bims-ginsta Biomed News
on Genome instability
Issue of 2025–10–19
forty-one papers selected by
Jinrong Hu, National University of Singapore
  1. HIF1A-mediated pathways promote euploid cell survival in chromosomally mosaic embryos.
  2. Vitamin C conveys geroprotection on primate ovaries.
  3. A post-implantation model of human embryo development includes a definitive hematopoietic niche.
  4. Choreography of rapid actin filament disassembly by coronin, cofilin, and AIP1.
  5. Hypoxia promotes airway differentiation in the human lung epithelium.
  6. Crosstalk between tissue mechanics and BMP4 signaling regulates symmetry breaking in human gastrula models.
  7. A continuous totipotent-like cell-based embryo model recapitulates mouse embryogenesis from zygotic genome activation to gastrulation.
  8. PRDM16 regulates smooth muscle cell identity and atherosclerotic plaque composition.
  9. Mechanics of force transmission in epithelia: From cell-to-cell propagation to nuclear response.
  10. Characterization of induced cohesin loop extrusion trajectories in living cells.
  11. Spatial metabolic gradients in the liver and small intestine.
  12. The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
  13. Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
  14. A conserved H3K14ub-driven H3K9me3 for chromatin compartmentalization.
  15. A key role of Canoe's intrinsically disordered region in linking cell junctions to the cytoskeleton.
  16. Vascular Niches Are the Primary Hotspots in Cardiac Aging.
  17. Temporal and spatial coordination of DNA segregation and cell division in an archaeon.
  18. Long noncoding RNA-dependent control of Myc transcriptional bursting.
  19. Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans.
  20. Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers.
  21. egal-1 and microtubules promote regeneration polarity in planarians.
  22. Aged mice exhibit widespread metabolic changes but preserved major fluxes.
  23. A molecular circuit regulates fate plasticity in emerging and adult AT2 cells.
  24. Multi-layered dosage compensation of the avian Z chromosome by increased transcriptional burst frequency and elevated translational rates.
  25. SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
  26. Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome.
  27. Dynamics of microcompartment formation at the mitosis-to-G1 transition.
  28. Flexible nanoelectronics reveal arrhythmogenesis in transplanted human cardiomyocytes.
  29. Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
  30. Targeting Genome Stability to Mitigate Human Aging and Disease.
  31. Slowing down to take it in: Endocytosis during cellular aging.
  32. Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.
  33. MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
  34. Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.
  35. Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.
  36. Niche-specific dermal macrophage loss promotes skin capillary ageing.
  37. Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility.
  38. Strings and topological defects govern ordering kinetics in endothelial cell layers.
  39. In vivo mechano-tissue engineering by hydrogels capable of transmitting intercellular mechanical stress.
  40. Tuning insulin receptor signaling using de novo-designed agonists.
  41. Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest.
  1. Elife. 2025 Oct 14. pii: RP101912. [Epub ahead of print]13
    HIF1A-mediated pathways promote euploid cell survival in chromosomally mosaic embryos.
    Estefania Sanchez-Vasquez, Marianne E Bronner, Magdalena Zernicka-Goetz.
      Human fertility is suboptimal in part by error-prone divisions during early cleavage stages, which frequently result in chromosomal aneuploidy. Most human pre-implantation embryos are mosaics of euploid and aneuploid cells, yet those with a low proportion of aneuploid cells can develop to term at rates similar to fully euploid embryos. How embryos manage aneuploidy during early development remains poorly understood - yet this knowledge is crucial for improving fertility outcomes and reducing developmental defects. To investigate these mechanisms, we established a new mouse model of chromosome mosaicism to trace the fate of aneuploid cells during pre-implantation development. We previously used the Mps1 inhibitor reversine to induce aneuploidy. Here, we demonstrate that the more specific Mps1 inhibitor AZ3146 similarly disrupts chromosome segregation but supports higher developmental potential than reversine. AZ3146-treated embryos transiently upregulate hypoxia-inducible factor-1A (HIF1A) without triggering Trp53 activation. Given that pre-implantation embryos develop in a hypoxic environment in vivo, we further explored the role of oxygen tension. Hypoxia exposure in vitro reduced DNA damage in response to Mps1 inhibition and increased the proportion of euploid cells in mosaic epiblast. Conversely, HIF1A inhibition decreased the proportion of aneuploid cells. Together, these findings uncover a role for hypoxia signaling in modulating the response to chromosomal errors and suggest new strategies to improve the developmental potential of mosaic human embryos.
    Keywords:  aneuploidy; chromosomes; developmental biology; gene expression; hypoxia; mosaicism; mouse
    DOI:  https://doi.org/10.7554/eLife.101912
  2. Cell Stem Cell. 2025 Oct 14. pii: S1934-5909(25)00339-X. [Epub ahead of print]
    Vitamin C conveys geroprotection on primate ovaries.
    Ying Jing, Huifen Lu, Jingyi Li, Zan He, Liyun Zhao, Chen Zhang, Ziqi Huang, Lixiao Liu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu.
      Ovarian aging plays a pivotal role in female reproductive health, with implications for treatment strategies and quality of life. However, the potential of a single pharmaceutical agent to mitigate primate ovarian aging remains largely unexplored. Our 3.3-year study in monkeys demonstrates that oral vitamin C has geroprotective effects against ovarian aging. Vitamin C diminishes key aging biomarkers, including oxidative stress and follicular depletion. Using a single-cell transcriptomic clock, we show that vitamin C can reduce the biological age of oocytes by 1.35 years and somatic cells by 5.66 years. This effect is partly mediated by the NRF2 pathway, which alleviates ovarian cell senescence and inflammation. Our findings highlight the role of vitamin C in combating primate ovarian aging and provide insights for developing interventions against human ovarian aging.
    Keywords:  NRF2; aging; aging clock; antioxidant; inflammation; ovary; oxidative stress; primate; senescence; vitamin C
    DOI:  https://doi.org/10.1016/j.stem.2025.09.008
  3. Cell Rep. 2025 Oct 13. pii: S2211-1247(25)01144-1. [Epub ahead of print] 116373
    A post-implantation model of human embryo development includes a definitive hematopoietic niche.
    Jitesh Neupane, Geraldine M Jowett, Baojiang Wu, Ankit Verma, Sabine Dietmann, Adam James Reid, M Azim Surani.
      Stem cell-derived embryo models are crucial for investigations to advance our knowledge of early human development. Here, we present a post-gastrulation three-dimensional (3D) embryo model that is kinetically matured to promote multi-lineage organogenesis with tissues comparable to those found in Carnegie stage (CS)12-CS16 human embryos. The resulting structures include cardiomyocytes, hepatocytes, endothelial cells, and hematopoietic cells, but they lack a yolk sac. Notably, we observe SOX17+RUNX1+ hemogenic buds, where we detect the maturation of hematopoietic stem cells (HSCs). These hemogenic niches, where endothelial-to-hematopoietic transition occurs, contain instructive (DLL4, SCF) and restrictive (FGF23) factors for the maturation of HSC. These HSCs have the potential to differentiate into myeloid and lymphoid lineages, and, therefore, they are equivalent to definitive hematopoiesis. Accordingly, we call our model hematoids, which offer both a versatile tool for investigating tissue-scale mechanisms of human development and a potential source of human HSCs for mechanistic studies and cell therapies.
