bims-ginsta Biomed News
on Genome instability
Issue of 2025–07–27
thirty-one papers selected by
Jinrong Hu, National University of Singapore
  1. The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.
  2. High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
  3. Microtubules coordinate mitochondria transport with myofibril morphogenesis during muscle development.
  4. Basement membrane perforations guide anterior-posterior axis formation.
  5. Jpx RNA controls Xist induction through spatial reorganization of the mouse X-inactivation center.
  6. 19S proteasome loss regulates mitotic spindle assembly through a ubiquitin-independent degradation mechanism.
  7. Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate.
  8. Anillin directly crosslinks microtubules with actin filaments.
  9. An extracellular matrix niche secreted by epithelial cells drives intestinal organoid formation.
  10. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
  11. Metabolic regulation of key developmental events during mammalian embryogenesis.
  12. Telocytes deliver essential Wnts directly to murine intestinal stem cells via synapse-like contacts.
  13. Regulation of inflammatory responses by pH-dependent transcriptional condensates.
  14. The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation.
  15. G-quadruplexes are promoter elements controlling nucleosome exclusion and RNA polymerase II pausing.
  16. NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
  17. mTORC1 senses glutamine and other amino acids through GCN2.
  18. β-catenin functions as a molecular adapter for disordered cBAF interactions.
  19. Pre-rRNA spatial distribution and functional organization of the nucleolus.
  20. Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
  21. The Unkempt RNA-binding protein reveals a local translation program in centriole overduplication.
  22. Rho-ROCK liberates sequestered claudin for rapid de novo tight junction formation.
  23. Polyploidy promotes transformation of epithelial cells into nonprofessional phagocytes.
  24. Breaking point: mechanical stress helps NINJ1 protein to rupture membranes.
  25. Spatial proteomics of Alzheimer's disease-specific human microglial states.
  26. Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration.
  27. A STAT3/integrin axis accelerates pancreatic cancer initiation and progression.
  28. Transmembrane coupling drives the growth of liquid-like protein condensates.
  29. Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.
  30. Small RNAs are modified with N-glycans and displayed on the surface of living cells.
  31. Age mosaic of gut epithelial cells prevents aging.
  1. Nat Cell Biol. 2025 Jul 22.
    The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.
    Harold C Marin, Charlie Allen, Eric Simental, Eric W Martin, Barbara Panning, Bassem Al-Sady, Abigail Buchwalter.
      Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the effect of spatial position on heterochromatin function has not been defined. Here we remove three nuclear lamins and the lamin B receptor (LBR) in mouse embryonic stem cells and show that heterochromatin detaches from the nuclear periphery. Mutant mouse embryonic stem cells sustain naive pluripotency and maintain H3K9me2 across the genome but cannot repress H3K9me2-marked genes or transposons. Further, mutant cells fail to differentiate into epiblast-like cells, a transition that requires the expansion of H3K9me2 across the genome. Mutant epiblast-like cells can silence naive pluripotency genes and activate epiblast-stage genes. However, H3K9me2 cannot repress markers of alternative fates, including primitive endoderm. We conclude that the lamins and LBR control the spatial position, dynamic remodelling and repressive capacity of H3K9me2-marked heterochromatin to shape cell fate decisions.
    DOI:  https://doi.org/10.1038/s41556-025-01703-z
  2. Science. 2025 Jul 24. eadx3800
    High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
    Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.
      Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.
    DOI:  https://doi.org/10.1126/science.adx3800
  3. Dev Cell. 2025 Jul 15. pii: S1534-5807(25)00411-3. [Epub ahead of print]
    Microtubules coordinate mitochondria transport with myofibril morphogenesis during muscle development.
    Jerome Avellaneda, Duarte Candeias, Ana da Rosa Soares, Edgar R Gomes, Nuno Miguel Luis, Frank Schnorrer.
      Muscle cells contain numerous energy-producing mitochondria and contractile myofibrils, whose myosin motors need ATP to generate force. Thus, myofibrils and mitochondria are in intimate contact in mature muscles. However, how their morphogenesis is coordinated during development remains largely unknown. Here, we used in vivo imaging to investigate myofibril and mitochondria network dynamics in developing Drosophila flight muscles. We found that mitochondria intercalate from the surface of actin bundles to their interior, and concomitantly, actin filaments condense to individual myofibrils. This ensures that mitochondria locate in proximity to every myofibril. Notably, antiparallel microtubules bundle with the assembling myofibrils, suggesting a key role in myofibril orientation. Indeed, microtubule severing affects myofibril orientation, whereas kinesin knockdown specifically blocks mitochondria intercalation. Importantly, mitochondria intercalation and their kinesin-dependent microtubule-based transport are conserved in mammalian muscle. Together, these data identify a key role for microtubules in coordinating mitochondria and myofibril morphogenesis to build functional muscles.
    Keywords:  Drosophila; development; kinesin; live imaging; microtubules; mitochondria; mouse; muscle; myofibrillogenesis; sarcomere
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.033
  4. Nat Commun. 2025 Jul 22. 16(1): 6763
    Basement membrane perforations guide anterior-posterior axis formation.
    Dong-Yuan Chen, Nikolas H Claussen, Shiny Titus, Wenqi Hu, Bailey A T Weatherbee, Rachel S Mandelbaum, Richard T Scott, Emre Seli, Sebastian J Streichan, Magdalena Zernicka-Goetz.
      Establishment of the anterior-posterior (AP) axis is a critical symmetry-breaking event in mammalian development. In mice, this process involves the directed migration of the distal visceral endoderm (DVE). Here, we use targeted perturbations to demonstrate that asymmetric perforations in the basement membrane guide DVE migration. During implantation, matrix metalloproteinases in extra-embryonic tissues create uneven basement membrane perforations, establishing directional cues for cohesive DVE migration. Using light-sheet microscopy and tissue cartography, we show that migrating DVE deforms surrounding tissues. Physical modeling and live imaging of DVE protrusions indicate that basement membrane perforations orchestrate active force generation within the DVE. Extending these findings to human embryos and stem cell-derived models, we identify basement membranes with enriched perforations near the anterior hypoblast in embryos, suggesting a conserved mechanism for AP axis specification. These findings reveal an unrecognized role of basement membrane remodeling and mechanical heterogeneity in guiding directional tissue migration during mammalian development.
    DOI:  https://doi.org/10.1038/s41467-025-61441-6
  5. Dev Cell. 2025 Jul 11. pii: S1534-5807(25)00406-X. [Epub ahead of print]
    Jpx RNA controls Xist induction through spatial reorganization of the mouse X-inactivation center.
    Hyun Jung Oh, Priyojit Das, Roy Blum, Andrea J Kriz, Hun-Goo Lee, Yong-Woo Lee, Jeannie T Lee.
      Known to regulate chromosome looping on a genome-wide scale, the noncoding Jpx RNA was originally shown to control X chromosome counting and induce Xist expression during X chromosome inactivation (XCI). Not fully understood is how Jpx upregulates Xist in coordination with Tsix downregulation in cis. Here, by integrating epigenomic data and polymer modeling in a mouse embryonic stem cell model, we demonstrate that Jpx controls architectural and transcriptional dynamics within anti- and pro-XCI zones of the X-inactivation center. Distinct topological changes occur on the future active X (Xa) and inactive X (Xi) chromosomes. Jpx binds the enhancer of Tsix on the future Xi and alters loop formation to favor Xist induction, coordinately releasing CTCF from Tsix and Xist in cis on the future Xi. Thus, by controlling a dynamic rewiring of functional loops, Jpx flips a transcriptional switch to control mutually exclusive Tsix and Xist expression in cis.
    Keywords:  3D genome structure; CTCF; Hi-C; Jpx RNA; X chromosome inactivation; X-inactivation center; XCI; Xist RNA; chromatin looping; epigenetics; loop extrusion
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.028
  6. Cell Rep. 2025 Jul 23. pii: S2211-1247(25)00812-5. [Epub ahead of print]44(8): 116041
    19S proteasome loss regulates mitotic spindle assembly through a ubiquitin-independent degradation mechanism.
    Océane Marescal, Iain M Cheeseman.
      During regulated protein degradation, the 26S proteasome recognizes ubiquitinated substrates through its 19S particle and then degrades them in its 20S enzymatic core. Despite this close interdependency between proteasome subunits, we demonstrate that knockouts from different proteasome subcomplexes result in distinct cellular phenotypes. In particular, depletion of 19S PSMD lid proteins, but not that of other proteasome subunits, prevents bipolar spindle assembly during mitosis. Despite decreased ubiquitin-mediated protein degradation in PSMD knockouts, we find that the monopolar spindle phenotype is instead caused by the aberrant degradation of the kinesin motor protein KIF11. We show that KIF11 degradation occurs through the 20S proteasome in a ubiquitin-independent manner upon loss of 19S proteins and that the resulting alterations in spindle forces lead to the unique monopolar phenotype. Thus, the presence of the 19S particle ensures proper spindle formation by restraining ubiquitin-independent degradation.
    Keywords:  CP: Cell biology; degradation; kinesin; mitosis; proteasome; spindle; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2025.116041
  7. EMBO J. 2025 Jul 21.
    Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate.
    Michael Namestnikov, Osnat Cohen-Zontag, Dorit Omer, Yehudit Gnatek, Sanja Goldberg, Thomas Vincent, Swati Singh, Yair Shiber, Tal Rafaeli Yehudai, Hadas Volkov, Dani Folkman Genet, Achia Urbach, Sylvie Polak-Charcon, Igor Grinberg, Naomi Pode-Shakked, Boaz Weisz, Zvi Vaknin, Benjamin S Freedman, Benjamin Dekel.
      Pluripotent stem cell (PSC)-derived kidney organoids are used to model human renal development and disease; however, accessible models of human fetal development to benchmark PSC-derived organoids remain underdeveloped. Here, we establish a chemically defined, serum-free protocol for prolonged culture of human fetal kidney-derived organoids (hFKOs) in vitro. hFKOs self-organize into polarized renal epithelium, reinitiate from NCAM1+ progenitors, and recapitulate nephrogenic and ureteric bud lineages. Bulk transcriptomics, single-cell RNA sequencing, pseudotime analysis, and immunostaining revealed diverse renal tissue cell populations, with a preserved epithelial progenitor pool and tubular differentiation axis. hFKOs were enriched for Notch signaling genes, enabling single-cell analysis of pharmacological Notch inhibition. This revealed a maturation block with increased nephron progenitors and a shift toward distal over early proximal tubule fates. We also identified a novel prominin-1-expressing cell state that evades Notch inhibition to generate both proximal and distal tubules. Overall, hFKOs provide a faithful model to gain insights into human kidney development, advancing the fields of stem cell biology and regenerative medicine.
    Keywords:  Human Fetal Kidney; Kidney Organoids; Nephrogenesis; Notch Pathway; Single-cell Transcriptomics
    DOI:  https://doi.org/10.1038/s44318-025-00504-2
  8. EMBO J. 2025 Jul 21.
    Anillin directly crosslinks microtubules with actin filaments.
    Ilina Bareja, Ondřej Kučera, Irene Istúriz Petitjean, Beatriz Eugenia Orozco Monroy, Jan Sabo, Marcus Braun, Zdenek Lansky, Gijsje H Koenderink, Marileen Dogterom.
      Complex morphogenetic processes such as cell division require a tight coordination of the activities of microtubules and actin filaments. There is evidence that anillin, conventionally known as an actin-binding and -bundling protein, regulates microtubule/actin crosstalk during cell division. However, it is unknown whether anillin binds directly to microtubules and whether it is sufficient to establish crosslinking between microtubules and actin filaments. Here we address both questions by developing an in vitro system for observing anillin-mediated interactions with actin filaments and dynamic microtubules via total internal-reflection fluorescence microscopy. We find that anillin can interact directly with microtubules and promote microtubule bundling. We confirm that anillin binds and bundles actin filaments, and find that it has a strong preference for actin bundles over individual filaments. Moreover, we show that anillin can directly crosslink microtubules and actin filaments, cause sliding of actin filaments on the microtubule lattice, and transport actin filaments by the growing microtubule tip. Our findings indicate that anillin can potentially serve as a direct regulator of microtubule/actin crosstalk, e.g., during cell division.
    Keywords:  Cell Division; Cytoskeleton; Dynamic Instability; Reconstituted System
    DOI:  https://doi.org/10.1038/s44318-025-00492-3
  9. Dev Cell. 2025 Jul 16. pii: S1534-5807(25)00404-6. [Epub ahead of print]
    An extracellular matrix niche secreted by epithelial cells drives intestinal organoid formation.
    Antonius Chrisnandy, Matthias P Lutolf.
      Intestinal organoids have become an important model system in basic and translational research, but their culture typically relies on an ill-defined laminin-rich extracellular matrix (ECM). Using tunable and chemically defined 3D hydrogels, we systematically explored the role of the ECM during murine and human intestinal organoid development. We discovered that without exogenous laminin, stem cells developed into intestinal epithelia with a large proportion of regenerative cells. This population secreted a laminin-rich basement membrane that functioned as a de novo stem cell niche, promoting organoid formation independent of exogenous laminin. We identified ubiquitous expression of laminin chains Lama3, Lamb3, and Lamc2, but Lamb1 and Lamc1 were spatially restricted to the crypt domain. Epithelial-cell-secreted basement membranes extracted from organoids promoted the formation of patterned organoids. Our results highlight the utility of chemically defined matrices for studying ECM biology and pave the way for the replacement of animal-derived matrices in organoid culture.
    Keywords:  ECM; basement membrane; epithelium; hydrogels; laminin; niche; organoid; small intestine; stem cells
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.026
  10. Nat Metab. 2025 Jul 21.
    LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
    Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.
      Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01333-7
  11. Nat Cell Biol. 2025 Jul 22.
    Metabolic regulation of key developmental events during mammalian embryogenesis.
    Yuyan Xu, Wei Xie, Jin Zhang.
      Metabolic regulation is critical in embryonic development and influences key processes such as fertilization, zygotic genome activation, cell compaction, implantation, gastrulation and organ development. Here we explore the interplay between metabolism and embryonic development in the context of important sequential key embryonic events, highlighting the orchestration of developmental processes by various metabolites and signalling molecules. Key metabolites, including glucose, fatty acids and amino acids, act as modulators of developmental processes, while also serving as energy sources and building blocks for cellular structures. Understanding the intricate relationship between metabolism and embryogenesis may provide insights into developmental disorders and potential therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41556-025-01720-y
  12. Dev Cell. 2025 Jul 19. pii: S1534-5807(25)00438-1. [Epub ahead of print]
    Telocytes deliver essential Wnts directly to murine intestinal stem cells via synapse-like contacts.
    Gediminas Greicius, Lorenz Mittermeier, Ruanyi Liang, Kristmundur Sigmundsson, Yarn Kit Chan, Pei-Ju Liao, Alexander Ludwig, David M Virshup.
      Spatial and temporal control of Wnt delivery to the intestinal stem cell niche regulates intestinal homeostasis. Telocytes, specialized stromal cells with characteristic long, thin cytoplasmic protrusions, produce essential Wnts for the development and maintenance of this niche. However, how Wnts travel from telocytes to stem cells in the gut remains unclear. Fluorescence and electron microscopy of murine telocytes co-cultured with intestinal organoids identified specialized telocyte extensions that transport and locally secrete Wnts on microvesicles and make intimate contacts with epithelial cells, reminiscent of neuronal contact-based signaling. Investigating the potential role of synapse-forming and plasma membrane-associated platform proteins, we found that depletion of either KANK1 or Liprins from telocytes markedly reduced their filopodia, compromised WNT2 presentation to epithelial cells, and impaired telocyte-dependent organoid growth. Characteristic telocyte structures facilitate Wnt delivery to the intestinal stem cell niche via synapse-like contacts.
    Keywords:  Wnt signaling; cytonemes; exovesicle; filopodia; intestinal stem cells; organoids; synapse; telocytes
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.040
  13. Cell. 2025 Jul 12. pii: S0092-8674(25)00735-4. [Epub ahead of print]
    Regulation of inflammatory responses by pH-dependent transcriptional condensates.
    Zhongyang Wu, Scott D Pope, Nasiha S Ahmed, Diana L Leung, Yu Hong, Stephanie Hajjar, Cathleen Krabak, Zhe Zhong, Krishnan Raghunathan, Qiuyu Yue, Diya M Anand, Elizabeth B Kopp, Daniel Okin, Weiyi Ma, Ivan Zanoni, Jonathan C Kagan, Jay R Thiagarajah, Diana C Hargreaves, Ruslan Medzhitov, Xu Zhou.
      Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here, we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as an intracellular pH sensor. Acidic pH disrupts transcription condensates containing BRD4 and MED1 via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.
    Keywords:  BRD4; IDR; acidosis; gene expression; histidine; inflammatory response; innate immunity; macrophage; pH; transcriptional condensates
    DOI:  https://doi.org/10.1016/j.cell.2025.06.033
  14. Cell Rep. 2025 Jul 23. pii: S2211-1247(25)00790-9. [Epub ahead of print]44(8): 116019
    The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation.
    Yoon Ki Joo, Carlos Ramirez Parrado, Wenxue Li, Ran Yang, Elizabeth Black, Franziska Bleichert, Yansheng Liu, Lilian Kabeche.
      Ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (Chk1) are crucial kinases in the DNA damage response (DDR) pathway. While the roles of ATR and Chk1 within the DDR are well established, their roles in mitosis are not fully understood. Here, we describe that the ATR-Chk1 pathway is rewired during mitosis to promote full CDK1 activity, starkly contrasting its role in interphase, where it inhibits CDK1 following DNA damage in human cells. In mitosis, Chk1 inhibits residual activity of PKMYT1 (Myt1) via direct phosphorylation at Serine 143. Partial loss of CDK1 activity caused by inhibition of mitotic Chk1 leads to different effects on mitotic progression than full CDK1 inhibition. It causes increased lagging chromosomes in part through loss of Aurora B activity. Thus, mitosis-specific ATR-Chk1 activity is necessary to promote faithful chromosome segregation by ensuring that CDK1 activity is maintained in mitosis.
    Keywords:  ATR; CDK1; CP: Molecular biology; Chk1; DNA damage response pathway; cell cycle; chromosome segregation; mitosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116019
  15. Nat Genet. 2025 Jul 22.
    G-quadruplexes are promoter elements controlling nucleosome exclusion and RNA polymerase II pausing.
    Cyril Esnault, Amal Zine El Aabidine, Marie-Cécile Robert, Anne Cucchiarini, Talha Magat, Alexia Pigeot, Soumya Bouchouika, Encar Garcia-Oliver, Kevin Gawron, Eugénia Basyuk, Magdalena A Karpinska, Alja Kozulic-Pirher, Yu Luo, Daniela Verga, Raphael Mourad, Ovidiu Radulescu, Jean-Louis Mergny, Edouard Bertrand, Jean-Christophe Andrau.
      Despite their central role in transcription, it has been difficult to define universal sequences associated with eukaryotic promoters. Within the chromatin context, recruitment of transcriptional machinery requires promoter opening, but how DNA elements contribute to this process is unclear. Here we show that G-quadruplex (G4) secondary DNA structures are highly enriched at mammalian promoters. G4s are located at the deepest point of nucleosome exclusion at promoters and correlate with maximum promoter activity. We found that experimental G4s exclude nucleosomes in vivo and in vitro while favouring strong positioning. At model promoters, impairing G4s affected both transcriptional activity and chromatin opening. G4 destabilization also resulted in an inactive promoter state and affected the transition to effective RNA production. Finally, G4 stabilization resulted in global reduction of proximal promoter pausing. Altogether, our data introduce G4s as bona fide promoter elements allowing nucleosome exclusion and facilitating pause-release by RNA polymerase II.
    DOI:  https://doi.org/10.1038/s41588-025-02263-6
  16. Nature. 2025 Jul 23.
    NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
    Janna Heide, Agnes J Bilecz, Samarjit Patnaik, Maria Francesca Allega, Leonhard Donle, Kaiting Yang, Ethan Teich, Yan Li, Qiaoshan Lin, Ke Kong, Li Liu, Tae Gyun Yang, Ken Chih-Chien Cheng, Jonathan H Shrimp, Quinlin M Hanson, Min Shen, Hongmao Sun, Hardik Shah, Lisa Schweizer, Katarzyna Zawieracz, Andrea Olland, Andre White, Robert K Suto, Razzaq Alhunayan, Medine Taşdemir, Noa Longman, Hua Liang, Matthias Mann, Gordon M Stott, Matthew D Hall, Simon Schwörer, Ralph R Weichselbaum, András Piffkó, Ernst Lengyel.
      Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking1,2. Here, using spatial transcriptomics and single-cell RNA sequencing, we investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumour. Nnmt knockout in immunocompetent mice impairs tumour growth in syngeneic ovarian, breast and colon tumour models through enhanced CD8+ T cell activation. Using high-throughput screening, we develop a potent and specific NNMT inhibitor that reduces the tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated recruitment of MDSCs and reinvigorating CD8+ T cell activation. Our findings establish NNMT as a central CAF regulator and a promising therapeutic target to mitigate immunosuppression in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41586-025-09303-5
  17. EMBO J. 2025 Jul 21.
    mTORC1 senses glutamine and other amino acids through GCN2.
    Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.
      mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.
    Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1
    DOI:  https://doi.org/10.1038/s44318-025-00505-1
  18. Mol Cell. 2025 Jul 15. pii: S1097-2765(25)00576-3. [Epub ahead of print]
    β-catenin functions as a molecular adapter for disordered cBAF interactions.
    Yuen San Chan, Qinyu Gao, Sarah A Robinson, Wenzhi Wang, Ruzena Filandrova, Lisa-Maria Weinhold, Mario Loeza Cabrera, Miao Zhang, Chandra Shekar R Ambati, Antonio M Lerario, Nagireddy Putluri, Katja Kiseljak-Vassiliades, Margaret E Wierman, Mouhammed Amir Habra, Gary D Hammer, Vaclav Veverka, Katerina Cermakova, H Courtney Hodges.
      BAF (SWI/SNF) chromatin remodelers engage binding partners to generate site-specific DNA accessibility. However, the basis for interaction between BAF and divergent binding partners has remained unclear. Here, we tested the hypothesis that scaffold proteins augment BAF's binding repertoire by examining β-catenin (CTNNB1) and steroidogenic factor 1 (SF-1, NR5A1), a transcription factor central to steroid production in human cells. BAF inhibition rapidly opposed SF-1/β-catenin enhancer occupancy, impairing SF-1 target activation and SF-1/β-catenin autoregulation. These effects arise due to β-catenin's role as a molecular adapter between SF-1 and an intrinsically disordered region (IDR) of the canonical BAF (cBAF) subunit ARID1A. In contrast to exclusively IDR-driven mechanisms, adapter function is mediated by direct association of ARID1A with β-catenin's folded Armadillo repeats. β-catenin similarly linked cBAF to YAP1, SOX2, FOXO3, and CBP/p300, reflecting a general IDR-mediated mechanism for modular coordination between factors. Molecular visualization highlights β-catenin's adapter role for interaction of cBAF with binding partners.
    Keywords:  IDRs; adrenocortical carcinoma; chromatin remodeling; co-activators; scaffold proteins; steroid hormones; transcription factors; transcription regulators; unstructured protein
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.026
  19. Nature. 2025 Jul 23.
    Pre-rRNA spatial distribution and functional organization of the nucleolus.
    Yu-Hang Pan, Lin Shan, Yu-Yao Zhang, Zheng-Hu Yang, Yuan Zhang, Shi-Meng Cao, Xiao-Qi Liu, Jun Zhang, Li Yang, Ling-Ling Chen.
      The multi-layered nucleolus serves as the primary site of ribosome biogenesis1,2, where successive maturation of small (SSU)3,4 and large (LSU)5 ribosomal subunit precursors occur. However, the spatio-functional relationship between pre-rRNA processing and nucleolar substructures and how this adapts to changing cellular physiological demands have remained incompletely understood6,7. Here, our spatiotemporal analyses revealed a compartment-specific ribosomal subunit processing in human nucleoli, with SSU processomes maintained in fibrillar center/dense fibrillar component/periphery dense fibrillar component (FC/DFC/PDFC) domains while LSU pre-rRNAs largely transited to PDFC/granular component (GC) regions. Slow proliferating cells exhibited unexpected 5' external transcribed space (5' ETS)-centered SSU processing impairment, accompanied by FC/DFC structural remodeling and retarded SSU outflux. Direct 5' ETS processing perturbation at least partially recapitulated these FC/DFC alterations, supporting the functional interdependence between SSU processing and nucleolar architecture. Notably, anamniote bipartite nucleoli with merged FC/DFC compartments8,9 exhibited distinct 5' ETS distribution and slower pre-rRNA flux compared to multi-layered nucleoli in amniotes. Introducing a FC/DFC interface to bipartite nucleoli enhanced processing efficiency, indicating that evolutionary emergence of nested FC/DFC may have optimized pre-rRNA processing. Collectively, depicting the spatiotemporal distribution of pre-rRNAs revealed an essential role of 5' ETS-centered SSU processing in maintaining nucleolar substructures and suggested a possible evolutionary advantage of the multi-layered structure in amniotes.
    DOI:  https://doi.org/10.1038/s41586-025-09412-1
  20. Immunity. 2025 Jul 12. pii: S1074-7613(25)00286-9. [Epub ahead of print]
    Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
    Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L S M Gordts, Joseph L Witztum, Talal A Chatila, Janet Chou, Xu Zhou, James R Springstead, Ivan Zanoni.
      Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.
    Keywords:  ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis
    DOI:  https://doi.org/10.1016/j.immuni.2025.06.017
  21. J Cell Biol. 2025 Aug 04. pii: e202407196. [Epub ahead of print]224(8):
    The Unkempt RNA-binding protein reveals a local translation program in centriole overduplication.
    Abraham Martinez, Alexander J Stemm-Wolf, Ryan M Sheridan, J Matthew Taliaferro, Chad G Pearson.
      Excess centrosomes cause defects in mitosis, cell-signaling, and cell migration, and therefore their assembly is tightly regulated. The divergent Polo kinase, PLK4, controls centriole duplication at the heart of centrosome assembly, and elevated PLK4 levels promote centrosome amplification (CA), a founding event of tumorigenesis. Here, we investigate the transcriptional consequences of elevated PLK4 and find Unkempt (UNK), a gene encoding an RNA-binding protein with roles in mRNA translational regulation, to be one of only two upregulated mRNAs. UNK protein localizes around centrosomes and with CEP131-positive centriolar satellites, promoting CEP131 localization to and around centrosomes. UNK's RNA-binding activity is required for PLK4-induced centriole overduplication. Consistent with the loss in PLK4-induced centriole overduplication, UNK depletion disrupts PLK4 and centriole assembly protein localization. Finally, translation is enriched at centrosomes and centriolar satellites, with UNK and CEP131 promoting this localized translation. In summary, UNK and CEP131 promote PLK4 localization and local translation at centrosomes during centriole overduplication.
    DOI:  https://doi.org/10.1083/jcb.202407196
  22. Elife. 2025 Jul 24. pii: RP102794. [Epub ahead of print]13
    Rho-ROCK liberates sequestered claudin for rapid de novo tight junction formation.
    Yuma Cho, Akari Taniguchi, Akiharu Kubo, Junichi Ikenouchi.
      The epithelial cell sheet maintains its integrity as a barrier while undergoing turnover of constituent cells. To sustain the barrier continuously, it's essential to preserve the 'old' tight junctions (TJs) between cells being excluded from the sheet and their neighbors while simultaneously forming de novo TJs between newly adjacent cells. However, the molecular mechanisms involved in the formation of de novo TJs remain largely unknown. This study investigates two scenarios: the formation of de novo TJs during the removal of apoptotic cells from mouse monolayer epithelial sheets and during the differentiation of the granular layer in mouse stratified epidermis. We revealed that rapid claudin assembly is achieved by actively regulating the dissociation of the EpCAM/TROP2-claudin complex in both situations. Furthermore, we found that the Rho-ROCK pathway initiates the activation of matriptase, which cleaves EpCAM/TROP2, resulting in the supply of polymerizable claudin from the stockpiled EpCAM/TROP2-claudin complex at the plasma membrane to induce rapid de novo TJ formation.
    Keywords:  Claudin; EpCAM; Trop2; cell biology; epidermis; matriptase; mouse; tight junction
    DOI:  https://doi.org/10.7554/eLife.102794
  23. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2427293122
    Polyploidy promotes transformation of epithelial cells into nonprofessional phagocytes.
    Yi-Chun Huang, Caique Almeida Machado Costa, Nicolas Vergara Ruiz, Xianfeng Wang, Allison Jevitt, Christina Marie Breneman, Chun Han, Wu-Min Deng.
      Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, nonprofessional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction, and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell-derived NPPs during oogenesis in Drosophila. In this study, we report that the transformation of follicle cells (FCs) into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). We further show that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of FCs into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, we show that polyploidy in epidermal cells, another type of NPPs, is important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions.
