N Nature Cell Biology · Dec 03, 2025 A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN—a distinct TGFβ family ligand—induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity. Embryonic stem cells Epithelial–mesenchymal transition Growth factor signalling biology
N Nature Cell Biology · Dec 02, 2025 Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation Multiple enhancers, often separated by vast genomic distances, regulate key genes. However, how the folding of individual chromatin fibres enables cell-type-restricted multi-enhancer regulation remains unclear. Here, using acute protein degradation and time-resolved chromatin conformation capture in mantle cell lymphoma, we found that the B cell-lineage-determining factor EBF1 organizes multiple enhancers around sparsely distributed genes essential for B cell identity and oncogenesis. Time-resolved sub-diffraction optical tracing of more than 100,000 chromatin fibres further revealed diverse topological conformations that facilitate multi-enhancer interactions. Mechanistically, we discovered that enhancer positioning at local topological centres is required for promoter engagement, with EBF1 acting as a permeable barrier to loop-extruding cohesin at enhancers. Extending these findings to T cell leukaemia, we show that lineage-determining transcription factors such as EBF1 and TCF1 radially position enhancers within gene loci to enable multi-enhancer regulation of key oncogenes at the single-allele level. Epigenetics Oncogenes biology
N Nature Cell Biology · Dec 02, 2025 Karyopherins remodel the dynamic organization of the nuclear pore complex transport barrier Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies. Atomic force microscopy Molecular biophysics Nuclear pore complex biology
N Nature Cell Biology · Dec 01, 2025 RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer Therapeutic targeting of mutant KRAS pathways driving cancers is being actively investigated to identify feedback mechanisms responsible for the development of adaptive resistance to mutant KRAS inhibitors undergoing clinical trials. Here we report RASH3D19 as a mediator of RAS pathway activation through a positive feedback loop involving the KRAS–microRNA signalling axis. KRAS-induced miR-222 represses ETS1 expression and downstream transactivation of miR-301a leading to elevation of its target RASH3D19. RASH3D19 facilitates activation of RAS pathways by promoting dimerization and interaction of EGFR with the SOS2, GRB2, SHP2 and GAB1 complex. Genetic deletion of RASH3D19 in mutant KRAS-expressing cancer cells exhibits growth retardation in vitro, in vivo and sensitized pancreatic ductal adenocarcinoma and colorectal cancer cells, organoids and xenografts to mutant KRAS inhibitors, suppressing feedback reactivation of RAS pathways. Therapeutic targeting of RASH3D19 is expected to lead to tumour debulking and alleviating resistance to KRAS inhibitors in mutant KRAS-expressing cancers. Cancer therapeutic resistance Oncogenes Targeted therapies biology
N Nature Cell Biology · Nov 28, 2025 Proximal proteomics reveals a landscape of human nuclear condensates Nuclear condensates (NCs) are membraneless organelles that enable spatial and functional compartmentalization in the nucleus. Yet, the components and functional co-organization of NCs have been poorly studied. Here, we used PhastID to explore the proximal interactome of 18 NCs in HeLa cells. Our data revealed the organizational flow of gene control among these NCs. Crucially, we developed an algorithm to dissect the intricate internal relations of NCs. This algorithm led to key discoveries: the identification of an uncharacterized BUD13 condensate, and the recognition of specific co-organizations between nuclear gems and Cajal bodies for telomerase maturation, and between nuclear gems and histone locus bodies for histone gene pre-mRNA processing. We also created a global reference map to understand NC dynamics under stresses and how disease-related mutations differentially affect NC interactomes. Overall, our work provides a proximal proteome-based atlas for human NCs, substantially advancing our spatiotemporal understanding of nuclear biological events. Nuclear organization Protein–protein interaction networks biology
N Nature Cell Biology · Nov 28, 2025 WDR4 drives tumour-associated macrophage reprogramming and tumour progression via selective translation and membrane cholesterol efflux Tumour-associated macrophages (TAMs) play a pivotal role in shaping the immune microenvironment of hepatocellular carcinoma (HCC), influencing tumour progression and immunotherapy response. WDR4, a tRNA-binding cofactor of theN7-methylguanosine (m7G) methyltransferase complex, remains poorly understood in its independent functions. Here we show that WDR4 is significantly upregulated in HCC-associated TAMs and correlates with poor prognosis. Loss of WDR4 in monocyte-derived macrophages, but not in resident Kupffer cells, reprogrammes TAMs towards an antitumoral phenotype and suppresses HCC progression. Mechanistically, cytoplasmic WDR4 acts independently of m7G modification by directly interacting with eIF4E2 to enhance eIF4E-mediated selective translation of ABCA1, thereby promoting membrane cholesterol efflux and maintaining pro-tumoral polarization. Targeted silencing of WDR4 in TAMs using a CpG-small interfering RNA delivery system enhances antitumour immunity, inhibits tumour progression and improves the efficacy of anti-PD-1 therapy. Our findings identify WDR4 as a key regulator of TAM polarization and a promising therapeutic target to enhance immunotherapeutic outcomes. Cancer metabolism Hepatocellular carcinoma Tumour immunology biology mouse experiments
