bims-ginsta Biomed News
on Genome instability
Issue of 2025–03–09
27 papers selected by
Jinrong Hu, National University of Singapore
  1. p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
  2. Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
  3. CTCF-mediated 3D chromatin sets up the gene expression program in the male germline.
  4. A subcellular map of translational machinery composition and regulation at the single-molecule level.
  5. RNA-binding proteins and glycoRNAs form domains on the cell surface for cell-penetrating peptide entry.
  6. Mechanical strain focusing at topological defect sites in regenerating Hydra.
  7. Multi-Omics Reveal the Metabolic Changes in Cumulus Cells During Aging.
  8. Dux cluster duplication ensures full activation of totipotent genes.
  9. Large-scale control over collective cell migration using light-activated epidermal growth factor receptors.
  10. Asymmetric microtubule nucleation from Golgi stacks promotes opposite microtubule polarity in axons and dendrites.
  11. Evolutionary fingerprints of epithelial-to-mesenchymal transition.
  12. Single-cell transcriptomic atlas of the human testis across the reproductive lifespan.
  13. Genome duplication in a long-term multicellularity evolution experiment.
  14. Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound.
  15. Mapping the nanoscale organization of the human cell surface proteome reveals new functional associations and surface antigen clusters.
  16. Transcription-coupled AID deamination damage depends on ELOF1-associated RNA polymerase II.
  17. In-cell structure and snapshots of copia retrotransposons in intact tissue by cryoelectron tomography.
  18. The complex interplay between aging and cancer.
  19. Uncoupling protein 3 protects against pathological cardiac hypertrophy via downregulation of aspartate.
  20. TIR1-produced cAMP as a second messenger in transcriptional auxin signalling.
  21. Spatiotemporal modeling of molecular holograms.
  22. Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature.
  23. Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
  24. Genetically encoded tension heterogeneity sculpts cardiac trabeculation.
  25. PIEZO1-dependent mode switch of neuronal migration in heterogeneous microenvironments in the developing brain.
  26. Cell2fate infers RNA velocity modules to improve cell fate prediction.
  27. Ubiquitous MEIS transcription factors actuate lineage-specific transcription to establish cell fate.
  1. Nat Commun. 2025 Mar 05. 16(1): 2229
    p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
    Karl N Miller, Brightany Li, Hannah R Pierce-Hoffman, Shreeya Patel, Xue Lei, Adarsh Rajesh, Marcos G Teneche, Aaron P Havas, Armin Gandhi, Carolina Cano Macip, Jun Lyu, Stella G Victorelli, Seung-Hwa Woo, Anthony B Lagnado, Michael A LaPorta, Tianhui Liu, Nirmalya Dasgupta, Sha Li, Andrew Davis, Anatoly Korotkov, Erik Hultenius, Zichen Gao, Yoav Altman, Rebecca A Porritt, Guillermina Garcia, Carolin Mogler, Andrei Seluanov, Vera Gorbunova, Susan M Kaech, Xiao Tian, Zhixun Dou, Chongyi Chen, João F Passos, Peter D Adams.
      Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
    DOI:  https://doi.org/10.1038/s41467-025-57229-3
  2. J Cell Biol. 2025 Apr 07. pii: e202407110. [Epub ahead of print]224(4):
    Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
    Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.
      Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.
    DOI:  https://doi.org/10.1083/jcb.202407110
  3. Nat Struct Mol Biol. 2025 Mar 03.
    CTCF-mediated 3D chromatin sets up the gene expression program in the male germline.
    Yuka Kitamura, Kazuki Takahashi, So Maezawa, Yasuhisa Munakata, Akihiko Sakashita, Shawna P Katz, Noam Kaplan, Satoshi H Namekawa.
