on the bisection axis, and the angle of the first division is variable, we propose that the variable partition of non-homogeneous ooplasm sets the stage for the epiblast imbalance. These results revive the role of the oocyte's molecular architecture on embryogenesis in a mammalian species hitherto considered mostly regulative in development.
    Keywords:  2-cell embryo; ICSI; RNA-sequencing; blastocyst; embryo splitting; epiblast; mass spectrometry; mouse; oocyte bisection; proteome
    DOI:  https://doi.org/10.1093/molehr/gaag004
  37. Cell Stem Cell. 2026 Feb 05. pii: S1934-5909(26)00025-1. [Epub ahead of print]33(2): 306-324.e8
    Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction.
    Mingxin Zhang, Xi Wu, Di Liu, Huaxing Li, Xulin Li, Wuqi Yang, Jialin Ye, Liyuan Hou, Shiyang Wang, Ning Ning, Hanfu Zhang, Yuhua Tian, Lu Yu, Kaichun Wu, Liping Wang, Maksim V Plikus, Cong Lv, Feng Wang, Zhengquan Yu.
      Sleep disturbances are associated with pathogenesis of numerous chronic disorders, including chronic gastrointestinal diseases. However, the mechanism that transmits sleep disturbance-induced aberrant neural signaling from the brain to the gut remains elusive. We show that acute sleep deprivation (SD) impairs intestinal stem cell (ISC) function, leading to shortening of crypt-villus architecture and Paneth cell loss. We identified the dorsal motor nucleus of vagus (DMV) as the SD-sensitive central nervous system center that transmits sleep effects to the gut. SD aberrantly activates DMV neurons, driving excessive acetylcholine release from the vagus nerve into the gut. Acetylcholine triggers 5-hydroxytryptamine (5-HT) release by enterochromaffin cells and suppresses its reuptake via muscarinic receptors, thereby causing a spike in 5-HT levels. Elevated 5-HT induces excessive oxidative stress in ISCs through its receptor HTR4, promoting gut pathologies. Overall, we reveal an SD-responsive neural circuit that controls ISCs and identify therapeutic strategies for mitigating SD-related gut diseases.
    Keywords:  5-hydroxytryptamine; acetylcholine; brain-gut communications; intestinal stem cells; oxidative stress; sleep disturbance; the dorsal motor nucleus of vagus; translation stress response
    DOI:  https://doi.org/10.1016/j.stem.2026.01.002
  38. Science. 2026 Feb 05. eadz1884
    Programmable genome editing in human cells using RNA-guided bridge recombinases.
    Oana Pelea, András Tálas, Javier Fernández Carrera, Nicolas Mathis, Lilly van de Venn, Charles D Yeh, Péter I Kulcsár, Kim F Marquart, Yanik Weber, Saskia E Gerecke, Isabelle F Harvey-Seutcheu, Dominic Mailänder, Moritz M Pfleiderer, Christelle Chanez, Jacob E Corn, Gerald Schwank, Martin Jinek.
      Site-specific insertion of gene-sized DNA fragments remains an unmet need in the genome editing field. IS110-family serine recombinases have recently been shown to mediate programmable DNA recombination in bacteria using a bispecific RNA guide (bridge RNA) that simultaneously recognizes target and donor sites. Here, we show that the bridge recombinase ISCro4 is highly active in human cells, and provide structural insights into its enhanced activity. Using plasmid- or all-RNA-based delivery, ISCro4 supports programmable multi-kilobase exisions and inversions, and facilitates donor DNA insertion at genomic sites with efficiencies exceeding 6%. Finally, we assess ISCro4 specificity and off-target activity. These results establish a framework for the development of bridge recombinases as next-generation tools for editing modalities that are beyond the capabilities of current technologies.
    DOI:  https://doi.org/10.1126/science.adz1884
  39. Res Sq. 2026 Jan 28. pii: rs.3.rs-8544414. [Epub ahead of print]
    Fork Reversal Safeguards Epigenetic Inheritance During Replication Stress.