N Nature Cell Biology · Nov 28, 2025 Multi-omics identify hallmark protein and lipid features of small extracellular vesicles circulating in human plasma Extracellular vesicles (EVs) are an essential signalling entity in human plasma implicated in health and disease. Still, their core protein and lipid componentry, which lie at the centre of EV form and function, remain poorly defined. Here we performed high-resolution density gradient fractionation of over 140 human plasma samples to isolate circulating EVs, and systematically constructed their quantitative proteome (4,500 proteins) and lipidome (829 lipids) landscapes using mass spectrometry. We identified a highly conserved panel of 182 proteins (including ADAM10, STEAP23 and STX7) and 52 lipids (including PS, PIPs, Hex2Cer and PAs), providing a deep survey of hallmark molecular features and biological pathways characteristic to circulating EVs. We also mapped the surfaceome diversity, identifying 151 proteins on the EV surface. We further established a set of 42 proteins and 114 lipids features that served as hallmark features of non-EV particles in plasma. We submit ADAM10 and PS(36:1) as conserved EV biological markers that precisely differentiate between EV and non-EV particles. Our findings, which can be explored via an open-source Shiny web tool (evmap.shinyapps.io/evmap/), will serve as a valuable repository to the research community for a clearer understanding of circulating EV biology. Extracellular signalling molecules Membrane trafficking Organelles Systems analysis biology
N Nature Cell Biology · Nov 26, 2025 Smart spatial omics (S2-omics) optimizes region of interest selection to capture molecular heterogeneity in diverse tissues Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we present Smart Spatial omics (S2-omics), an end-to-end workflow that automatically selects ROIs from histology images with the goal of maximizing molecular information content in the ROIs. Through comprehensive evaluations across multiple spatial omics platforms and tissue types, we demonstrate that S2-omics enables systematic and reproducible ROI selection and enhances the robustness and impact of downstream biological discovery. Biotechnology Computational biology and bioinformatics Transcriptomics biology
N Nature Cell Biology · Nov 24, 2025 Hierarchical interactions between nucleolar and heterochromatin condensates are mediated by a dual-affinity protein Nucleoli are surrounded by pericentromeric heterochromatin (PCH), reflecting a conserved spatial association between the two largest biomolecular condensates in eukaryotic nuclei. Nucleoli are the sites of ribosome synthesis, whereas the repeat-rich PCH is essential for chromosome segregation, genome stability and transcriptional silencing, yet the mechanisms for their co-assembly are unclear. Here we use high-resolution live imaging duringDrosophilaembryogenesis and reveal that de novo establishment of PCH–nucleolar associations is highly dynamic, as PCH transitions from extending along the nuclear edge to surrounding the nucleolus. Elimination of the nucleolus by removing the ribosomal RNA genes disrupted this process causing increased PCH compaction, followed by its reorganization into a toroidal structure. Furthermore, in embryos lacking ribosomal RNA genes, nucleolar proteins were redistributed into new bodies or ‘neocondensates’, including enrichment in the PCH toroidal hole. Combining these in vivo observations with molecular dynamics simulations based on multiphase wetting theory revealed that nucleolar–PCH associations can be mediated by a hierarchy of interaction strengths between PCH, nucleoli and proteins with dual affinities for both compartments. We validate this model by identifying such a protein, a DEAD-box RNA helicase called Pitchoune, and show that modulation of its affinity for either nucleolar or PCH components alters nucleolar–PCH organization. Together, this study unveils a dynamic programme for establishing nucleolar–PCH associations during animal development and demonstrates how interaction hierarchies and dual-affinity molecular linkers co-organize compositionally distinct condensates. Chromatin Molecular biophysics Nucleolus biology
N Nature Cell Biology · Nov 24, 2025 Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis Ageing dampens the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent, using proteomic and metabolomic profiling of intestinal tissues together with functional assays. The comparison of regeneration dynamics in mice of different ages revealed the emergence of proteostasis stress and increased levels of polyamines following injury exclusively in old epithelia. We show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and the accumulation of ubiquitylated proteins. The inhibition of the polyamine pathway in vivo further delays regeneration in old mice, whereas its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight the promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with ageing. Proteomics Translation biology mouse experiments
N Nature Cell Biology · Nov 21, 2025 Transcription factors instruct DNA methylation patterns in plant reproductive tissues DNA methylation is maintained by forming self-reinforcing connections with other repressive chromatin modifications, resulting in stably silenced genes and transposons. However, these mechanisms fail to explain how new methylation patterns are generated. InArabidopsis, CLASSY3 targets the RNA-directed DNA methylation machinery to different loci in reproductive tissues, generating distinct epigenomes via unknown mechanism(s). Here we discovered that several different REPRODUCTIVE MERISTEM (REM) transcription factors are required for methylation at CLASSY3 targets specific to anther or ovule tissues. We designate these factors as REM INSTRUCTS METHYLATION (RIMs) and demonstrate that disruption of their DNA-binding domains, or the motifs they recognize, blocks RNA-directed DNA methylation. Furthermore, we demonstrate that mis-expression of RIM12 is sufficient to initiate siRNA production at ovule targets in anthers. These findings reveal a critical role for genetic information in targeting DNA methylation in reproductive tissues, expanding our understanding of how methylation is regulated to include inputs from both genetic and epigenetic information. DNA methylation Plant sciences biology