    Keywords:  AGM; CP: Developmental biology; CP: Stem cell research; HSC; aorta-gonad-mesonephros-like hemogenic niche; definitive hematopoiesis; hematopoietic stem cells; multilineage organogenesis; post-implantation human embryo development; self-organization; stem cell-based embryo model
    DOI:  https://doi.org/10.1016/j.celrep.2025.116373
  4. Cell. 2025 Oct 10. pii: S0092-8674(25)01084-0. [Epub ahead of print]
    Choreography of rapid actin filament disassembly by coronin, cofilin, and AIP1.
    Wout Oosterheert, Micaela Boiero Sanders, Oliver Hofnagel, Peter Bieling, Stefan Raunser.
      Rapid remodeling of actin filament (F-actin) networks is essential for the movement and morphogenesis of eukaryotic cells. The conserved actin-binding proteins coronin, cofilin, and actin-interacting protein 1 (AIP1) act in synergy to promote rapid F-actin network disassembly, but the underlying mechanisms have remained elusive. Here, using cryo-electron microscopy (cryo-EM), we uncover the concerted molecular actions of coronin, cofilin, and AIP1 that lead to actin filament aging and severing. We find that the cooperative binding of coronin allosterically promotes inorganic phosphate release from F-actin and induces filament undertwisting, thereby priming the filament for cofilin binding. Cofilin then displaces coronin from the filament via a strand-restricted cooperative binding mechanism. The resulting cofilactin serves as a high-affinity platform for AIP1, which induces severing by acting as a clamp that disrupts inter-subunit filament contacts. In this "molecular squeezing" mechanism, AIP1 and not cofilin is responsible for filament severing. Our work redefines the role of key disassembly factors in actin dynamics.
    Keywords:  actin disassembly factors; actin filament; actin network turnover; cell migration; cryo-EM; cytoskeleton; structural biology
    DOI:  https://doi.org/10.1016/j.cell.2025.09.016
  5. Cell Stem Cell. 2025 Oct 10. pii: S1934-5909(25)00338-8. [Epub ahead of print]
    Hypoxia promotes airway differentiation in the human lung epithelium.
    Ziqi Dong, Niek Wit, Aastha Agarwal, Adam James Reid, Dnyanesh Dubal, Sina Beier, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Jelle van den Ameele, James A Nathan, Emma L Rawlins.
      Human lungs experience dynamic oxygen tension during development. Here, we show that hypoxia directly regulates human lung epithelial cell identity using tissue-derived organoids. Fetal multipotent lung epithelial progenitors remain undifferentiated in a self-renewing culture condition under normoxia but spontaneously differentiate toward multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation depends on hypoxia-inducible factor (HIF) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. KLF4 and KLF5 are direct HIF targets that promote basal and secretory cell fates. Moreover, hypoxia is sufficient to convert alveolar type 2 cells derived from both human fetal and adult lungs to airway cells, including aberrant basal-like cells that exist in human fibrotic lungs. These findings reveal roles for hypoxia and HIF activity in the developing human lung epithelium and have implications for aberrant cell fate changes in pathological lungs.
    Keywords:  HIFs; KLF4; KLF5; aberrant basal cells; airway differentiation; alveolar type 2 cells; human lung epithelial progenitors; hypoxia; hypoxia-inducible factors; organoids
    DOI:  https://doi.org/10.1016/j.stem.2025.09.007
  6. Cell Stem Cell. 2025 Oct 13. pii: S1934-5909(25)00337-6. [Epub ahead of print]
    Crosstalk between tissue mechanics and BMP4 signaling regulates symmetry breaking in human gastrula models.
    Riccardo De Santis, Laurent Jutras-Dubé, Sophia Bourdrel, Eleni Rice, Francesco M Piccolo, Ali H Brivanlou.
      The spatiotemporal regulation of morphogenetic signals, along with local tissue mechanics, guides morphogenesis and determines the shape of the embryo. However, how these signals integrate into developmental circuits remains poorly understood. Here, we developed a light-inducible strategy to induce BMP4 signaling with precise spatial coordinates in human pluripotent stem cells. Light-controlled BMP4 induces SMAD1-5 phosphorylation, resulting in amnion differentiation, and relies on a tension-dependent induction of WNT and NODAL for mesoderm differentiation. In response to BMP4 signaling, the mechanosensitive transcription factor YAP1 accumulates in the nucleus, where it represses WNT3 mRNA, regulating the induction of the three germ layers. Based on these findings, we developed a mathematical model that integrates tissue mechanics into morphogen dynamics, quantitatively explaining tissue-scale responses to BMP4 signaling. Thus, light induction of the morphogen BMP4 in human stem cell models elucidated the interplay between tissue mechanics and signaling at the onset of gastrulation.
    Keywords:  BMP4; YAP1; gastrulation; mechanics; mechanochemical; optogenetics; self-organization; stem cell models
    DOI:  https://doi.org/10.1016/j.stem.2025.09.006
  7. Nat Cell Biol. 2025 Oct 15.
    A continuous totipotent-like cell-based embryo model recapitulates mouse embryogenesis from zygotic genome activation to gastrulation.
    Yixuan Ren, Xuyang Wang, Haiyin Liu, Yaxing Xu, Ruoqi Cheng, Shengnan Ren, Zining Li, Yunfei Huo, Bo Li, Jingyang Guan, Cheng Li, Hongkui Deng, Jun Xu.
      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.
    DOI:  https://doi.org/10.1038/s41556-025-01793-9
  8. Nat Cardiovasc Res. 2025 Oct 17.
    PRDM16 regulates smooth muscle cell identity and atherosclerotic plaque composition.
    Josephine M E Tan, Lan Cheng, Ryan P Calhoun, Angela H Weller, Karima Drareni, Skylar Fong, Eirlys Barbara, Hee-Woong Lim, Chenyi Xue, Hanna Winter, Gaëlle Auguste, Clint L Miller, Muredach P Reilly, Lars Maegdefessel, Esther Lutgens, Patrick Seale.
      Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, 'synthetic' SMCs-defined by migration, proliferation and extracellular matrix production-accumulate in atherosclerotic lesions and contribute to fibrous cap formation. The mechanisms driving this synthetic transition remain unclear. Here we identify PRDM16, a gene linked to cardiovascular disease, as a critical transcriptional repressor of the synthetic SMC phenotype. PRDM16 expression declined during SMC modulation, and its deletion in mice induced a synthetic program across all SMC subtypes even without pathological stimuli. Under atherogenic conditions, PRDM16 deficiency resulted in the formation of fibroproliferative plaques with more synthetic SMCs and fewer foam cells. Conversely, enforced PRDM16 expression suppressed SMC migration, proliferation and fibrosis. Mechanistically, PRDM16 occupied chromatin and suppressed activating marks at synthetic loci. These findings establish PRDM16 as a gatekeeper of SMC fate and reveal its role in shaping atherosclerotic plaque composition.
    DOI:  https://doi.org/10.1038/s44161-025-00737-8
  9. Semin Cell Dev Biol. 2025 Oct 15. pii: S1084-9521(25)00072-2. [Epub ahead of print]175 103662
    Mechanics of force transmission in epithelia: From cell-to-cell propagation to nuclear response.
    Ronan Bouzignac, Magali Suzanne.
      Mechanical forces play essential roles during morphogenesis, enabling cells to change shape or reorganize to form new structures. Recent questions in the field of mechanobiology focus on how these locally generated forces propagate and the extent of their propagation. This phenomenon can be observed at multiple scales (across tissues, where supracellular actomyosin structures interconnected at cell-cell junctions transmit forces, or within individual cells, where mechanical cues can influence the nucleus). In the first part of this review, we highlight recent advances in our understanding of force propagation along epithelial apical surfaces, including factors that facilitate it, such as tissue curvature and polarity. In the second part, we examine how mechanical forces affect nuclear shape and integrity at the single-cell level, beginning with in vitro studies of nuclear responses to mechanical stress and extending to the less-explored mechanical behavior of nuclei in more complex, integrated model systems.