    Wenpeng Liu, Qiong Wu, Caixian Zhou, Yue Dou, Nadia Martin, Maria Gwit, Tae-Hee Lee, Mark Hedglin, Roséa Chen, Ke Zhu, Tianpeng Zhang, Shangming Tang, Tian Zhang, Tyler Weaver.
      During DNA replication, epigenetic information carried by histone modifications is faithfully propagated and re-established on sister chromatids, ensuring cell identity. Chromatin reassembly is tightly coupled to DNA replication, however, whether and how perturbations to DNA replication affects the fidelity of epigenetic inheritance remain unclear. In this study, we reveal a critical role for replication fork reversal in maintaining the transmission of epigenetic information under replication stress. Cells defective in fork reversal exhibit reduced nucleosome density at replication forks, accompanied by the loss of parental histones during their transfer onto nascent DNA. Mechanistically, we demonstrate that PrimPol activation leads to single-stranded DNA gaps in fork reversal deficient cells, and that subsequent PARylation (poly ADP-ribosylation) and DNA-protein crosslinking on these gaps cause nucleosomes loss. Our findings demonstrate that replication fork reversal, a widespread physiological process, is not only essential for preserving genome integrity but also for safeguarding epigenetic stability.
    DOI:  https://doi.org/10.21203/rs.3.rs-8544414/v1
  40. Nature. 2026 Feb 04.
    PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling.
    Jay Xiaojun Tan, Bo Lv, Jie Li, Tuo Li, Fenghe Du, Xiang Chen, Xuewu Zhang, Xiao-Chen Bai, Zhijian J Chen.
      Exposure to cytosolic DNA triggers innate immune responses through cyclic GMP-AMP (cGAMP) synthase (cGAS)1,2,3. After binding to DNA, cGAS produces cGAMP as a second messenger that binds to stimulator of interferon genes (STING), a signalling adaptor protein anchored to the endoplasmic reticulum (ER)3-5. STING then traffics from the ER through the Golgi to perinuclear vesicle clusters, which leads to activation of the kinases TBK1 and IKK and subsequent induction of interferons and other cytokines6-9. Here we show that phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2; also known as PI(3,5)P2) is an endogenous ligand of STING that functions together with cGAMP to induce STING activation. Proteomic analyses identified a constitutive interaction between STING and PIKFYVE, an enzyme that produces PtdIns(3,5)P2 in mammalian cells. Deletion of PIKFYVE blocked STING trafficking from the ER and TBK1 activation. In vitro reconstitution uncovered a strong and selective effect of PtdIns(3,5)P2 on STING activation by cGAMP. PtdIns(3,5)P2 bound directly to STING in fluorescence resonance energy transfer assays. Consistently, cryo-electron microscopy revealed that PtdIns(3,5)P2 promotes cGAMP-induced STING oligomerization10, functioning as a molecular glue. Similar to PIKFYVE depletion, mutation of the PtdIns(3,5)P2-binding residues in STING largely blocked its trafficking and downstream signalling. These findings reveal that PtdIns(3,5)P2 is a lipid ligand of STING with essential roles in innate immunity.
    DOI:  https://doi.org/10.1038/s41586-025-10084-0
  41. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  42. EMBO J. 2026 Feb 03.
    CaMKII nucleates an osmotic protein supercomplex to induce cellular bleb expansion.
    Yuki Fujii, Yuji Sakai, Kenji Matsuzawa, Junichi Ikenouchi.
      Blebs are membrane protrusions formed when localized regions of the plasma membrane detach from the actin cortex, enabling outward expansion driven by intracellular pressure. These structures play critical roles in cell migration and proliferation. While cortical actin contraction has been proposed as the primary driver of cytoplasmic fluid influx during bleb expansion, our prior observations revealed compartmentalization of Ca²⁺ ions and specific proteins (e.g., Mena) within expanding blebs. The functional significance of these components remained unresolved. In this study, we demonstrate that elevated Ca²⁺ levels during bleb expansion induce the assembly of a protein superstructure built around the CaMKII holoenzyme, incorporating Mena and other regulatory proteins. This complex exhibits intrinsic osmotic activity, facilitating water influx and directly contributing to bleb expansion. These findings elucidate a novel mechanism underlying bleb expansion and provide new insights into the dynamic regulation of physicochemical properties of the cytoplasm.
    Keywords:  CaMKII; Cell Migration; Cytoplasmic Mechanics; Membrane Blebbing; Osmotically Driven Deformation
    DOI:  https://doi.org/10.1038/s44318-026-00703-5
  43. Cell Chem Biol. 2026 Feb 04. pii: S2451-9456(26)00023-1. [Epub ahead of print]
    Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
    Wei Liu, Tianyi Zhang, Bohong Wang, Hang Yin.
      Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.
    Keywords:  NLRP3 inflammasome; lactylation; pyroptosis
    DOI:  https://doi.org/10.1016/j.chembiol.2026.01.003
  44. Cancer Cell. 2026 Feb 05. pii: S1535-6108(26)00045-0. [Epub ahead of print]
    CCL3 is produced by aged neutrophils across cancers and promotes tumor growth.
    Evangelia Bolli, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Marie Siwicki, Florent Duval, Anne-Gaëlle Goubet, Máté Kiss, Béatrice Zitti, Thomas Zwahlen, Sheri Mcdowell, Ruben Bill, Simona Angerani, Camilla Engblom, Seth Anderson, Aiping Jiang, Oliver Hartley, David B Sykes, Maja Jankovic, Nadine Fournier, Matthias Gunzer, David Tarussio, Stéphanie Tissot, Peter M Sadow, William C Faquin, Moshe Sade-Feldman, Ralph Weissleder, Sara Pai, François Mercier, Robert Manguso, Mikaël J Pittet.
      Tumor-associated neutrophils (TANs) are abundant across cancers, yet their phenotypic diversity and functional states remain poorly defined. Here, we introduce a cell-type probability classifier that recovers low-transcript neutrophils from scRNAseq datasets, enabling pan-cancer analyses of TAN heterogeneity. Across >190 human and murine tumors, we identify a conserved differentiation trajectory that culminates in a terminal CCL3hi state. This state exhibits pro-tumor transcriptional programs, including those involved in hypoxic adaptation and senescence. Consistently, CCL3hi TANs are enriched in hypoxic tumor niches in both humans and mice. Through mechanistic perturbations of neutrophil-derived CCL3 in mice, we show that it sustains TAN survival in hypoxic tumor regions via CCR1-dependent signaling. These findings establish CCL3 as a conserved marker and functional driver of pro-tumor neutrophils in growing tumors, and provide a scalable framework for dissecting neutrophil biology across cancer types.
    Keywords:  CCL3-CCR1 signaling; CRISPR perturbation; hypoxia; neutrophil aging; neutrophil differentiation; neutrophil heterogeneity; pan-cancer analysis; single-cell RNA sequencing; tumor microenvironment; tumor-promoting neutrophils
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.006
  45. Circulation. 2026 Feb 06.
    TRPM7 Deficiency Protects Against Myocardial Ischemia-Reperfusion Injury by Regulating Intracellular Zn2+ Homeostasis.
    Xin Li, Xiaohan Li, Cindy Xintong Li, Jianlin Feng, Zhichao Yue, Jiajie Yan, Masayuki Matsushita, Yibing Qyang, Loren W Runnels, Xun Ai, Lixia Yue.
       BACKGROUND: Ischemic heart disease is one of the leading causes of death worldwide. Timely reperfusion is necessary for myocardium salvage but triggers paradoxical cardiomyocyte death and contributes to up to 50% of the final infarct size, known as lethal ischemia/reperfusion (I/R) injury. TRPM7 (transient receptor potential melastatin 7) is a divalent cation-permeable, nonselective channel kinase that can sense oxidative stress and release Zn2+ from unique intracellular TRPM7 vesicles. However, the pathophysiological role of intracellular TRPM7 remains poorly understood.
    METHODS: TRPM7 expression was determined in hearts from patients with ischemic heart failure and I/R-injured mice. Global cardiomyocyte-specific (cmTrpm7-/-) and fibroblast-specific (fibTrpm7-/-) Trpm7 knockout mice were used to determine the role of TRPM7 in I/R injury. Mechanistic investigations were conducted in primary neonatal mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes with patch-clamp, Zn2+ imaging, and molecular biology techniques. A novel inducible TRPM7 channel dead (TRPM7-E1047K) knock-in mouse model was generated to elucidate the functional domains of TRPM7 for therapeutic strategies.