N Nature Cell Biology · Nov 18, 2025 Inhibiting ferroptosis enhances ex vivo expansion of human haematopoietic stem cells Improved ex vivo expansion of human haematopoietic stem cells (HSCs) would considerably advance transplantation and genome-engineered therapies, yet existing culture methods still allow substantial HSC loss. Here we show that this attrition is driven largely by ferroptosis, a metabolically regulated, iron-dependent cell-death pathway, and that it can be blocked to augment HSC expansion. Inhibiting ferroptosis with liproxstatin-1 or ferrostatin-1 markedly increases the expansion of cord blood and adult HSCs consistently across donors in both widely used serum-free cultures and recently reported chemically defined conditions. The expanded cells retain phenotypic and molecular stem cell identity and mediate improved durable, multilineage engraftment in xenotransplanted mice without genotoxicity or aberrant haematopoiesis. Mechanistically, ferroptosis blockade is accompanied by upregulated ribosome biogenesis and cholesterol synthesis, increasing levels of 7-dehydrocholesterol—a potent endogenous ferroptosis inhibitor that itself promotes HSC expansion. Crucially, this approach enhances yields of therapeutically genome-modified HSCs, paving a path for clinical applications. Bone marrow transplantation Cell death Haematopoiesis Haematopoietic stem cells
N Nature Cell Biology · Nov 17, 2025 DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Apoptosis Cancer
N Nature Cell Biology · Nov 11, 2025 Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a ‘leaky’ H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment. DNA methylation Embryogenesis Epigenomics
N Nature Cell Biology · Nov 11, 2025 Ca2+-driven PDIA6 biomolecular condensation ensures proinsulin folding The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca2+storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca2+triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin. Chaperones Endoplasmic reticulum
N Nature Cell Biology · Nov 04, 2025 Designing protein-based artificial kinetochores as decoys to prevent meiotic errors in oocytes Chromosome mis-segregation during meiosis in oocytes causes miscarriages and congenital diseases. Ageing-associated premature chromosome separation is a major cause of mis-segregation. Effective prevention of premature chromosome separation has not yet been achieved. Here we design protein-based artificial kinetochores that act as decoys to prevent premature chromosome separation. Designed artificial kinetochore-like decoys are submicroscale clusters of NDC80-NUF2-tethered protein particles that can establish a biorientation-like state by competing with chromosomal kinetochores for HURP-decorated microtubules. This competition reduces excessive bipolar microtubule pulling forces exerted on chromosomes, thereby effectively preventing premature chromosome separation during meiosis I and II in aged mouse oocytes. These effects suppress egg aneuploidy. This study provides a decoy strategy with biocompatible artificial kinetochores to prevent ageing-associated meiotic errors in oocytes. Chromosome segregation Kinetochores Synthetic biology
N Nature Cell Biology · Oct 31, 2025 Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility inCaenorhabditiselegansand render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine–GCN2–SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer. Genetics Mitochondria Ubiquitylation
N Nature Cell Biology · Oct 31, 2025 TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin inDrosophilaameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion. Cytoskeleton Mechanisms of disease Protein folding
N Nature Cell Biology · Oct 29, 2025 FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here we identify LD-localized ferroptosis suppressor protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, inducing polyunsaturated fatty acid-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality-control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the build-up of oxidized lipids and induction of ferroptosis. Fats Lipidomics Organelles
N Nature Cell Biology · Oct 28, 2025 TemporalVAE: atlas-assisted temporal mapping of time-series single-cell transcriptomes during embryogenesis International efforts have yielded extensive single-cell time-series atlas datasets, such as those on mouse embryogenesis, providing a reference for mapping disease models across biomedical research. However, effectively using such data for temporal analysis of individual datasets is challenging due to the intricate nature of cell states and the tight coupling between time stamps and experimental batches. Here we introduce TemporalVAE, a deep generative model in a dual-objective setting that infers the biological time of each cell from a compressed latent space, even in a zero-shot setting. With a mouse development atlas, we demonstrated its scalability with millions of cells, accuracy in atlas-based cell staging across platforms and interpretability by identifying temporally sensitive genes with in silico perturbation. TemporalVAE effectively stages cells during human peri-implantation under both in vivo and in vitro conditions, and supports cross-primate comparisons among human, cynomolgus and marmoset embryos, highlighting its potential for broad biomedical applications. Cell biology Computational biology and bioinformatics Developmental biology
N Nature Cell Biology · Oct 24, 2025 A comprehensive tRNA pseudouridine map uncovers targets dependent on human stand-alone pseudouridine synthases Pseudouridine (Ψ) is one of the most abundant RNA modifications in human cells, introduced post-transcriptionally by pseudouridine synthases (PUS). Despite its prevalence, the biological functions of Ψ remain poorly understood, largely due to the limited knowledge linking specific PUS enzymes to their targets. Here, to address this gap, we systematically knocked out or knocked down nine stand-alone PUS in HCT116 cells and mapped their Ψ profiles using 2-bromoacrylamide-assisted cyclization sequencing. Through this approach, we uncovered previously unknown targets of several PUS enzymes, including RPUSD1, RPUSD2, PUS3, PUSL1 and PUS7L. In addition, we revealed that TRUB1 and PUS10 function redundantly to catalyse the highly conserved Ψ55 modification in cytosolic tRNAs. Intriguingly, we found that RPUSD3 and TRUB2 do not exhibit noticeable enzymatic activities in human cells. By integrating these findings with earlier results for TRUB1, PUS7 and PUS1, we constructed a comprehensive map of stand-alone PUS-dependent Ψ modifications across human tRNAs. Using this map, we further demonstrated that different PUS enzymes introduce Ψ modifications at distinct stages of pre-tRNA processing. RNA
N Nature Cell Biology · Oct 21, 2025 Enhancer activation from transposable elements in extrachromosomal DNA Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoural heterogeneity in aggressive cancers. While transposable element reactivation is common in cancer, its role on ecDNA remains unexplored. Here we map the 3D architecture ofMYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements—genomic loci enriched for transposable elements that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified withMYC, which functions only in the ecDNA-amplified context. Using CRISPR-CATCH, CRISPR interference and reporter assays, we confirm its presence on ecDNA, enhancer activity and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumour evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy. Cancer Cell biology Gene regulation
N Nature Cell Biology · Oct 16, 2025 Epigenetic alterations facilitate transcriptional and translational programs in hypoxia Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5′UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5′UTRome. Cancer microenvironment Computer modelling Dynamic networks Gene regulatory networks
N Nature Cell Biology · Oct 15, 2025 A continuous totipotent-like cell-based embryo model recapitulates mouse embryogenesis from zygotic genome activation to gastrulation The development of stem-cell-derived models of mammalian embryogenesis has provided invaluable tools for investigating embryo development. However, constructing embryo models that can continuously recapitulate the developmental trajectory, from zygotic genome activation to gastrulation, remains challenging. Here we report the development of a chemical cocktail to induce totipotent-like cells with robust proliferative ability and leverage these cells to establish a stepwise protocol for generating a continuous embryo model. This model sequentially mimics mouse embryogenesis from embryonic day 1.5 to 7.5. It recapitulates key developmental milestones, including zygotic genome activation in 2-cell embryos, the diversification of embryonic and extraembryonic lineages from 4-cell to 64-cell stages, the formation of blastocysts and the subsequent development into post-implantation egg cylinders. Notably, these structures undergo gastrulation, as indicated by the formation of a primitive streak-like structure and the subsequent emergence of several early organogenesis hallmarks. Our study opens avenues for modelling mammalian embryogenesis in vitro. Gastrulation Totipotent stem cells
N Nature Cell Biology · Oct 14, 2025 Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer’s disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline. Chaperone-mediated autophagy Protein quality control Proteins
N Nature Cell Biology · Oct 13, 2025 Cholesterol sensing by the SCAP–FAM134B complex regulates ER-phagy and STING innate immunity The endoplasmic reticulum (ER) is central to cholesterol biosynthesis and trafficking, yet paradoxically maintains low cholesterol levels, enabling it to sense fluctuations that impact various signalling pathways. However, the role of ER cholesterol in cellular signalling remains unclear. Here we show that the ER-phagy receptor FAM134B interacts directly with both cholesterol and SCAP, a key regulator of cholesterol biosynthesis. When ER cholesterol is high, FAM134B and SCAP are sequestered by cholesterol-tightened interactions, halting ER-phagy, STING activation and cholesterol synthesis. Under low cholesterol conditions, FAM134B dissociates from SCAP, allowing SCAP to activate SREBP2 and upregulate cholesterol synthesis, while FAM134B either facilitates ER-phagy through oligomerization or aids STING trafficking to activate innate immune responses. These findings reveal that the SCAP–FAM134B complex senses ER cholesterol levels, regulating both ER-phagy and immune signalling, with implications for diseases linked to cholesterol imbalance. Innate immunity Lipid signalling Macroautophagy
N Nature Cell Biology · Oct 13, 2025 CoCo-ST detects global and local biological structures in spatial transcriptomics datasets Spatial domain detection methods often focus on high-variance structures, such as tumour-adjacent regions with sharp gene expression changes, while missing low-variance structures with subtle gene expression shifts, like those between adjacent normal and early adenoma regions. Here, to address this, we introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive feature representation framework. By comparing a target sample with a background sample, CoCo-ST detects both high-variance, broadly shared structures and low-variance, tissue-specific features. It offers technical advantages, including multisample integration, batch-effect correction and scalability across technologies from spot-level Visium data to single-cell Xenium Prime 5K and subcellular Visium HD data. We benchmarked CoCo-ST against ten state-of-the-art spatial-domain-detection algorithms using mouse lung precancerous samples, demonstrating its superior ability to identify low-variance spatial structures overlooked by other methods. CoCo-ST also effectively distinguishes cell clusters and niche structures in Visium HD and Xenium Prime 5K data. CoCo-ST is accessible at GitHub ( https://github.com/WuLabMDA/CoCo-ST ). Wu, Zhang and colleagues introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive learning-based method for spatial transcriptomics analysis that detects low-variance structures. Bioinformatics Cancer models Computational biology and bioinformatics
N Nature Cell Biology · Oct 13, 2025 MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson’s disease-related genes, includingVPS35andLRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL,LRRK2orVPS35inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria–lysosome pathway at the nexus of immune signalling and cell death. Cell death Cell death and immune response Inflammation Lysosomes Mitochondria
N Nature Cell Biology · Oct 06, 2025 Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes, including hair greying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate tracking in mice revealed that McSCs undergo cellular senescence-coupled differentiation (seno-differentiation) in response to DNA double-strand breaks, resulting in their selective depletion and hair greying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in cells harbouring double-strand breaks, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones—expansion versus exhaustion—cumulatively and antagonistically governs ageing phenotypes through interaction with the niche. Ageing Skin stem cells
N Nature Cell Biology · Oct 03, 2025 CellNavi predicts genes directing cellular transitions by learning a gene graph-enhanced cell state manifold A select few genes act as pivotal drivers in the process of cell state transitions. However, finding key genes involved in different transitions is challenging. Here, to address this problem, we present CellNavi, a deep learning-based framework designed to predict genes that drive cell state transitions. CellNavi builds a driver gene predictor upon a cell state manifold, which captures the intrinsic features of cells by learning from large-scale, high-dimensional transcriptomics data and integrating gene graphs with directional connections. Our analysis shows that CellNavi can accurately predict driver genes for transitions induced by genetic, chemical and cytokine perturbations across diverse cell types, conditions and studies. By leveraging a biologically meaningful cell state manifold, it is proficient in tasks involving critical transitions such as cellular differentiation, disease progression and drug response. CellNavi represents a substantial advancement in driver gene prediction and cell state manipulation, opening new avenues in disease biology and therapeutic discovery. Cell biology Computational biology and bioinformatics Drug discovery
N Nature Cell Biology · Oct 01, 2025 Remodelling bivalent chromatin is essential for mouse peri-implantation embryogenesis Bivalency regulates developmental genes during lineage commitment. However, mechanisms governing bivalent domain establishment, maintenance and resolution in early embryogenesis remain unclear. Here we comprehensively trace bivalent chromatin remodelling throughout mouse peri-implantation development, revealing bifurcated establishment modes that partition epiblast and primitive endoderm regulatory programmes. We identify transiently maintained bivalent domains (TB domains) enriched in the epiblast, where gradual resolution fine-tunes pluripotency progression. Through targeted screening in embryos, we uncover 22 TB domain regulators, including the essential factor ZBTB17. Genetic ablation or degradation of ZBTB17 causes peri-implantation arrest. Mechanistically, ZBTB17 collaborates with KDM6A/B to resolve bivalency by removing H3K27me3 and priming the activation of key pluripotency genes. Remarkably, TB domain dynamics are evolutionarily shared in human pluripotent transitions, with ZBTB17 involvement despite species differences. Our work establishes a framework for bivalent chromatin regulation in early mammalian development and elucidates how its resolution precisely controls lineage commitment. Embryogenesis Epigenetics
N Nature Cell Biology · Oct 01, 2025 Microtubule architecture connects AMOT stability to YAP/TAZ mechanotransduction and Hippo signalling Cellular mechanotransduction is a key informational system, yet its mechanisms remain elusive. Here we unveil the role of microtubules in mechanosignalling, operating downstream of subnuclear F-actin and nuclear envelope mechanics. Upon mechanical activation, microtubules reorganize from a perinuclear cage into a radial array nucleated by centrosomes. This structural rearrangement triggers degradation of AMOT proteins, which we identify as key mechanical rheostats that sequester YAP/TAZ in the cytoplasm. AMOT is stable in mechano-OFF but degraded in mechano-ON cell states, where microtubules allow AMOT rapid transport to the pericentrosomal proteasome in complex with dynein/dynactin. This process ensures swift control of YAP/TAZ function in response to changes in cell mechanics, with experimental loss of AMOT proteins rendering cells insensitive to mechanical modulations. Ras/RTK oncogenes promote YAP/TAZ-dependent tumorigenesis by corrupting this AMOT-centred mechanical checkpoint. Notably, the Hippo pathway fine-tunes mechanotransduction: LATS kinases phosphorylate AMOT, shielding it from degradation, thereby indirectly restraining YAP/TAZ. Thus, AMOT protein stability serves as a hub linking cytoskeletal reorganization and Hippo signalling to YAP/TAZ mechanosignalling. Cytoskeleton Developmental biology
N Nature Cell Biology · Sep 30, 2025 Phase-separated NDF−FACT condensates facilitate transcription elongation on chromatin How the facilitates chromatin transcription (FACT) complex enables RNA polymerase II to overcome chromatin barriers in cells remains poorly understood—especially given the limited direct interactions of FACT with polymerases, DNA or nucleosomes. Here we demonstrate that phase separation, mediated by nucleosome destabilizing factor (NDF), is a key mechanism enabling the function of FACT during transcription elongation. Through biochemical and single-molecule assays, we found that NDF−FACT condensates create specialized biochemical environments that enhance transcription efficiency approximately 20-fold compared with FACT alone. These dynamic condensates form on transcribing RNA polymerase II and travel along chromatin, where they promote efficient nucleosome disassembly at barriers while retaining histones on DNA to preserve chromatin integrity. In human stem cells, disruption of these condensates leads to genome-wide transcriptional defects and chromatin instability, mirroring the effects of FACT depletion. By showing that phase separation enhances FACT function during transcription elongation, our study reveals a key mechanism that preserves chromatin integrity and transcriptional homeostasis in human stem cells. Nuclear organization Transcriptional regulatory elements