    Keywords:  JNK signaling; Notch signaling; germline cell death; nonprofessional phagocytes; polyploid cells
    DOI:  https://doi.org/10.1073/pnas.2427293122
  24. Nature. 2025 Jul 22.
    Breaking point: mechanical stress helps NINJ1 protein to rupture membranes.
    Ishan Deshpande, Vishva M Dixit.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-02130-8
  25. Nat Immunol. 2025 Jul 22.
    Spatial proteomics of Alzheimer's disease-specific human microglial states.
    Dunja Mrdjen, Bryan J Cannon, Meelad Amouzgar, YeEun Kim, Candace Liu, Kausalia Vijayaragavan, Christine Camacho, Angie Spence, Erin F McCaffrey, Anusha Bharadwaj, Dmitry Tebaykin, Syed Bukhari, Marc Bosse, Felix J Hartmann, Adam Kagel, John Paul Oliveria, Koya Yakabi, Geidy E Serrano, Maria M Corrada, Claudia H Kawas, Robert Tibshirani, Thomas G Beach, M Ryan Corces, Will Greenleaf, R Michael Angelo, Thomas Montine, Sean C Bendall.
      Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.
    DOI:  https://doi.org/10.1038/s41590-025-02203-w
  26. Cell. 2025 Jul 17. pii: S0092-8674(25)00738-X. [Epub ahead of print]
    Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration.
    Qiaoling Zhu, Feng Yin, Jiachen Qin, Wanyu Shi, Yaojia Liu, Yuanyuan Zhao, Jianfang Wang, Lei Zhang, Aoyuan Fan, Dandan Cao, Qiqi Peng, Bin Zhou, Lijun Wang, Weiguo Zou, Rui Yue.
      Protein C receptor+ (Procr+) cells were identified as stem or progenitor cells in multiple adult tissues. However, whether mechanical stimuli fine-tune their activation and differentiation remain unknown. Here, we found rare Procr+ cells in the superficial layer of tibial articular cartilage and meniscus, which keep replenishing chondrocytes in postnatal knee joints. Mechanical stimulation by forced running significantly increased the frequency of Procr+ cells, whereas mechanical unloading by tail suspension showed opposite effects. Osteoarthritis (OA) activated Procr+ cells to repair cartilage erosion, whereas genetic ablation of Procr+ cells accelerated OA progression. Pharmacological or genetic inhibition of the mechanosensor Piezo1 significantly blunted cartilage regeneration by Procr+ cells and exacerbated OA. In contrast, intra-articular administration of a Piezo1 agonist ameliorated OA symptoms. Purified mouse or human Procr+ superficial cells robustly repair articular cartilage after expansion and in vivo transplantation. Together, we discovered a mechanosensitive chondroprogenitor population indispensable for articular cartilage maintenance and regeneration.
    Keywords:  chondroprogenitor; mechanical stimulation; osteoarthritis; procr; regeneration
    DOI:  https://doi.org/10.1016/j.cell.2025.06.036
  27. Cell Rep. 2025 Jul 18. pii: S2211-1247(25)00781-8. [Epub ahead of print] 116010
    A STAT3/integrin axis accelerates pancreatic cancer initiation and progression.
    Alejandro D Campos, Ryan M Shepard, Zachary Ortega, Ingrid Heumann, Anna E Wilke, Arin Nam, Carson Cable, Kourosh Kouhmareh, Richard Klemke, Nicole M Mattson, Trey Ideker, Camila De Arruda Saldanha, Sven Heinz, Valerie Weaver, Tami Von Schalscha, Hiromi I Wettersten, Sara M Weis, David A Cheresh.
      The signal transducer and activator of transcription 3 (STAT3) pathway drives pancreatic ductal adenocarcinoma (PDAC) progression by coordinating cellular responses to stress and inflammation. We perform ChIP-seq on hypoxia- or oncostatin-M-treated PDAC cells to identify sites at which phospho-STAT3 binds to regulate the expression of genes linked to poor survival. A top hit among these is ITGB3, which we show promotes PDAC initiation and progression. Single-cell transcriptomics reveal that ITGB3 expression is enriched in PDAC cells experiencing oxidative stress due to chemotherapy. Moreover, high ITGB3 expression positively correlates with STAT3 signaling, hypoxia, and the basal subtype. Mechanistically, chromatin accessibility at ITGB3 enhancers controls STAT3's ability to induce ITGB3 expression, illuminating a plastic regulatory mechanism modulating STAT3 activity. Leveraging this insight, we identify additional STAT3 target genes regulated similarly to ITGB3 to establish an 18-gene signature involved in adaptive responses and able to stratify survival outcomes. Collectively, these findings highlight a novel opportunity to stratify PDAC subpopulations for STAT3-targeted therapies.
    Keywords:  CP: Cancer; STAT3; cellular stress; cytokine; enhancer; gene signature; hypoxia; inflammation; integrin; pancreatic cancer; tumor initiation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116010
  28. Biophys J. 2025 Jul 23. pii: S0006-3495(25)00457-6. [Epub ahead of print]
    Transmembrane coupling drives the growth of liquid-like protein condensates.
    Yohan Lee, Feng Yuan, Jerry L Cabriales, Jeanne C Stachowiak.
      Timely and precise assembly of protein complexes on membrane surfaces is essential to the physiology of living cells. Recently, protein phase separation has been observed at cellular membranes, suggesting it may play a role in the assembly of protein complexes. Inspired by these findings, we observed that two-dimensional protein condensates on one side of a planar suspended membrane spontaneously colocalized with those on the opposite side. How might this phenomenon contribute to the assembly of stable transmembrane complexes? To address this question, we examined the diffusion and growth of two-dimensional protein condensates on both sides of membranes. Our results reveal that transmembrane coupling of protein condensates on opposite sides of the membrane slows down condensate diffusion while promoting condensate growth. How can the condensate growth be driven simultaneously with a decrease in the rate of condensate diffusion? We provide insights into these seemingly contradictory observations by distinguishing between diffusion-limited and coupling-driven growth processes. While transmembrane coupling slows down diffusion, it also locally concentrates condensates within a confined area. This confinement increases the probability of condensate coalescence and thereby promotes the growth of coupled condensates. These findings suggest that transmembrane coupling could play a role in the assembly of diverse membrane-bound structures by promoting the localization and growth of protein complexes on both membrane surfaces. This phenomenon could help to promote the assembly of transmembrane structures in diverse cellular contexts.
    DOI:  https://doi.org/10.1016/j.bpj.2025.07.022
  29. Nat Commun. 2025 Jul 19. 16(1): 6668
    Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.
    Xue Han, Ruyi Zheng, Jiajia Zhang, Yanan Liu, Ze Li, Guoxuan Liu, Jianing Zheng, Weiqi Li, Zijun Liang, Mengyang Wang, Jie Yu, Qiaojuan Shi, Huazhong Ying, Guang Liang.
      Deubiquitinating modification of proteins is involved in the pathogenesis of diseases. Here, we investigated the role and regulating mechanism of a deubiquitinating enzyme (DUB), ovarian tumor domain-containing protein 1 (OTUD1), in diabetic cardiomyopathy (DCM). We find a significantly increased OTUD1 expression in diabetic mouse hearts, and single-cell RNA sequencing shows OTUD1 mainly distributing in cardiomyocytes. Cardiomyocyte-specific OTUD1 knockout prevents cardiac hypertrophy and dysfunction in both type 2 and type 1 diabetic male mice. OTUD1 deficiency restores cardiac AMPK activity and mitochondrial function in diabetic hearts and cardiomyocytes. Mechanistically, OTUD1 binds to AMPKα2 subunit, deubiquitinates AMPKα2 at K60/K379 sites, and then inhibits AMPKT172 phosphorylation through impeding the interaction of AMPKα2 and its upstream kinase CAMKK2. Finally, silencing AMPKα2 in cardiomyocytes abolishes the cardioprotective effects of OTUD1 deficiency in diabetic mice. In conclusion, this work identifies a direct regulatory DUB of AMPK and presents a OTUD1-AMPK axis in cardiomyocytes for driving DCM.
    DOI:  https://doi.org/10.1038/s41467-025-61901-z
  30. Cell. 2025 Jul 21. pii: S0092-8674(25)00808-6. [Epub ahead of print]
    Small RNAs are modified with N-glycans and displayed on the surface of living cells.
    Ryan A Flynn, Kayvon Pedram, Stacy A Malaker, Pedro J Batista, Benjamin A H Smith, Alex G Johnson, Benson M George, Karim Majzoub, Peter W Villalta, Jan E Carette, Carolyn R Bertozzi.
      
    DOI:  https://doi.org/10.1016/j.cell.2025.07.019
  31. Nat Commun. 2025 Jul 22. 16(1): 6734
    Age mosaic of gut epithelial cells prevents aging.
    Peizhong Qin, Qi Wang, You Wu, Qiqi You, Mingyu Li, Zheng Guo.
      Improving gut health by altering the activity of intestinal stem cells is thought to have the potential to reverse aging. The aged Drosophila midgut undergoes hyperplasia and barrier dysfunction. However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we show that early midgut injury prevents the abrupt onset of aging hyperplasia and extends lifespan in flies. Daily transcriptome profiling and lineage tracing analysis show that the abrupt onset of aging hyperplasia is due to the collective turnover of developmentally generated "old" enterocytes (ECs). Early injury introduces new ECs into the old EC population, forming the epithelial age mosaic. Age mosaic avoids collective EC turnover and facilitates septate junction formation, thereby improving the epithelial barrier and extending lifespan. Furthermore, we found that intermittent time-restricted feeding benefits health by creating an EC age mosaic. Our findings suggest that age mosaic may become a therapeutic approach to reverse aging.
    DOI:  https://doi.org/10.1038/s41467-025-62043-y
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