    RESULTS: We found that TRPM7 was significantly upregulated in myocardium from both patients with ischemic heart failure and I/R-injured mice. Global TRPM7 deficiency markedly reduced infarct size and improved cardiac function after I/R injury. Using cmTrpm7-/- and fibTrpm7-/- mice, we demonstrated that TRPM7 deficiency in myocytes rather than in fibroblasts confers protection against I/R injury by inhibiting pyroptosis as evaluated. Furthermore, using mouse primary cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes, we revealed that Zn2+ release from intracellular TRPM7 vesicles during I/R injury triggers cardiomyocyte death by activating gasdermin-D to release its N-terminal and form the membrane pore. The critical role of intracellular TRPM7 was further supported by the inability of membrane TRPM7 inhibition to protect mice against I/R injury. To elucidate whether the channel or kinase activity of TRPM7 mediates pyroptosis in I/R injury, we generated a new inducible channel-dead TRPM7-E1047K knock-in mouse model. By comparing with kinase-inactive TRPM7 knock-in mice, we uncovered that the channel but not the kinase function of TRPM7 mediates I/R injury.
    CONCLUSIONS: TRPM7-mediated intracellular Zn2+ release contributes to myocardial I/R injury by triggering apoptotic and pyroptotic cardiomyocyte death. Given that TRPM7 is highly upregulated in patients with ischemic heart failure, our findings suggest that targeting TRPM7 may represent a novel therapeutic strategy for ischemic heart disease.
    Keywords:  TRPM7 protein, human; ischemia; pyroptosis; reperfusion; zinc
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.074791
  46. Cell Res. 2026 Feb 03.
    Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity.
    Yingze Li, Mengge Zheng, Zhenyan Zhu, Yajuan Zhang, Peng Ning, Haotian Chen, Rui Gao, Chang Xu, Xueyan Wei, Yali Liu, Yingying Wang, Ruimei Zhou, Yuan Li, Zhenguang Li, Cheng Lv, Chen Liu, Junfang Xu, Zihan Guo, Zhixiang Hu, Lan Fang, Ke Wei, Mengying Feng, Changshi Zhou, Yunlang She, Weiyan Sun, Erzhen Chen, Gustavo R Plaza, Bin He, Jason Miska, Weiwei Yang, Yichao Tang, Haipeng Liu, Chang Chen, Yu Cheng.
      Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.
    DOI:  https://doi.org/10.1038/s41422-025-01217-1
  47. Nature. 2026 Feb 04.
    A pore-forming antiphage defence is activated by oligomeric phage proteins.
    Pramalkumar H Patel, Matthew R McCarthy, Véronique L Taylor, Gregory B Cole, Chi Zhang, Matthew M Edghill, Landon J Getz, Beatrice C M Fung, Trevor F Moraes, Alan R Davidson, Michael J Norris, Karen L Maxwell.
      Bacteria have evolved a wide array of defence systems to combat phage infection, many of which rely on complex signalling systems and large protein complexes to function1. Here we describe a 164-residue prophage-encoded protein that defends bacteria by sensing conserved oligomeric components of phage assembly. This protein, called ring interacting pore 1 (Rip1), is activated by the portal or small terminase proteins of infecting phages-oligomeric ring-shaped complexes that are essential for virion maturation. Rip1 uses these phage protein ring complexes as a template to assemble into membrane-disrupting pores that inhibit phage virion assembly and cause premature death of the host cell. Rip1 homologues are widely distributed across bacteria and provide robust defence against diverse phages. This study reveals a strategy by which a small defence protein integrates both sensing and effector activity by exploiting a conserved feature of viral assembly. The mechanism mirrors eukaryotic pore-forming immunity but is executed by a single protein, offering an evolutionarily streamlined solution to viral detection and defence.
    DOI:  https://doi.org/10.1038/s41586-025-10075-1
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