N Nature Cell Biology · Sep 30, 2025 Defining heterogeneity in core regulatory circuitry reveals HOXB3 condensation as a potential target in glioblastoma Glioblastoma (GBM) exhibits marked heterogeneity, yet therapeutic strategies effectively targeting this variability remain inadequately developed. Here we employed single-cell CUT&Tag analysis to investigate H3K27ac modifications, uncovering pronounced heterogeneity within the core regulatory circuitry (CRC) of GBM. Notably, we observed heterogeneous condensation states of CRC factors, particularly HOXB3, which are shaped by its intrinsically disordered regions and interactions with RUNX1, driving the phenotypic manifestations. Leveraging these findings, we synthesized the peptide P621-R9, which effectively disrupted HOXB3 condensation, altered chromatin structure and reduced transcription at super-enhancer-associated oncogenic sites in GBM cells exhibiting HOXB3 condensation. Treatment with P621-R9 selectively diminished tumourigenic potential in GBM patient-derived xenograft models characterized by HOXB3 condensates, but showed no efficacy in the models lacking these condensates. These results highlight the critical role of CRC condensation in GBM heterogeneity and suggest that peptide-based targeting of distinct GBM subpopulations could represent an avenue for therapeutic exploration. Cancer epigenetics Cancer immunotherapy CNS cancer
N Nature Cell Biology · Sep 29, 2025 Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although signalling circuits and gene regulatory networks that regulate pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological changes and mechanical deformations to control state transitions remains a fundamental open question. Here we focus on two distinct models of pluripotency, preimplantation inner cell mass cells of human embryos and primed pluripotent stem cells, to discover that cell fate transitions associate with rapid, compaction-triggered changes in nuclear shape and volume. These phenotypical changes and the associated active deformation of the nuclear envelope arise from growth factor signalling-controlled changes in cytoskeletal confinement and chromatin mechanics. The resulting osmotic stress state triggers global transcriptional repression, macromolecular crowding and remodelling of nuclear condensates that prime chromatin for a cell fate transition by attenuating repression of differentiation genes. However, while this mechano-osmotic chromatin priming has the potential to accelerate fate transitions and differentiation, sustained biochemical signals are required for robust induction of specific lineages. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signalling and chromatin state to control cell fate transition dynamics. Biophysics Cell biology
N Nature Cell Biology · Sep 26, 2025 Remote control of AMPK via extracellular adenosine controls tissue growth Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a regulator of cellular catabolism that is activated by AMP. As AMP accumulates in cells with low ATP, AMPK is considered a stress-activated kinase. While studying organ growth duringDrosophiladevelopment, we find that AMPK can also be activated by a signalling metabolite not related to stress. Specifically, we find that two physiological inputs known to regulate organ growth rates (ecdysone (a steroid hormone) and dietary protein) modulate expression of adenosine deaminase in the intestine. This, in turn, alters circulating adenosine levels. Circulating adenosine acts as a signalling molecule by entering cells, becoming phosphorylated to AMP and activating AMPK to inhibit organ growth. Thus, AMPK activity is regulated developmentally, and AMPK activity in one tissue can be remote controlled by another tissue via circulating adenosine. Notably, this mechanism accounts for half the effect of dietary protein on tissue growth rates inDrosophila. Cell growth Cell signalling Drosophila
N Nature Cell Biology · Sep 22, 2025 Membrane receptors cluster phosphatidylserine to activate LC3-associated phagocytosis LC3-associated phagocytosis (LAP) represents a non-canonical function of autophagy proteins in which ATG8-family proteins (LC3 and GABARAP proteins) are lipidated onto single-membrane phagosomes as particles are engulfed by phagocytic cells. LAP plays roles in innate immunity, inflammation and anticancer responses, and is initiated following phagocytosis of particles that stimulate Toll-like receptors (TLR) and Fc receptors as well as following engulfment of dying cells. However, how this molecular process is initiated remains elusive. Here we report that receptors that engage LAP enrich phosphatidylserine (PS) in the phagosome membrane via membrane-proximal domains that are necessary and sufficient for LAP to proceed. Subsequently, PS recruits the Rubicon-containing PI3-kinase complex to initiate the enzymatic cascade leading to LAP. Manipulation of plasma membrane PS content, PS binding by Rubicon or the PS-clustering domains of receptors prevents LAP and delays phagosome maturation. Therefore, the initiation of LAP represents a novel mechanism of PS-mediated signal transduction following ligation of surface receptors. Here the authors show that LC3-associated phagocytosis is initiated by various receptors, which enrich phosphatidylserine in the membrane domains proximal to the phagosome, recruiting Rubicon to the membrane for phagosome maturation. Autophagy Innate immunity Lipid signalling Lipidomics Monocytes and macrophages
N Nature Cell Biology · Sep 17, 2025 A subset of transposable elements as mechano-response enhancer elements in controlling human embryonic stem cell fate Transposable elements (TEs), constituting half of the human genome, are essential for development and diseases. While the regulation of TE activity by cellular intrinsic mechanisms is well documented, their response to microenvironmental signals, particularly mechanical cues involving numerous biological processes, remains unknown. Here we show that various TE families, notably LTR7, undergo transcriptomic, epigenetic and three-dimensional genome changes in response to matrix mechanical cues in human embryonic stem cells. Interestingly, LTR7s act as ‘mechano-response enhancer elements’ (MREEs), controlling the gene expression and cell fate of human embryonic stem cells. Mechanistically, mechano-effectors YAP/TEAD1 control LTR7’s epigenetic activity by engaging with BRD4. Furthermore, YAP recruits CTCF, a key genome architecture protein, to facilitate long-range interactions between gene promoters and TEs as MREEs. In particular, a mechano-responsive LTR7 element is a distal enhancer forFAM189A2, thereby inhibiting definitive endoderm differentiation. These findings highlight the underappreciated role of TEs as MREEs that control human cell fate and gene expression. Chromatin structure Epigenomics Gene regulation
N Nature Cell Biology · Sep 16, 2025 Two microbiome metabolites compete for tRNA modification to impact mammalian cell proliferation and translation quality control The microbiome affects eukaryotic host cells via many metabolites, including the well-studied queuine as substrate for host tRNA queuosine modification. The microbial metabolite pre-queuosine 1 (preQ1) is produced in the bacterial tRNA queuosine biosynthesis pathway, with unknown effects on host cell biology. Here we show that preQ1strongly represses cell proliferation in both human and mouse cells. Queuine reverses this effect by competing with preQ1to modify the same tRNA. PreQ1is detectable in the plasma and tissues of mice, and its injection suppresses tumour growth in a mouse cancer model. Mechanistically, preQ1reduces cognate tRNA levels specifically, as well as codon-dependent translation of housekeeping genes. We identify the endoplasmic reticulum-localized inositol-requiring enzyme 1 (IRE1) ribonuclease as the enzyme responsible for the selective degradation of preQ1-modified tRNAs on translating ribosomes. Our results identify two microbial metabolites competing for host tRNA modification, which elicits translation quality control and impacts cell proliferation. RNA Translation
N Nature Cell Biology · Sep 09, 2025 Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)–paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FATL994Eknock-in mouse, which disrupts FAK–paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK–paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer. Cell migration Mechanotransduction Pancreatic cancer
N Nature Cell Biology · Sep 09, 2025 CD160 dictates anti-PD-1 immunotherapy resistance by regulating CD8+T cell exhaustion in colorectal cancer The colon exhibits higher propensity for tumour development than ileum. However, the role of immune microenvironment differences in driving this disparity remains unclear. Here, by comparing paired ileum and colon samples from patients with colorectal cancer (CRC) and healthy donors, we identified ileum-enriched CD160+CD8+T cells with previously unrecognized characteristics, including resistance to terminal exhaustion and strong clonal expansion. The transfer of CD160+CD8+T cells significantly inhibits tumour growth in microsatellite instability-high and inflammation-induced CRC models.Cd160knockout accelerates tumour growth, which is mitigated by transferring CD160+CD8+T cells. Notably, in microsatellite instability-high and anti-PD-1-resistant CRC models, CD160+CD8+T cells improve anti-PD-1 efficacy and overcome its resistance by increasing tumour-infiltrating progenitor-exhausted T cells, nearly eradicating tumours. Mechanistically, we uncover a CD160–PI3K (p85α) interaction that promotes FcεR1γ and 4-1BB expression via the AKT–NF-κB pathway, thereby enhancing CD8+T cell cytotoxicity. Our study reveals CD160 as a crucial regulator of CD8+T cell function and proposes an innovative immunotherapy strategy of transferring CD160+CD8+T cells to overcome anti-PD-1 resistance. Cancer immunotherapy Cancer therapeutic resistance Colorectal cancer T cells
N Nature Cell Biology · Sep 08, 2025 Hbo1 and Msl complexes preserve differential compaction and H3K27me3 marking of active and inactive X chromosomes during mitosis In mammals, chromosome-wide regulatory mechanisms ensure a balance of X-linked gene dosage between males (XY) and females (XX). In female cells, expression of genes from one of the two X chromosomes is curtailed, with selective accumulation of Xist-RNA, Xist-associated proteins, specific histone modifications (for example, H3K27me3) and Barr body formation observed throughout interphase. Here we show, using chromosome flow-sorting, that during mitosis, Xist-associated proteins dissociate from inactive X (Xi) chromosomes, while high levels of H3K27me3 and increased compaction of the Xi relative to active X (Xa), are retained. Proteomic comparison of mitotic Xi and Xa revealed that components of Hbo1 and Msl/Mof histone acetyltransferase complexes are significantly enriched on Xa as compared to Xi and autosomes. By contrast, inhibitors of histone acetylation co-enrich with Xi. Furthermore, inhibition of Hbo1 or deletion of Msl/Mof components functionally abolishes mitotic differences in H3K27me3 marking and chromosome compaction. These data uncover critical roles for acetylation pathways in preserving X chromosome properties during mitosis. Dosage compensation Mitosis
N Nature Cell Biology · Sep 08, 2025 RNA-binding proteins mediate the maturation of chromatin topology during differentiation Topologically associating domains (TADs) and chromatin architectural loops impact promoter–enhancer interactions, with CCCTC-binding factor (CTCF) defining TAD borders and loop anchors. TAD boundaries and loops progressively strengthen upon embryonic stem (ES) cell differentiation, underscoring the importance of chromatin topology in ontogeny. However, the mechanisms driving this process remain unclear. Here we show a widespread increase in CTCF–RNA-binding protein (RBP) interactions upon ES to neural stem (NS) cell differentiation. While dispensable in ES cells, RBPs reinforce CTCF-anchored chromatin topology in NS cells. We identify Pantr1, a non-coding RNA, as a key facilitator of CTCF–RBP interactions, promoting chromatin maturation. Using acute CTCF degradation, we find that, through its insulator function, CTCF helps maintain neuronal gene silencing in NS cells by acting as a barrier to untimely gene activation during development. Altogether, we reveal a fundamental mechanism driving developmentally linked chromatin structural consolidation and the contribution of this process to the control of gene expression in differentiation. Differentiation Nuclear organization Stem-cell differentiation
N Nature Cell Biology · Sep 05, 2025 Phase separation of ERCC6L2–CtIP regulates the extent of DNA end resection The ataxia telangiectasia mutated (ATM) kinase orchestrates the early stages of DNA double-strand break repair by promoting hyperphosphorylation of CtIP, a key step in the initiation of DNA end resection. However, the regulatory mechanisms controlling resection extent remain incompletely understood. Here we identify ERCC6L2 as a key regulator of DNA end resection in response to ATM inhibition. ERCC6L2 undergoes liquid–liquid phase separation via its intrinsically disordered regions, forming dynamic nuclear condensates that regulate CtIP stability. Disruption of these condensates renders CtIP susceptible to RNF138-mediated ubiquitination and degradation, thereby mitigating the heightened chromatin recruitment of CtIP induced by ATM inhibition. Intriguingly, ERCC6L2 is frequently downregulated in multiple cancer types and correlates with resistance to ATM inhibitors in both in vitro and in vivo settings. Our findings unveil the crucial role of ERCC6L2–CtIP condensates in governing the extent of DNA end resection and underscore the potential significance of ERCC6L2 as a predictive biomarker for ATM inhibitor response. DNA damage and repair Targeted therapies
N Nature Cell Biology · Sep 05, 2025 MLKL PARylation in the endothelial niche triggers angiocrine necroptosis to evade cancer immunosurveillance and chemotherapy Chemoresistance is the leading cause of cancer-related death. How chemotherapy subjugates the cellular crosstalk in the tumour microenvironment to cause chemoresistance remains to be defined. Here we find chemotherapy enables immunosuppressive SDF1+endothelial niche to evade immunosurveillance in ovarian and breast cancers. We integrated human patient data and mouse models to show that chemotherapy selectively activates PARP1–SDF1 axis in tumour endothelial cells (ECs). This angiocrine SDF1 interferes with antitumour interplay between CXCL10+macrophages and CXCR3+CD8+T cells and promotes tumour progression in ovarian and breast cancers. Proteome-based screening revealed that endothelial PARP1 PARylates MLKL, a key necroptosis effector to upregulate angiocrine SDF1 in ECs. In sum, we identify PARylation-dependent necroptosis in tumour ECs as an important step in subverting the tumour microenvironment to evade immunosurveillance. Cancer microenvironment Chemotherapy Immunosurveillance Necroptosis
N Nature Cell Biology · Aug 27, 2025 Synthetic ZFTA fusions pinpoint disordered protein domain acquisition as a mechanism of brain tumorigenesis Arabzade, Shirnekhi, Varadharajan, Ippagunta and colleagues show that the zinc finger translocation-associated (ZFTA) fusion oncoproteins gain intrinsically disordered regions, inducing nuclear condensate formation and oncogenic activation.
N Nature Cell Biology · Aug 27, 2025 Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing Xu et al. perform a whole-genome CRISPR-Cas9 knockout screen using directed differentiation systems. They find that MEN1 and SUZ12 modulate human developmental timing by epigenetically controlling bivalent promoters of developmental genes.
N Nature Cell Biology · Aug 27, 2025 A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy Mauthe et al. find that protein aggregate clearance requires fragmentation of the aggregate by a chaperone module and a proteasomal regulatory particle for recruitment and clustering of selective autophagy receptors to initiate phagophore formation.
N Nature Cell Biology · Aug 27, 2025 NOX1 and NPY1R mark regional colon stem cell populations that serve as cancer origins in vivo Gasnier et al. identify NOX1 and NPY1R as markers of colon stem cells within the mouse caecum and the middle and distal colorectum, respectively. These stem cells contribute to the initiation of invasive colon tumours in mice.
N Nature Cell Biology · Aug 19, 2025 Systematic decoding of functional enhancer connectomes and risk variants in human glioma Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR–Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNPrs2297440regulatesSOX18expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma. Cancer epigenetics CNS cancer Epigenomics
N Nature Cell Biology · Aug 18, 2025 Edge curvature drives endoplasmic reticulum reorganization and dictates epithelial migration mode From single-cell extrusion to centimetre-sized wounds, epithelial gaps of various sizes and geometries appear across organisms. Their closure involves two orthogonal modes: lamellipodial crawling at convex edges and purse string-like movements at concave edges. The mechanisms driving this curvature-dependent migration remain unclear. Here we perform an intracellular cartography to reveal that in both micropatterned and naturally arising gaps, the endoplasmic reticulum (ER) undergoes edge curvature-dependent morphological reorganizations, forming tubules at convex edges and sheets at concave edges. This reorganization depends on cytoskeleton-generated protrusive and contractile forces. Mathematical modelling reveals that these morphologies minimize strain energy under their respective geometric regime. Functionally, ER tubules at the convex edge favour perpendicularly oriented focal adhesions, supporting lamellipodial crawling, while ER sheets at the concave edge favour parallelly oriented focal adhesions, supporting purse string-like movements. Altogether, ER emerges as a central mechanotransducer, integrating signals from cytoskeletal networks to orchestrate two orthogonal modes of cell migration. Collective cell migration Computational biophysics Endoplasmic reticulum