    Keywords:  Mechanical forces; Morphogenesis; Nuclear colapse; Nuclear envelope; Nuclear rupture; Propagation
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103662
  10. Nat Genet. 2025 Oct 16.
    Characterization of induced cohesin loop extrusion trajectories in living cells.
    Ruiqi Han, Yike Huang, Michelle J Robers, Mikhail Magnitov, Iwan Vaandrager, Amin Allahyar, Marjon J A M Verstegen, Kexin Zhang, Elzo de Wit, Wouter de Laat, Peter H L Krijger.
      Cohesin (SMC1-SMC3-RAD21) constantly extrudes DNA loops to organize chromosomes into structural domains, pausing and anchoring at specific DNA-bound CTCF molecules. To study the detailed consequences of cohesin loop extrusion, we developed TArgeted Cohesin Loader (TACL) for controlled pan-cellular activation of chromatin loop formation at defined genomic locations in living cells. With TACL, we show that highly complex looping networks can exist, with extruding cohesin complexes that block each other, drive cohesin queuing and induce loop anchoring at nearly all CTCF-bound sites. TACL loops extend upon acute depletion of STAG2, PDS5A or WAPL. Activated cohesin loop extrusion hinders local gene transcription and can alter chromatin accessibility and H3K27ac distribution. TACL shows that the loading/extrusion complex NIPBL-MAU2 can be transported by cohesin to CTCF sites but, together with SMC1, to enhancers in a RAD21-independent manner. TACL thus enables studying the consequences of activated loop extrusion at defined genomic locations.
    DOI:  https://doi.org/10.1038/s41588-025-02358-0
  11. Nature. 2025 Oct 15.
    Spatial metabolic gradients in the liver and small intestine.
    Laith Z Samarah, Clover Zheng, Xi Xing, Won Dong Lee, Amichay Afriat, Uthsav Chitra, Michael R MacArthur, Wenyun Lu, Connor S R Jankowski, Cong Ma, Craig J Hunter, Michael Neinast, Daniel R Weilandt, Benjamin J Raphael, Joshua D Rabinowitz.
      The properties of mammalian cells depend on their location within organs. Gene expression in the liver varies between periportal and pericentral hepatocytes1-3, and in the intestine from crypts to villus tips4,5. A key element of tissue spatial organization is probably metabolic, but direct assessments of spatial metabolism remain limited. Here we map spatial metabolic gradients in the mouse liver and intestine. We develop an integrated experimental-computational workflow using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), isotope tracing and deep-learning artificial intelligence. Most measured metabolites (>90%) showed significant spatial concentration gradients in the liver lobules and intestinal villi. In the liver, tricarboxylic acid (TCA)-cycle metabolites and their isotope labelling from both glutamine and lactate localized periportally. Energy-stress metabolites, including adenosine monophosphate (AMP), also localized periportally, consistent with a high periportal energy demand. In the intestine, the TCA intermediates malate (tip) and citrate (crypt) showed opposite spatial patterns, aligning with higher glutamine catabolism in tips and lactate oxidation in crypts based on isotope tracing. Finally, we mapped the fate of the obesogenic dietary sugar fructose. In the intestine, oral fructose was catabolized faster in the villus bottom than in the tips. In the liver, fructose-derived carbon accumulated pericentrally as fructose-1-phosphate and triggered pericentral adenosine triphosphate (ATP) depletion. Thus, we both provide foundational knowledge regarding intestine and liver metabolic organization and identify fructose-induced focal derangements in liver metabolism.
    DOI:  https://doi.org/10.1038/s41586-025-09616-5
  12. Nat Commun. 2025 Oct 13. 16(1): 9071
    The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
    Shicong Xie, Shuyuan Zhang, Gustavo de Medeiros, Prisca Liberali, Jan M Skotheim.
      Cell growth and division must be coordinated to maintain a stable cell size, but how this coordination is implemented in multicellular tissues remains unclear. In unicellular eukaryotes, autonomous cell size control mechanisms couple cell growth and division with little extracellular input. However, in multicellular tissues we do not know if autonomous cell size control mechanisms operate the same way or whether cell growth and cell cycle progression are separately controlled by cell-extrinsic signals. Here, we address this question by tracking single epidermal stem cells growing in the mouse ear. We find that a cell-autonomous size control mechanism, dependent on the RB pathway, sets the timing of S phase entry based on the cell's current size. Cell-extrinsic variations in the cellular microenvironment affect cell growth rates but not this autonomous coupling. Our work reassesses long-standing models of cell cycle regulation in complex animal tissues and identifies cell-autonomous size control as a critical mechanism regulating cell division.
    DOI:  https://doi.org/10.1038/s41467-025-64150-2
  13. Curr Biol. 2025 Oct 15. pii: S0960-9822(25)01246-1. [Epub ahead of print]
    Mitochondrial function regulates cell growth kinetics to maintain mitochondrial homeostasis.
    Leeba A Chacko, Hidenori Nakaoka, Richard G Morris, Wallace F Marshall, Vaishnavi Ananthanarayanan.
      Mitochondria are not produced de novo in newly divided daughter cells but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast "mother machine," we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the "sizer" mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division; cells born with lower-than-average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modeling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Altogether, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.
    Keywords:  S. pombe; fission yeast; growth kinetics; homeostasis; microfluidics; mitochondria; yeast mother machine
    DOI:  https://doi.org/10.1016/j.cub.2025.09.046
  14. Nature. 2025 Oct 15.
    A conserved H3K14ub-driven H3K9me3 for chromatin compartmentalization.
    Yuanyong Huang, Yimei Sun, Hongyun Qi, Quanlong Jiang, Jialun Li, Mingzhi Chang, Xinyan Li, Lei Shu, Xiaoya Duan, Yiqin Wang, Kailun Fang, Hailei Mao, Mengmeng Han, Yuan Weng, Qiao Zhang, Zhaosu Chen, Wei Wei, Gaojie Song, Qiansen Zhang, Jiwen Li, Jing-Dong J Han, Charlie Degui Chen, Jiemin Wong.
      Compartmentalization of eukaryotic genome into euchromatin and heterochromatin is of critical biological significance1-3. Previous studies have suggested a self-templating pathway involving the reading and writing of histone H3 lysine 9 methylation by SUV39H as the core mechanism for heterochromatin reassembly during cell division1,3. In fission yeast, the mammalian SUV39H homologue Clr4 forms a complex containing ubiquitin ligase Cul4, which catalyses H3K14 mono-ubiquitination (H3K14ub) to promote heterochromatin formation. However, whether heterochromatin reassembly in dividing mammalian cells involves a similar pathway is unknown. Here we identified G2E3 as an H3K14ub-specific, pericentromeric heterochromatin-localized E3 ligase. G2E3-catalysed H3K14ub potentiates histone H3 lysine 9 trimethylation (H3K9me3) by SUV39H and is specifically required for SUV39H compartmentalization and H3K9me3 in pericentromeric heterochromatin. Mechanistically, we found that G2E3 is highly expressed in G2/M phase and associates with mitotic chromosomes in an RNA-dependent manner to catalyse H3K14ub, which is essential for the subsequent sequential recruitment of SUV39H and HP1. The SUV39H chromodomain is a reader of dual H3K9me3 and H3K14ub modifications and SUV39H associates with pericentromeric heterochromatin primarily through its H3K14ub-binding activity. Notably, loss of G2E3 severely impairs pericentromeric heterochromatin organization and results in the aberrant accumulation of SUV39H and H3K9me3 in numerous euchromatin regions and widespread transcriptional repression. Thus, our findings revealed the H3K14ub-dependent SUV39H compartmentalization as a unified mechanism of pericentromeric heterochromatin formation, which is essential for proper euchromatin compartmentalization and transcriptional regulation.
    DOI:  https://doi.org/10.1038/s41586-025-09624-5
  15. J Cell Biol. 2025 Dec 01. pii: e202505135. [Epub ahead of print]224(12):
    A key role of Canoe's intrinsically disordered region in linking cell junctions to the cytoskeleton.
    Corbin C Jensen, Noah J Gurley, Avery J Mathias, Leah R Wolfsberg, Yufei Xiao, Zixi Zhou, Maik C Bischoff, Sarah E Clark, Kevin C Slep, Mark Peifer.
      Adherens junctions regulate tissue architecture, mediating robust yet dynamic cell-cell adhesion and, via cytoskeletal linkage, allowing cells to change shape and move. Adherens junctions contain thousands of molecules linked by multivalent interactions of folded protein domains and intrinsically disordered regions (IDRs). One key challenge is defining mechanisms conferring robust linkage and mechanosensing. Drosophila Canoe and mammalian Afadin provide superb entry points to explore how their complex protein structures and shared IDRs enable function. We combined genetic, cell biological, and biochemical tools to define how Canoe's IDR functions during morphogenesis. Unlike many of Canoe's folded domains, the proximal IDR is critical for junctional localization, mechanosensing, and function. In its absence, the mutant protein localizes to nuclei. We took the IDR apart, identifying two conserved stickers that directly bind F-actin, separated by less-conserved spacers. Surprisingly, while mutants lacking the IDR die as embryos with morphogenesis defects, no IDR subregion is essential for viability. Instead, stickers and spacers act combinatorially to ensure localization, mechanosensing, and function.
    DOI:  https://doi.org/10.1083/jcb.202505135
  16. Circ Res. 2025 Oct 15.
    Vascular Niches Are the Primary Hotspots in Cardiac Aging.
    David Rodriguez Morales, Veronica Larcher, Mariano Ruz Jurado, Denada Arifaj, Lukas Tombor, Lukas Zanders, Andreas M Zeiher, Christoph Kuppe, David John, Julian U G Wagner, Marcel H Schulz, Stefanie Dimmeler.
       BACKGROUND: Aging is a major, yet unmodifiable, cardiovascular risk factor and is associated with vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations within the multicellular architecture of the cardiac tissue is unknown.
    METHODS: We investigated local microenvironments in aged mice hearts by applying an integrative approach combining single-nucleus RNA sequencing and spatial transcriptomics of 3- and 18-month-old mice. We defined distinct cardiac niches and studied changes in their cellular composition and functional characteristics. We treated mice with broad-spectrum senolytics dasatinib and quercetin, and endothelial-specific senolytic fisetin and studied their effects on senescence and macrophage populations.
    RESULTS: Integration of spatial transcriptomics data across 3- and 18-month-old hearts allowed the identification of 11 cardiac niches, which were characterized by distinct cellular composition and functional signatures. Aging did not alter the overall proportions of cardiac niches but led to distinct regional changes, particularly in the left ventricle. While cardiomyocyte-enriched niches showed disrupted circadian clock gene expression, vascular niches showed major changes in proinflammatory and profibrotic signatures and altered cellular composition. We particularly identified larger vessel-associated cellular niches as key hotspots for activated fibroblasts and bone marrow-derived Lyve1- and resident Lyve1+ macrophages in aged hearts, with interactions of both cell types through the C3:C3ar1 axis. These niches were also enriched in senescent cells exhibiting high expression of immune evasion mechanisms that may impair senescent cell clearance. Removal of senescent cells by senolytics reduced the presence of Lyve1- macrophages.
    CONCLUSIONS: Our findings indicate that the perivascular microenvironment is particularly susceptible to age-related changes and serves as a primary site for inflammation-driven aging, so-called inflammaging. This study provides new insights into how aging reshapes cardiac cellular architecture, highlighting vessel-associated niches as potential therapeutic targets for age-related cardiac dysfunction.
    Keywords:  aging; bone marrow; cardiovascular diseases; heart failure; stroke volume
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327060
  17. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2513939122
    Temporal and spatial coordination of DNA segregation and cell division in an archaeon.
    Joe Parham, Valerio Sorichetti, Alice Cezanne, Sherman Foo, Yin-Wei Kuo, Baukje Hoogenberg, Arthur Radoux-Mergault, Eloise Mawdesley, Lydia Daniels Gatward, Jerome Boulanger, Ulrike Schulze, Anđela Šarić, Buzz Baum.
      Cells must coordinate DNA segregation with cytokinesis to ensure that each daughter cell inherits a complete genome. Here, we explore how DNA segregation and division are mechanistically coupled in archaeal relatives of eukaryotes, which lack Cyclin-dependent kinase (CDK)/Cyclins. Using live cell imaging, we first describe the series of sequential changes in DNA organization that accompany cell division in Sulfolobus, which computational modeling shows likely aid genome segregation. Through a perturbation analysis we identify a regulatory checkpoint which ensures that the compaction of the genome into two spatially segregated nucleoids only occurs once cells have assembled a division ring-which also defines the axis of DNA segregation. Finally, we show that DNA compaction and segregation depend, in part, on a ParA homologue, SegA, and its partner SegB, whose absence leads to bridging DNA. Taken together, these data show how regulatory checkpoints like those operating in eukaryotes aid high-fidelity division in an archaeon.
    Keywords:  archaea; cell division; checkpoint; chromosome segregation; evolution
    DOI:  https://doi.org/10.1073/pnas.2513939122
  18. Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01210-0. [Epub ahead of print]44(10): 116439
    Long noncoding RNA-dependent control of Myc transcriptional bursting.
    Qiao Li, Corinne Dilsavor, Valid Gahramanov, Erin Floyd, Jane Ding, J Justin Glynn, Ioannis Chiotakakos, Christiane E Olivero, Jesse R Zamudio, Nadya Dimitrova.
      Genes are transcribed in short periods of activity, called bursts. Bursts are initiated by enhancer-promoter contacts and dynamically controlled by the levels of enhancer- and promoter-produced RNAs through a negative feedback mechanism. Here, by direct visualization of nascent transcripts, we show that chromatin-associated long noncoding RNAs (lncRNAs) contribute to the regulation of transcriptional bursting. We find that production of Pvt1 raises the baseline of RNA concentration in the locus of the Myc proto-oncogene and acts locally and in a dose-dependent manner to decrease the duration of Myc bursting. Premature termination of Pvt1 led to higher Myc expression and transcriptional activities, resulting in increased cellular proliferation and advanced tumor development in autochthonous models of lung cancer. These findings point to a critical lncRNA-mediated mechanism for Myc regulation and suggest a potentially widespread role for lncRNAs in fine-tuning gene expression through local control of transcriptional bursting.
    Keywords:  CP: Molecular biology; Myc; Pvt1; long noncoding RNA; transcriptional bursting; tumorigenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116439
  19. Am J Hum Genet. 2025 Oct 14. pii: S0002-9297(25)00390-8. [Epub ahead of print]
    Maternal age and genome-wide failure of meiotic recombination are associated with triploid conceptions in humans.
    Ludovica Picchetta, Christian Simon Ottolini, Xin Tao, Yiping Zhan, Vaidehi Jobanputra, Carlos Marin Vallejo, Francesca Mulas, Elvezia Maria Paraboschi, Maria José Escribá Pérez, Thomas Molinaro, Christine Whitehead, Pavan Gill, Emily Mounts, Dhruti Babariya, Laura Francesca Rienzi, Filippo Maria Ubaldi, Juan Antonio Garcia-Velasco, Antonio Pellicer, Shai Carmi, Eva R Hoffmann, Antonio Capalbo.
      Triploid and haploid conceptions are not viable and are a common occurrence in humans, where they account for 10% of all pregnancy losses. Despite the parent of origin being important in the etiology of the pregnancy, our knowledge of their causes is limited, especially at the point of conception. Using a dataset of 96,660 biopsies and a validation dataset of 44,324 from human blastocyst embryos generated by intracytoplasmic sperm injection, we estimate that 1.1% of human conceptions (n = 1,063) contain extra or missing chromosome sets in zygotes. In our cohort of intracytoplasmic-sperm-injection-derived embryos, where the risk of polyspermy is inherently lower compared to natural conception, we identify for the first time a maternal age effect, with a 1.046-per-year increased risk in triploidy/haploidy (p < 0.001). In 0.03% of couples, we identified three or more triploid/haploid embryos, suggesting a personal risk effect (p = 0.03). Genotype analysis of 41 triploid embryo biopsies and their parents shows that around one-third of maternal triploid conceptions originate in meiosis I and two-thirds in meiosis II. Seven of these embryos are inferred to have entirely failed to initiate meiotic recombination genome wide, a surprising finding suggesting that human oocytes with pervasive meiotic recombination failure that are formed during fetal development are capable of ovulation in adult life. Finally, we identify a type of genome-wide maternal isodiploidy (two maternal chromosome sets) in 0.05% of embryos (41/74,009). Collectively, our findings shed light on the biology of meiosis and the formation of human oocytes with the number of chromosome sets.
    Keywords:  embryos; genotyping; haploidy; human development; pregnancy loss; triploidy
    DOI:  https://doi.org/10.1016/j.ajhg.2025.09.014
  20. Nat Genet. 2025 Oct 16.
    Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers.
    Setor Amuzu, Amy X Xie, Xuechun Bai, Kelly R Pekala, Nicholas A Pickersgill, David Ma, Tomin Perea-Chamblee, Kanika Arora, Walid K Chatila, Andriy Derkach, Ronglai Shen, Garrett M Frampton, Michael Berger, Nikolaus Schultz, Justin Y Newberg, Jian Carrot-Zhang.
      Genetic similarity of populations (or genetic ancestry) is associated with differences in somatic alterations in cancers. We meta-analyze two targeted panel sequencing cohorts with 275,605 samples from 14 cancer types. Here we find a recurrent depletion of TERT promoter mutations in patients of African and East Asian ancestry across multiple cancers. Several clinically actionable alterations, such as ERBB2 mutations in lung adenocarcinoma and MET mutations in papillary renal cell carcinoma, occur at a higher frequency in patients of non-European ancestry. Furthermore, in both cohorts, we show depletions in total driver alterations in non-European ancestries in multiple cancer types, potentially reflecting biases in current panel-based testing that prioritize established targets derived from predominantly patients of European ancestry. Our study highlights a need to increase population diversity in genomic studies to find new drivers and enhance precision oncology interventions for all populations.
    DOI:  https://doi.org/10.1038/s41588-025-02371-3
  21. Development. 2025 Oct 15. pii: dev204668. [Epub ahead of print]152(20):
    egal-1 and microtubules promote regeneration polarity in planarians.
    Yochabed Miliard, Shannon Moreno, Lauren E Cote, Peter W Reddien.
      A central problem in regeneration is how the identity of new tissues is specified. A classic example is the head-versus-tail regeneration decision in planarians. notum is wound induced at anterior-facing planarian wounds, where it triggers head regeneration through inhibition of canonical Wnt signaling. This represents the earliest known asymmetric regeneration step between anterior- and posterior-facing wounds. Wound-induced notum is specific to longitudinal (anterior-posterior-axis oriented) muscle cells, suggesting these fibers might harbor polarity harnessed for the head-tail regeneration decision. The processes that occur within longitudinal muscle after injury for preferential notum activation at anterior-facing wounds are poorly understood. We utilized single-cell RNA sequencing to identify multiple wound-induced genes in longitudinal muscle cells and identified processes required for wound-induced notum asymmetry. Egalitarian-like-1 (Egal-1) is wound induced in longitudinal muscle and has some domain similarity with Drosophila Egalitarian, which facilitates asymmetric RNA localization. Both egal-1 RNAi animals and animals with destabilized microtubules (via colchicine or nocodazole treatment) show ectopic notum expression at posterior-facing wounds. We suggest that Egal-1 and microtubules are together required for longitudinal muscle fibers to promote planarian regeneration polarity.
    Keywords:  Blastema; Egalitarian; Microtubules; Muscle; Neoblasts; Planaria; Regeneration; Stem cells; Wound signaling
    DOI:  https://doi.org/10.1242/dev.204668
  22. Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]
    Aged mice exhibit widespread metabolic changes but preserved major fluxes.
    Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.
      Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.
    Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
  23. Nat Commun. 2025 Oct 14. 16(1): 8924
    A molecular circuit regulates fate plasticity in emerging and adult AT2 cells.
    Amitoj S Sawhney, Brian J Deskin, Junming Cai, Daniel Gibbard, Gibran Ali, Annika Utoft, Xianmei Qi, Aaron Olson, Hannah Hausman, Liberty Sabol, Shannon Holmberg, Ria Shah, Rachel Warren, Stijn De Langhe, Zintis Inde, Kristopher A Sarosiek, Evan Lemire, Adam Haber, Liu Wang, Zong Wei, Rui Benedito, Douglas G Brownfield.
      Alveolar Type 1 and Type 2 cells are vital for lung gas exchange and become compromised in several diseases. While key differentiation signals are known, their emergence and fate plasticity are unclear. Here we show in the embryonic lung that single AT2s emerge at intermediate zones, extrude, and connect with nearby epithelium via interlumenal junctioning. We observe AT2s retain fate plasticity until the bZIP transcription factor C/EBPα suppresses Notch signaling at a novel Dlk1 enhancer. Both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), which together form a "pulse generator" circuit that times Dlk1 expression and thus Notch activation, resulting in a "salt and pepper" pattern of AT1 and AT2 fate. In injured adult lungs, C/EBPα downregulation is required to re-access AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, Cebpa loss also activates a "defender" AT2 state, distinct from its reparative state, and we propose AT2s toggle between either state following infection to protect and repair alveoli.
    DOI:  https://doi.org/10.1038/s41467-025-64224-1
  24. Nat Commun. 2025 Oct 13. 16(1): 9088
    Multi-layered dosage compensation of the avian Z chromosome by increased transcriptional burst frequency and elevated translational rates.
    Natali Papanicolaou, Antonio Lentini, Sebastian Wettersten, Michael Hagemann-Jensen, Annika Krüger, Jilin Zhang, Christos Coucoravas, Ioannis Petrosian, Xian Xin, Ilhan Ceyhan, Joanna Rorbach, Dominic Wright, Björn Reinius.
      Sex-chromosome dosage poses a challenge for heterogametic species in maintaining the proper balance of gene products across chromosomes in each sex. While therian mammals (XX/XY system) achieve near-perfect balance of X-chromosome mRNAs through X-upregulation and X-inactivation, birds (ZW/ZZ system) have been found to lack efficient compensation at RNA level, challenging the necessity of resolving major gene-dosage asymmetries in avian cells. Through comprehensive allele-resolved multiome analyses, we examine dosage compensation in female (ZW), male (ZZ), and rare intersex (ZZW) chicken. Our data reveal that females upregulate their single Z chromosome through increased transcriptional burst frequency, mirroring mammalian X upregulation. Z-protein levels are further balanced in females through enhanced translation efficiency. Additionally, we present a global analysis of promoter elements regulating transcriptional burst kinetics in birds, revealing evolutionary conservation of the genomic encoding of burst kinetics between birds and mammals. Our study provides insights into the regulation of avian dosage compensation, and when considering all regulatory layers collectively, an unexpected similarity between avian and mammalian dosage compensation becomes apparent.
    DOI:  https://doi.org/10.1038/s41467-025-64817-w
  25. Mol Cell. 2025 Oct 10. pii: S1097-2765(25)00703-8. [Epub ahead of print]
    SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.
    Marilia M Dias, Martin S King, Engy Shokry, Sergio Lilla, Nikki Paul, Peter Thomason, Sara Zanivan, David Sumpton, Edmund R S Kunji, Thomas MacVicar.
      Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signaling pathways. Disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism, but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier 25A45 (SLC25A45) is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilizes the carrier by limiting its proteolytic degradation and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key amino acid derivative, carnitine. SLC25A45 is therefore an essential mediator of compartmentalized methylated amino acid metabolism.
    Keywords:  SLC25; carnitine; metabolism; metabolite transport; methylated amino acids; mitochondria; solute carriers
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.018
  26. Nat Cell Biol. 2025 Oct;27(10): 1688-1707
    Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome.
    Rabia R Khawaja, Ernesto Griego, Kristen Lindenau, Asma Salek, Jessica Gambardella, Aurora Scrivo, Hannah R Monday, Mathieu Bourdenx, Jesús Madero-Pérez, Zohaib N Khan, Bhakti Chavda, Ronald Cutler, Sarah Graff, Simone Sidoli, Gaetano Santulli, Laura Santambrogio, Inmaculada Tasset, Susmita Kaushik, Li Gan, Pablo E Castillo, Ana Maria Cuervo.
      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.
    DOI:  https://doi.org/10.1038/s41556-025-01771-1
  27. Nat Struct Mol Biol. 2025 Oct 17.
    Dynamics of microcompartment formation at the mitosis-to-G1 transition.
    Viraat Y Goel, Nicholas G Aboreden, James M Jusuf, Haoyue Zhang, Luisa P Mori, Leonid A Mirny, Gerd A Blobel, Edward J Banigan, Anders S Hansen.
      As cells exit mitosis and enter G1, chromosomes decompact and transcription is reestablished. Hi-C studies have indicated that all interphase three-dimensional genome features, including A/B compartments, topologically associating domains and CCCTC-binding factor loops, are lost during mitosis. However, Hi-C is insensitive to features such as microcompartments, nested focal interactions between cis-regulatory elements. Here we apply region capture Micro-C to mouse erythroblasts from mitosis to G1. We unexpectedly observe microcompartments in prometaphase, which strengthen in anaphase and telophase before weakening throughout G1. Microcompartment anchors coincide with transcriptionally spiking promoters during mitosis. Loss of condensin loop extrusion differentially impacts microcompartments and A/B compartments, suggesting that they are partially distinct. Polymer modeling shows that microcompartment formation is favored by chromatin compaction and disfavored by loop extrusion, providing a basis for strong microcompartmentalization in anaphase and telophase. Our results suggest that compaction and homotypic affinity drive microcompartment formation, which may explain transient transcriptional spiking at mitotic exit.
    DOI:  https://doi.org/10.1038/s41594-025-01687-2
  28. Science. 2025 Oct 16. eadw4612
    Flexible nanoelectronics reveal arrhythmogenesis in transplanted human cardiomyocytes.
    Junya Aoyama, Ren Liu, Xinhe Zhang, Anthony Y Zhu, Pichayathida Luanpaisanon, Nivedhitha Velayutham, Jessica C Garbern, Fang Cao, Irving Barrera, Hannah Fandl, Morgan Sokol, Satvik Dasariraju, Eun Seok Gil, Elton Aleksi, Toshi Amanuma, Jeffrey J Saucerman, Fei Chen, Jia Liu, Richard T Lee.
      The transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offers a potential treatment for heart failure, but arrhythmogenic automaticity arising from transplanted cells can arise. In this study, we investigated the effects of RADA16, a clinically approved self-assembling peptide that forms nanofibers after injection, on the vascularization, myofibril structure, and electrophysiological adaptation of hiPSC-CMs transplanted into rat hearts. RADA16 accelerated the transition of hiPSC-CMs toward adult-like gene expression profiles, enhanced sarcomere organization, and improved vascularization in the transplanted site. Flexible mesh nanoelectronics revealed fibrillation of transplanted hiPSC-CMs within the beating recipient heart, and RADA16 dramatically reduced the automaticity of hiPSC-CMs. Our findings demonstrate the potential of self-assembling nanofibers to advance cardiac cell therapy and how flexible mesh nanoelectronics technology could improve safety.
    DOI:  https://doi.org/10.1126/science.adw4612
  29. Am J Physiol Cell Physiol. 2025 Oct 16.
    Postnatal Developmental Dynamics of Mitochondrial Complex I in Mouse Tissues.
    Max Siragusa, Belem Yoval-Sánchez, Ivan Guerrero, Alexander Galkin.
      Although the content of mitochondrial enzymes in different tissues can vary greatly, understanding the regulation behind these differences has been hampered by a lack of quantitative knowledge in relation to postnatal development. Here we report a quantitative analysis of developing brain, heart, kidneys, and muscle tissue of C57BL/6J mice, focusing on the content of mitochondrial complex I, a key component of the respiratory chain: We found that in all tissues except kidneys, complex I content gradually increases after birth, reaching a plateau level at around 25 days. Complex I content in muscles does not change significantly until postnatal day 7-10, and then also increases. The greatest increment was found in kidneys, where a 16-fold increase in complex I level after birth was observed. We also found that content of complex I in all postnatal tissues, but muscle, is higher in males than in females. These baseline dynamics of this key mitochondrial flavoprotein serve as a reference for evaluating genetic influences on development and provide a standard for assessing mitochondrial complex I function during postnatal growth.
    Keywords:  MItochondria; Postnatal Development; mitochondrial complex I; mouse; tissue specificity
    DOI:  https://doi.org/10.1152/ajpcell.00692.2025
  30. Annu Rev Pathol. 2025 Oct 14.
    Targeting Genome Stability to Mitigate Human Aging and Disease.
    Debra Toiber, Björn Schumacher.
      The maintenance of a stable genome requires constant repair. Congenital DNA repair defects lead to cancer susceptibility and progeroid (premature aging-like) syndromes. Even with intact repair, DNA lesions accumulate in aging organisms, leading to replication and transcription stress and age-dependent somatic mutations. These, in turn, can compromise cellular function and elevate cancer risk. DNA damage response (DDR) mechanisms can lead to cellular death and senescence, and targeting the DDR has emerged as therapeutic strategy not only in cancer but also to protect from age-associated phenotypes. Inhibiting DNA repair can promote cancer cell death. Eliminating senescent cells may alleviate proinflammatory consequences on their tissue environment. Moreover, strategies to limit DNA damage and augment repair in normal cells are in active development. Here, we review emerging concepts for targeting genome maintenance mechanisms to lower cancer risk and lengthen healthy lifespan by extending the integrity and functionality of somatic genomes.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-042624-105942
  31. J Cell Biol. 2025 Nov 03. pii: e202510010. [Epub ahead of print]224(11):
    Slowing down to take it in: Endocytosis during cellular aging.
    Derek C Prosser.
      Aging cells functionally decline and accumulate damage through poorly understood mechanisms. In this issue, Antentor et al. (https://doi.org/10.1083/jcb.202412064) find that increased vacuolar pH in older yeast cells slows clathrin-mediated endocytosis. These findings have broad implications in aging-related plasma membrane protein quality control.
    DOI:  https://doi.org/10.1083/jcb.202510010
  32. J Clin Invest. 2025 Oct 15. pii: e184522. [Epub ahead of print]135(20):
    Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.
    Vincent C Auyeung, Tavienne L Steinberg, Alina Olivier, Luka Suzuki, Mary E Moreno, Imran S Khan, Michael S Downey, Maike Thamsen, Lu Guo, Dustin J Maly, Bradley J Backes, Dean Sheppard, Feroz R Papa.
      Stress-induced epithelial plasticity is central to lung regeneration, fibrosis, and malignancy, but how cellular stress leads to differentiation is incompletely understood. Here, we found a central role for IRE1α, a conserved mediator of the unfolded protein response (UPR), in stimulating the plasticity of alveolar type 2 (AT2) cells. In single-cell RNA-seq, IRE1α activity was associated with loss of AT2 identity and progression toward a damage-associated transitional state unique to fibrosis. AT2 plasticity required destructive regulated IRE1α-dependent decay (RIDD), which we demonstrated by deploying PAIR2, a kinase modulator that inhibits RIDD while preserving IRE1α's adaptive XBP1 mRNA splicing activity. In vivo, selective inhibition of RIDD with PAIR2 reduced AT2 differentiation into profibrotic transitional cells and protected mice from bleomycin-induced pulmonary fibrosis. Mechanistically, we identified the Fgfr2 mRNA as a direct and regulated substrate for IRE1α's RNase in primary AT2 cells and in a biochemically reconstituted cell-free system. Loss of Fgf signaling caused AT2 differentiation, while gain of signaling protected cells from IRE1α-induced differentiation. We propose that IRE1α downregulates Fgf signaling through RIDD, provoking loss of AT2 identity and differentiation towards a profibrotic phenotype. Thus, IRE1α's RIDD activity emerges as a novel target for treatment of pulmonary fibrosis and potentially other diseases driven by aberrant epithelial cell plasticity.
    Keywords:  Cell stress; Fibrosis; Protein kinases; Pulmonology; Stem cells; Therapeutics
    DOI:  https://doi.org/10.1172/JCI184522
  33. Nat Cell Biol. 2025 Oct;27(10): 1708-1724
    MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
    Mai Nguyen, Jack J Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J Milnerwood, Sidong Huang, Michel Desjardins, Heidi M McBride.
      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, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.
    DOI:  https://doi.org/10.1038/s41556-025-01774-y
  34. Nat Cell Biol. 2025 Oct 16.
    Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.
    Kathleen Watt, Bianca Dauber, Krzysztof J Szkop, Laura Lee, Predrag Jovanovic, Shan Chen, Ranveer Palia, Julia A Vassalakis, Tyler T Cooper, David Papadopoli, Laìa Masvidal, Michael Jewer, Kristofferson Tandoc, Hannah Plummer, Gilles A Lajoie, Ivan Topisirovic, Ola Larsson, Lynne-Marie Postovit.
      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.
    DOI:  https://doi.org/10.1038/s41556-025-01786-8
  35. Circ Res. 2025 Oct 15.
    Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.
    Julius Ryan D Pronto, Fleur E Mason, Eva A Rog-Zielinska, Funsho E Fakuade, Donata Bülow, Marcell Tóth, Khaled Machwart, Paulina Brandes, Felix Wiedmann, Michael Kohlhaas, Alexander Nickel, Matthias Wolf, Julian Mustroph, Kim-Chi Vu, Sören Brandenburg, Tri Q Do, Peter Joshua Siedler, Katharina Ritzenhoff, Zongqian Xue, Xiaobo Zhou, Stefanie Kestel, Olga Dschun, Oksana Kyshynska, George Kensah, Robyn T Rebbeck, Aschraf El-Essawi, Ahmad Fawad Jebran, Bernhard C Danner, Hassina Baraki, Johann Schredelseker, Ivan Bogeski, Bianca J J M Brundel, Stephan E Lehnart, Constanze Bening, Ingo Kutschka, Felix Bremmer, Stefan Kallenberger, Silvio O Rizzoli, Björn C Knollmann, Stefan Neef, Katrin Streckfuss-Bömeke, Constanze Schmidt, Christoph Maack, Niels Voigt.
       BACKGROUND: Mitochondrial calcium (Ca2+) is a key regulator of cardiac energetics by stimulating the tricarboxylic acid cycle during elevated workload. Atrial fibrillation (AF) is associated with a reduction in cytosolic Ca2+ transient amplitude, but its effect on mitochondrial Ca2+ handling and cellular redox state has not been explored in AF.
    METHODS: Cardiac myocytes isolated from patient-derived right atrial biopsies were subjected to workload transitions using patch-clamp stimulation and β-adrenergic stimulation (isoproterenol). In conjunction, NAD(P)H/flavin adenine dinucleotide autofluorescence, cytosolic and mitochondrial [Ca2+] were monitored using epifluorescence microscopy. Sarcoplasmic reticulum and mitochondria were imaged using electron tomography and stimulated emission depletion microscopy. The effects of the mitochondrial Ca2+ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated.
    RESULTS: Mitochondrial Ca2+ accumulation during increased workload was blunted in AF, and was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. Nanoscale imaging revealed spatial disorganization of sarcoplasmic reticulum and mitochondria, associated with microtubule destabilization. This was confirmed in human induced pluripotent stem cell-derived myocytes, where nocodazole treatment displaces mitochondria and increases proarrhythmic Ca2+ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca2+ release events both in AF myocytes and nocodazole-treated human induced pluripotent stem cell-derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients on ezetimibe treatment.
    CONCLUSIONS: Mitochondrial Ca2+ uptake and accumulation are impaired in atrial myocytes from patients with AF. The disturbed spatial association between sarcoplasmic reticulum and mitochondria driven by destabilized microtubules may underlie impaired Ca2+ transfer in AF. Enhancing mitochondrial Ca2+ uptake potentially protects against arrhythmogenic events.
    Keywords:  atrial fibrillation; calcium; ezetimibe; microtubules; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325658
  36. Nature. 2025 Oct 15.
    Niche-specific dermal macrophage loss promotes skin capillary ageing.
    Kailin R Mesa, Kevin A O'Connor, Charles Ng, Steven P Salvatore, Alexandra Dolynuk, Michelle Rivera Lomeli, Dan R Littman.
      All mammalian organs depend on resident macrophage populations to coordinate repair and facilitate tissue-specific functions1-3. Functionally distinct macrophage populations reside in discrete tissue niches and are replenished through a combination of local proliferation and monocyte recruitment4,5. Declines in macrophage abundance and function have been linked to age-associated pathologies, including atherosclerosis, cancer and neurodegeneration6-8. However, the mechanisms that coordinate macrophage organization and replenishment within ageing tissues remain largely unclear. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, contributing to impaired vascular repair and reduced tissue perfusion in older mice. To investigate resident macrophage behaviour in vivo, we used intravital two-photon microscopy in live mice to non-invasively image the skin capillary plexus, a spatially well-defined vascular niche that undergoes rarefication and functional decline with age. We find that CAMs are lost at a rate exceeding capillary loss, resulting in macrophage-deficient vascular niches in both mice and humans. CAM phagocytic activity was locally required to repair obstructed capillary blood flow, leaving macrophage-deficient niches selectively vulnerable under homeostatic and injury conditions. Our study demonstrates that homeostatic renewal of resident macrophages is less precisely regulated than previously suggested9-11. Specifically, neighbouring macrophages do not proliferate or reorganize to compensate for macrophage loss without injury or increased growth factors, such as colony-stimulating factor 1 (CSF1). These limitations in macrophage renewal may represent early and targetable contributors to tissue ageing.
    DOI:  https://doi.org/10.1038/s41586-025-09639-y
  37. Nat Med. 2025 Oct 16.
    Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility.
    Changlong Zhang, Wei Zheng, Honghui Zhang, Shuai Zhao, Huiling Hu, Xilin Xu, Xian Wan, Jiaqi Sun, Wei Su, Yang Wang, Ying Cui, Bohan Yang, Changjian Yin, Xin Zhang, Cheng Li, Xin Zhang, Changming Zhang, Zhao Wang, Ying Yuan, Liu Liu, Fei Meng, Jiangtao Zhang, Yongzhi Cao, Yuan Gao, Shigang Zhao, Fei Gong, Keliang Wu, Feng Zhang, Shuyan Tang, Ge Lin, Han Zhao, Zi-Jiang Chen.
      Oocyte and early embryo competence defects (OECD) represent a recently recognized cause of female infertility with the application of assisted reproductive technology, characterized by impaired oocyte or early embryo development. To investigate the genetic landscape and subtypes of OECD, we performed whole-exome sequencing on 2,140 patients, classifying them into six distinct subtypes. We identified 183 pathogenic/likely pathogenic variants across 28 established genes. Notably, distinct genetic profiles and diagnostic rates emerged across subtypes, with a rate of 53% in the Empty Follicle subtype. Additionally, we identified and validated two potentially causative genes, MLH3 and CENPH. Gene burden analysis, using 2,424 fertile controls, suggested nine potential previously unreported associated genes and offered biological insights into the underlying pathogenic mechanisms of OECD. Collectively, these genetic findings accounted for 12.8-23.1% of OECD cases. This study delineates the genetic architecture of OECD, offering insights that may inform the development of diagnostic genetic screenings and provide a reference for standardized subtyping of patients with OECD.
    DOI:  https://doi.org/10.1038/s41591-025-04001-1
  38. Nat Phys. 2025 ;21(10): 1629-1637
    Strings and topological defects govern ordering kinetics in endothelial cell layers.
    Iris Ruider, Kristian Thijssen, Daphné Raphaëlle Vannier, Valentina Paloschi, Alfredo Sciortino, Amin Doostmohammadi, Andreas R Bausch.
      Many physiological processes, such as the shear flow alignment of endothelial cells in the vasculature, depend on the transition of cell layers between disordered and ordered phases. Here we demonstrate that such a transition is driven by the non-monotonic evolution of nematic topological defects in a layer of endothelial cells and the emergence of string excitations that bind the defects together. This suggests the existence of an intermediate phase of ordering kinetics in biological matter. We use time-resolved large-scale imaging and physical modelling to analyse the non-monotonic decrease in the number of defect pairs. The interaction of the intrinsic cell layer activity and the alignment field determines the occurrence of defect domains, which defines the nature of the transition. Defect pair annihilation is mediated by string excitations spanning multicellular scales within the cell layer. Our results, therefore, suggest a mechanism by which intermediate ordering and string excitation might contribute to regulating morphogenetic movements and tissue remodelling in vivo.
    Keywords:  Biological physics; Topological defects
    DOI:  https://doi.org/10.1038/s41567-025-03014-4
  39. Nat Commun. 2025 Oct 15. 16(1): 8847
    In vivo mechano-tissue engineering by hydrogels capable of transmitting intercellular mechanical stress.
    Natsumi Ueda, Hayato Okazaki, Akihiro Mikuma, Ayane Kunieda, Soma Kawashima, Takeru Torii, Keiko Kawauchi, Masatake Matsuoka, Tomohiro Onodera, Norimasa Iwasaki, Koji Nagahama.
      Integrating the latest insights from mechanobiology into tissue engineering could lead to innovative technologies. Here we show a method to effectively elicit the regenerative response of transplanted cells by utilizing mechanical stress generated in vivo. The essential feature of our method is that it does not use specific ligands for the vital mechanosensor integrins to mechanically activate them. In our method, azide groups are introduced into the integrin, and the hydrogel is modified with cyclooctyne (DBCO) groups. Thus, bioorthogonal click reaction between the azide groups and the DBCO groups forms direct, stable, irreversible covalent bonds between the cellular integrin and the hydrogel. We demonstrate that the integrin-hydrogel linkage is in ON state regardless of the intensity of the stress, the cell cycle, or the extracellular environment, so that mechanical stress is rapidly and reliably transmitted to the nucleus through the linkage in vivo, resulting in regenerative response of the transplanted cells.
    DOI:  https://doi.org/10.1038/s41467-025-64656-9
  40. Mol Cell. 2025 Oct 13. pii: S1097-2765(25)00780-4. [Epub ahead of print]
    Tuning insulin receptor signaling using de novo-designed agonists.
    Xinru Wang, Sarah Cardoso, Kai Cai, Preetham Venkatesh, Albert Hung, Michelle Ng, Catherine Hall, Brian Coventry, David S Lee, Rishabh Chowhan, Stacey Gerben, Jie Li, Weidong An, Mara Hon, Michael Gao, Ya-Cheng Liao, Domenico Accili, Eunhee Choi, Xiao-Chen Bai, David Baker.
      Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulating metabolism and proliferation. We reasoned that designed agonists inducing different IR conformational changes might induce different downstream responses. We used de novo protein design to generate binders for individual IR extracellular domains and fused them in different orientations with different conformational flexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPK activation, trafficking, and proliferation responses. We identified designs more potent than insulin, causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, while largely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes in IR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.
    Keywords:  cancer; computational protein design; diabetes; insulin; insulin receptor; metabolism; receptor tyrosine kinase; severe insulin-resistance syndromes; signaling; trafficking
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.020
  41. Cancer Cell. 2025 Oct 16. pii: S1535-6108(25)00402-7. [Epub ahead of print]
    Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest.
    Jorge Luis Galeano Niño, Falk Ponath, Victor A Ajisafe, Clara R Becker, Andrew G Kempchinsky, Martha A Zepeda-Rivera, Javier A Gomez, Hanrui Wu, Jessica G Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G White, Y Nancy You, Scott Kopetz, Nadim J Ajami, Jennifer A Wargo, Christopher D Johnston, Susan Bullman.
      Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals downregulation of cell cycle, transcription, and antigen presentation genes in bacteria-enriched regions, consistent with a quiescent, immune-evasive phenotype. In an independent rectal cancer cohort, high Fusobacterium burden correlates with reduced therapy response. These results link extracellular bacteria to cancer cell quiescence and chemoresistance, highlighting microbial-tumor interactions as therapeutic targets.
    Keywords:  Fusobacterium; cancer progression; cell-cycle arrest; chemoresistance; colorectal cancer; epithelial cell-to-cell contacts; host-pathogen interactions; intratumoral bacteria; live-cell confocal imaging; spatial single-cell transcriptomics; tumor microenvironment; tumor-infiltrating bacteria
    DOI:  https://doi.org/10.1016/j.ccell.2025.09.010
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