      Spermatogenesis is a unidirectional differentiation process that generates haploid sperm, but how the gene expression program that directs this process is established is largely unknown. Here we determine the high-resolution three-dimensional (3D) chromatin architecture of mouse male germ cells during spermatogenesis and show that CTCF-mediated 3D chromatin dictates the gene expression program required for spermatogenesis. In undifferentiated spermatogonia, CTCF-mediated chromatin interactions between meiosis-specific super-enhancers (SEs) and their target genes precede activation of these SEs on autosomes. These meiotic SEs recruit the master transcription factor A-MYB (MYBL1) in meiotic spermatocytes, which strengthens their 3D contacts and instructs a burst of meiotic gene expression. We also find that at the mitosis-to-meiosis transition, the germline-specific Polycomb protein SCML2 facilitates the resolution of chromatin loops that are specific to mitotic spermatogonia. Moreover, SCML2 and A-MYB help shape the unique 3D chromatin organization of sex chromosomes during meiotic sex chromosome inactivation. We propose that CTCF-mediated 3D chromatin organization regulates epigenetic priming that directs unidirectional differentiation, thereby determining the cellular identity of the male germline.
    DOI:  https://doi.org/10.1038/s41594-025-01482-z
  4. Science. 2025 Mar 07. 387(6738): eadn2623
    A subcellular map of translational machinery composition and regulation at the single-molecule level.
    Zijian Zhang, Adele Xu, Yunhao Bai, Yuxiang Chen, Kitra Cates, Craig Kerr, Abel Bermudez, Teodorus Theo Susanto, Kelsie Wysong, Fernando J García Marqués, Garry P Nolan, Sharon Pitteri, Maria Barna.
      Millions of ribosomes are packed within mammalian cells, yet we lack tools to visualize them in toto and characterize their subcellular composition. In this study, we present ribosome expansion microscopy (RiboExM) to visualize individual ribosomes and an optogenetic proximity-labeling technique (ALIBi) to probe their composition. We generated a super-resolution ribosomal map, revealing subcellular translational hotspots and enrichment of 60S subunits near polysomes at the endoplasmic reticulum (ER). We found that Lsg1 tethers 60S to the ER and regulates translation of select proteins. Additionally, we discovered ribosome heterogeneity at mitochondria guiding translation of metabolism-related transcripts. Lastly, we visualized ribosomes in neurons, revealing a dynamic switch between monosomes and polysomes in neuronal translation. Together, these approaches enable exploration of ribosomal localization and composition at unprecedented resolution.
    DOI:  https://doi.org/10.1126/science.adn2623
  5. Cell. 2025 Feb 21. pii: S0092-8674(25)00109-6. [Epub ahead of print]
    RNA-binding proteins and glycoRNAs form domains on the cell surface for cell-penetrating peptide entry.
    Jonathan Perr, Andreas Langen, Karim Almahayni, Gianluca Nestola, Peiyuan Chai, Charlotta G Lebedenko, Regan F Volk, Diego Detrés, Reese M Caldwell, Malte Spiekermann, Helena Hemberger, Namita Bisaria, Toshihiko Aiba, Francisco J Sánchez-Rivera, Konstantinos Tzelepis, Eliezer Calo, Leonhard Möckl, Balyn W Zaro, Ryan A Flynn.
      The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA-binding proteins (RBPs) is present on the surface of living cells. These cell-surface RBPs (csRBPs) precisely organize into well-defined nanoclusters enriched for multiple RBPs and glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell-surface interaction for the cell-penetrating peptide trans-activator of transcription (TAT). Removal of RNA from the cell surface, or loss of RNA-binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.
    Keywords:  RNA-binding proteins; cell surface; cell-penetrating peptides; glycoRNA
    DOI:  https://doi.org/10.1016/j.cell.2025.01.040
  6. Development. 2025 Feb 15. pii: DEV204514. [Epub ahead of print]152(4):
    Mechanical strain focusing at topological defect sites in regenerating Hydra.
    Yonit Maroudas-Sacks, S Suganthan, Liora Garion, Yael Ascoli-Abbina, Ariel Westfried, Noam Dori, Iris Pasvinter, Marko Popović, Kinneret Keren.
      The formation of a new head during Hydra regeneration involves the establishment of a head organizer that functions as a signaling center and contains an aster-shaped topological defect in the organization of the supracellular actomyosin fibers. Here, we show that the future head region in regenerating tissue fragments undergoes multiple instances of extensive stretching and rupture events from the onset of regeneration. These recurring localized tissue deformations arise due to transient contractions of the supracellular ectodermal actomyosin fibers that focus mechanical strain at defect sites. We further show that stabilization of aster-shaped defects is disrupted by perturbations of the Wnt signaling pathway. We propose a closed-loop feedback mechanism promoting head organizer formation, and develop a biophysical model of regenerating Hydra tissues that incorporates a morphogen source activated by mechanical strain and an alignment interaction directing fibers along morphogen gradients. We suggest that this positive-feedback loop leads to mechanical strain focusing at defect sites, enhancing local morphogen production and promoting robust organizer formation.
    Keywords:   Hydra regeneration; Actomyosin fibers; Mechanochemical feedback; Morphogenesis; Topological defects
    DOI:  https://doi.org/10.1242/dev.204514
  7. Cell Prolif. 2025 Mar 05. e70014
    Multi-Omics Reveal the Metabolic Changes in Cumulus Cells During Aging.
    Liangyue Shi, Hengjie Wang, Shuai Zhu, Minjian Chen, Xuejiang Guo, Qiang Wang, Ling Gu.
      Maternal age has been reported to impair oocyte quality. However, the molecular mechanisms underlying the age-related decrease in oocyte competence remain poorly understood. Cumulus cells establish direct contact with the oocyte through gap junctions, facilitating the provision of crucial nutrients necessary for oocyte development. In this study, we obtained the proteomic and metabolomic profiles of cumulus cells from both young and old mice. We found that fatty acid beta-oxidation and nucleotide metabolism, markedly active in aged cumulus cells, may serve as a compensatory mechanism for energy provision. Tryptophan undergoes two principal metabolic pathways, including the serotonin (5-HT) synthesis and kynurenine catabolism. Notably, we discovered that kynurenine catabolism is reduced in aged cumulus cells compared to young cells, whereas 5-HT synthesis exhibited a significant decrease. Furthermore, the supplement of 5-HT during cumulus-oocyte complexes (COCs) culture significantly ameliorated the metabolic dysfunction and meiotic defects in old oocytes. In sum, our data provide a comprehensive multiple omics resource, offering potential insights for improving oocyte quality and promoting fertility in aged females.
    Keywords:  aging; cumulus cells; metabolomics; oocyte; proteomic
    DOI:  https://doi.org/10.1111/cpr.70014
  8. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2421594122
    Dux cluster duplication ensures full activation of totipotent genes.
    Meiqi Lin, Zeling Du, Dan Guo, Yiran Zhang, Jiameng Dan.
      Zygotic genome activation (ZGA) confers to the mouse two-cell (2C) embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL retrotransposons. Intriguingly, those genes are duplicated and clustered in the genome during evolution, including Dux cluster, Obox, and Zscan4 family members in mice. However, the contribution and biological significance of the totipotency-related gene duplication events in early embryo development remain poorly understood. Here, we focus on Dux cluster, the master regulator of ZGA that is necessary and sufficient for the induction of 2C-like cells and activation of totipotency-related genes in mouse embryonic stem cells (mESCs). By reducing Dux gene copies from 31 to 0 or 1 through CRISPR-Cas9 technology, we generate Dux-KO and Dux (n = 1) mESC lines, respectively. We uncover that the totipotency-related gene transcriptional profile is awakened to a much lesser extent in Dux (n = 1) mESCs compared to wild type mESCs following global DNA demethylation reprogramming or induction of DNA damage, mimicking the intrinsic events in preimplantation development. Together, Dux cluster duplication is critically required for full activation of ZGA transcripts.
    Keywords:  2C-like state; Dux cluster duplication; totipotency; zygotic genome activation
    DOI:  https://doi.org/10.1073/pnas.2421594122
  9. Cell Syst. 2025 Feb 26. pii: S2405-4712(25)00036-5. [Epub ahead of print] 101203
    Large-scale control over collective cell migration using light-activated epidermal growth factor receptors.
    Kevin Suh, Richard H Thornton, Long Nguyen, Payam E Farahani, Daniel J Cohen, Jared E Toettcher.
      Receptor tyrosine kinases (RTKs) play key roles in coordinating cell movement at both single-cell and tissue scales. The recent development of optogenetic tools for controlling RTKs and their downstream signaling pathways suggests that these responses may be amenable to engineering-based control for sculpting tissue shape and function. Here, we report that a light-controlled epidermal growth factor (EGF) receptor (OptoEGFR) can be deployed in epithelial cells for precise, programmable control of long-range tissue movements. We show that in OptoEGFR-expressing tissues, light can drive millimeter-scale cell rearrangements to densify interior regions or produce rapid outgrowth at tissue edges. Light-controlled tissue movements are driven primarily by phosphoinositide 3-kinase (PI3K) signaling, rather than diffusible ligands, tissue contractility, or ERK kinase signaling as seen in other RTK-driven migration contexts. Our study suggests that synthetic, light-controlled RTKs could serve as a powerful platform for controlling cell positions and densities for diverse applications, including wound healing and tissue morphogenesis.
    Keywords:  collective cell migration; epidermal growth factor receptor; optogenetics; tissue mechanics
    DOI:  https://doi.org/10.1016/j.cels.2025.101203
  10. Curr Biol. 2025 Feb 27. pii: S0960-9822(25)00147-2. [Epub ahead of print]
    Asymmetric microtubule nucleation from Golgi stacks promotes opposite microtubule polarity in axons and dendrites.
    Akila Yagoubat, Paul T Conduit.
      The neuronal microtubule cytoskeleton is highly polarized, with most microtubules growing away from the soma in axons (plus-end-out), but many microtubules growing toward the soma in dendrites (minus-end-out). This differential microtubule polarity allows directional trafficking of specific organelles, vesicles, and molecules into either axons or dendrites, but how it is established and maintained remains unclear. We showed previously that microtubules are nucleated asymmetrically from Golgi stacks within the soma of Drosophila neurons, with their plus ends growing preferentially toward and into axons and away from dendrites. Here, we show that this microtubule nucleation asymmetry correlates with a cis-to-trans orientation of specific Golgi stacks toward the axon and depends on microtubule-nucleating γ-tubulin ring complexes (γ-TuRCs) at the cis-Golgi and the plus-end-stabilizing protein CLASP at the trans-Golgi. Depleting CLASP or reducing γ-TuRC localization to the Golgi by depleting the Golgin protein GMAP (Golgi microtubule-associated protein) perturbs asymmetric microtubule nucleation and growth within the soma and results in polarity changes in proximal axons and dendrites. We propose that the plus ends of microtubules nucleated by γ-TuRCs at the cis-Golgi are stabilized by CLASP at the trans-Golgi to promote the growth of microtubules along the cis-to-trans Golgi axis. This, coupled with oriented Golgi stacks, promotes microtubule growth toward and into axons and away from dendrites, helping promote plus-end-out microtubule polarity in axons and maintain minus-end-out microtubule polarity in dendrites.
    Keywords:  CLASP; asymmetric; dendritic arborisation; g-TuRC; golgi; microtubule; neuron; nucleation; polarity
    DOI:  https://doi.org/10.1016/j.cub.2025.02.013
  11. Nature. 2025 Mar 05.
    Evolutionary fingerprints of epithelial-to-mesenchymal transition.
    Luigi Perelli, Li Zhang, Sarah Mangiameli, Francesca Giannese, Krishnan K Mahadevan, Fuduan Peng, Francesca Citron, Hania Khan, Courtney Le, Enrico Gurreri, Federica Carbone, Andrew J C Russell, Melinda Soeung, Truong Nguyen Anh Lam, Sebastian Lundgren, Sujay Marisetty, Cihui Zhu, Desiree Catania, Alaa M T Mohamed, Ningping Feng, Jithesh Jose Augustine, Alessandro Sgambato, Giampaolo Tortora, Giulio F Draetta, Giovanni Tonon, Andrew Futreal, Virginia Giuliani, Alessandro Carugo, Andrea Viale, Michael P Kim, Timothy P Heffernan, Linghua Wang, Raghu Kalluri, Davide Cittaro, Fei Chen, Giannicola Genovese.
      Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.
    DOI:  https://doi.org/10.1038/s41586-025-08671-2
  12. Nat Aging. 2025 Mar 03.
    Single-cell transcriptomic atlas of the human testis across the reproductive lifespan.
    Lina Cui, Xichen Nie, Yixuan Guo, Pengcheng Ren, Yifei Guo, Xiaoyan Wang, Ran Li, James M Hotaling, Bradley R Cairns, Jingtao Guo.
      Testicular aging is associated with declining reproductive health, but the molecular mechanisms are unclear. Here we generate a dataset of 214,369 single-cell transcriptomes from testicular cells of 35 individuals aged 21-69, offering a resource for studying testicular aging and physiology. Machine learning analysis reveals a stronger aging response in somatic cells compared to germ cells. Two waves of aging-related changes are identified: the first in peritubular cells of donors in their 30s, marked by increased basement membrane thickness, indicating a priming state for aging. In their 50s, testicular cells exhibit functional changes, including altered steroid metabolism in Leydig cells and immune responses in macrophages. Further analyses reveal the impact of body mass index on spermatogenic capacity as age progresses, particularly after age 45. Altogether, our findings illuminate molecular alterations during testis aging and their relationship with body mass index, providing a foundation for future research and offering potential diagnostic markers and therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00824-2
  13. Nature. 2025 Mar 05.
    Genome duplication in a long-term multicellularity evolution experiment.
    Kai Tong, Sayantan Datta, Vivian Cheng, Daniella J Haas, Saranya Gourisetti, Harley L Yopp, Thomas C Day, Dung T Lac, Ahmad S Khalil, Peter L Conlin, G Ozan Bozdag, William C Ratcliff.
      Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution1-4. However, given the instability of newly formed polyploid genomes5-7, understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Here, using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE)8, we show that diploid snowflake yeast (Saccharomyces cerevisiae) under selection for larger multicellular size rapidly evolve to be tetraploid. From their origin within the first 50 days of the experiment, tetraploids persisted for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in 10 replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modelling and counter-selection, we found that tetraploidy evolved because it confers immediate fitness benefits under this selection, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, having a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection and fuel long-term innovations by creating additional dimensions of heritable genetic variation.
    DOI:  https://doi.org/10.1038/s41586-025-08689-6
  14. Aging Cell. 2025 Mar 03. e70008
    Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound.
    Sanjay K Kureel, Rosario Maroto, Maisha Aniqua, Simon Powell, Ekta Singh, Felix Margadant, Brandon Blair, Blake B Rasmussen, Michael P Sheetz.
      The presence of senescent cells causes age-related pathologies since their removal by genetic or pharmacological means, as well as possibly by exercise, improves outcomes in animal models. An alternative to depleting such cells would be to rejuvenate them to promote their return to a replicative state. Here we report that treatment of non-growing senescent cells with low-frequency ultrasound (LFU) rejuvenates the cells for growth. Notably, there are 15 characteristics of senescent cells that are reversed by LFU, including senescence-associated secretory phenotype (SASP) plus decreased cell and organelle motility. There is also inhibition of β-galactosidase, p21, and p16 expression, telomere length is increased, while nuclear 5mC, H3K9me3, γH2AX, nuclear p53, ROS, and mitoSox levels are all restored to normal levels. Mechanistically, LFU causes Ca2+ entry and increased actin dynamics that precede dramatic increases in autophagy and an inhibition of mTORC1 signaling plus movement of Sirtuin1 from the nucleus to the cytoplasm. Repeated LFU treatments enable the expansion of primary cells and stem cells beyond normal replicative limits without altering phenotype. The rejuvenation process is enhanced by co-treatment with cytochalasin D, rapamycin, or Rho kinase inhibition but is inhibited by blocking Sirtuin1 or Piezo1 activity. