Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signa...Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signature and molecular behaviour of human telomeric chromatin. Recent structural and genetic studies further highlight the distinctive and dynamic nature of the telomeric architecture. Here we present an updated perspective on telomeric chromatin, focusing on the unique features that set telomeres apart from other genomic regions and that equip them to address the specific challenges at chromosome ends. In addition, we discuss how alterations in telomeric chromatin influence stem cells, inherited diseases and cancer, demonstrating how telomere architecture governs both its integrity and function.
Tang J, Chen Z, Qian K
… +9 more, Huang S, He Y, Yin S, He X, Ye B, Zhuang Y, Meng H, Xi JJ, Xi R
Nat Cell Biol
· 2026 Feb · PMID 41495202
·
Full text
Spatial transcriptomics (ST) technologies revolutionized tissue architecture studies by capturing gene expression with spatial context. However, high-dimensional ST data often have limited spatial resolution and exhibit...Spatial transcriptomics (ST) technologies revolutionized tissue architecture studies by capturing gene expression with spatial context. However, high-dimensional ST data often have limited spatial resolution and exhibit considerable noise and sparsity, posing substantial challenges in deciphering subtle spatial structures and underlying biological activities. Here we introduce 'spatial high-definition embedding mapping' (SpaHDmap), an interpretable dimension reduction framework that enhances spatial resolution by integrating ST gene expression with high-resolution histology images. SpaHDmap incorporates non-negative matrix factorization into a deep learning framework, enabling the identification of high-resolution spatial metagenes (embeddings). Furthermore, SpaHDmap can simultaneously analyse multiple samples and is compatible with various types of histology images. Extensive evaluations on synthetic, public and newly sequenced ST datasets from various technologies and tissue types demonstrate that SpaHDmap can effectively produce high-resolution spatial metagenes, and detect refined spatial structures. SpaHDmap represents a powerful approach for integrating ST data and histology images, offering deeper insights into complex tissue structures and functions.
Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular proces...Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations.
Li D, Cui G, Yang K
… +27 more, Lu C, Jiang Y, Zhang L, Wu Q, Dixit D, Zhu Z, Gimple RC, Gu D, Gao J, Lin Q, Yu H, Shi Z, Chen Y, Wang Q, Jin G, Lin F, Shao J, Zhou Q, Liu C, Li C, You Y, Zhang N, Zhang J, Qian X, Zhang Q, Rich JN, Wang X
Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate...Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4-MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.
Nat Cell Biol
· 2026 Jan · PMID 41495199
·
Full text
Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detect...Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detecting and eliminating cells dividing outside the stereotyped duration of successful mitosis. This Perspective examines recent advances in our understanding of mitotic timing mechanisms, presents emerging evidence for novel mitotic clocks and proposes a conceptual framework for how cells integrate temporal cues to preserve genomic integrity.
Scourzic L, Izzo F, Teater M
… +21 more, Polyzos AP, Cucereavii L, Chin CR, Papin A, Pinto HB, Mlynarczyk C, Tsialta I, Xia M, Lidoski A, Myers RM, Israel EM, Venturutti L, Mackay SP, Hoehn KB, Skoultchi AI, Béguelin W, Stadtfeld M, Chen Z, Landau DA, Melnick AM, Apostolou E
Nat Cell Biol
· 2026 Jan · PMID 41466145
·
Full text
During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently a...During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (T) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other T-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis.
Seufert I, Gerosa I, Varamogianni-Mamatsi V
… +11 more, Vladimirova A, Sen E, Mantz S, Rademacher A, Schumacher S, Liakopoulos P, Kolovos P, Anders S, Mallm JP, Papantonis A, Rippe K
Gene activation and coregulation have been attributed to different mechanisms, such as enhancer-promoter interactions via chromatin looping or the accumulation of transcription factors into hubs or condensates. However,...Gene activation and coregulation have been attributed to different mechanisms, such as enhancer-promoter interactions via chromatin looping or the accumulation of transcription factors into hubs or condensates. However, genome-wide studies exploring mechanistic differences in endogenous gene regulation in primary human cells are scarce. Here we dissect the proinflammatory gene expression programme induced by tumor necrosis factor (TNF) in human endothelial cells using sequencing- and imaging-based methods. Our findings, enabled by the co-accessibility analysis of deep-coverage single-cell chromatin accessibility data with our RWireX software, identified two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) between separated sites and domains of contiguous co-accessibility (DCs) with increased local transcription factor binding. The TNF-dependent induction timing and strength as well as changes in transcriptional bursting kinetics differed for genes in the AC and DC modules, pointing to functionally distinct regulatory mechanisms. These findings provide a framework for understanding how cells achieve rapid and precise control of gene expression.
Schooley A, Venev SV, Aksenova V
… +5 more, Lehman JW, Navarrete E, Pai AA, Dasso M, Dekker J
Nat Cell Biol
· 2026 Jan · PMID 41429936
·
Full text
Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those...Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those propagated through the cytoplasm during G1 nuclear reassembly. Inducible degradation of proteins essential for the establishment of nucleocytoplasmic transport during mitotic exit enabled analysis of folding programmes with distinct modes of inheritance. Here we show that genome compartmentalization is driven entirely by chromosome-intrinsic factors. In addition to conventional compartmental segregation, the chromosome-intrinsic folding programme leads to prominent genome-scale microcompartmentalization of mitotically bookmarked cis-regulatory elements. The microcompartment conformation forms transiently during telophase and is subsequently modulated by a second folding programme inherited through the cytoplasm in early G1. This programme includes cohesin-mediated loop extrusion and factors involved in transcription and RNA processing. The combined and interdependent action of chromosome-intrinsic and cytoplasmic inherited folding programmes determines the interphase chromatin conformation as cells exit mitosis.
Lee BH, Fuji K, Petzold H
… +8 more, Seymour P, Yennek S, Schewin C, Lewis A, Riveline D, Hiraiwa T, Sano M, Grapin-Botton A
Nat Cell Biol
· 2026 Jan · PMID 41419573
·
Full text
Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex st...Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment.
Nat Cell Biol
· 2026 Jan · PMID 41419572
·
Full text
When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translatio...When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.
Borsa M, Lechuga-Vieco AV, Kayvanjoo AH
… +13 more, Jenkins E, Yazicioglu Y, Compeer EB, Richter FC, Rapp S, Mitchell R, Youdale T, Bui H, Kuuluvainen E, Dustin ML, Sinclair LV, Katajisto P, Simon AK
Nat Cell Biol
· 2026 Jan · PMID 41419571
·
Full text
T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8 T cells. Using a mouse model that enables...T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8 T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
Makwana K, Tilley L, Chakravarty P
… +4 more, Thompson J, Baillie-Benson P, Rodriguez-Polo I, Moris N
Nat Cell Biol
· 2025 Dec · PMID 41402467
·
Full text
Human stem cell-based embryo models provide experimentally amenable in vitro systems for developmental research. A key feature of embryo models is their multi-lineage differentiation, which allows for the study of tissue...Human stem cell-based embryo models provide experimentally amenable in vitro systems for developmental research. A key feature of embryo models is their multi-lineage differentiation, which allows for the study of tissue co-development. Here we develop human trunk-like structures that have morphologically organized somites and a neural tube that form through self-organized, endogenous signalling. Transcriptomic comparison with human embryo datasets suggests that human trunk-like structure cells approximate Carnegie stage 13-14 (28-35 days after fertilization). The absence of a notochord leads to a dorsal identity, but exogenous Sonic Hedgehog signalling activation ventralizes both the somites and the neural tube in a dose-dependent manner. We further identify reciprocal signalling: neural tube-derived cues induce medial ALDH1A2 in somites, which in turn generate retinoic acid signals that drive spontaneous neural-tube patterning. Together, our data highlight the value of modularity in embryo models, which we leverage to explore human trunk co-development.
Hauth A, Panten J, Kneuss E
… +15 more, Picard C, Servant N, Rall I, Pérez-Rico YA, Clerquin L, Servaas N, Villacorta L, Jung F, Luong C, Chang HY, Zaugg JB, Stegle O, Odom DT, Heard E, Loda A
Nat Cell Biol
· 2026 Jan · PMID 41398052
·
Full text
In placental XX females, one X chromosome is silenced during a narrow developmental time window by X-chromosome inactivation, which is mediated by Xist noncoding RNA. Although most X-linked genes are silenced during X-ch...In placental XX females, one X chromosome is silenced during a narrow developmental time window by X-chromosome inactivation, which is mediated by Xist noncoding RNA. Although most X-linked genes are silenced during X-chromosome inactivation, some genes can escape. Here, by increasing its endogenous level, we show that Xist RNA can silence escapees well beyond early embryogenesis both in vitro, in differentiated cells, as well as in vivo, in mouse pre- and post-implantation embryos. We further demonstrate that Xist RNA plays a role in eliminating topologically associating domain-like structures spanning clusters of escapees, and this is dependent on SPEN. The function of Xist in silencing escapees and eliminating topological domains is initially fully reversible, but sustained Xist upregulation leads to irreversible silencing and CpG island DNA methylation of escapees. Thus, gene activity and three-dimensional topology of the inactive X chromosome are directly controlled by Xist, well beyond an early developmental time window.
Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we...Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
Benito-Martínez S, Salavessa L, Macé AS
… +19 more, Rouabah M, Lardier N, Fraisier V, Sirés-Campos J, Jani RA, Romao M, Roca V, Gayrard C, Plessis M, Hurbain I, Nait-Meddour C, Etienne-Manneville S, Morel E, Boniotto M, Manneville JB, Bernerd F, Duval C, Raposo G, Delevoye C
Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by...Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress.
Cornell CE, Chorlay A, Krishnamurthy D
… +3 more, Martin NR, Baldauf L, Fletcher DA
Nat Cell Biol
· 2025 Dec · PMID 41387582
·
Full text
Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis vers...Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension, they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that the target cell, rather than the macrophage, determines whether phagocytosis or trogocytosis occurs, and that macrophages do not require a distinct molecular pathway for trogocytosis.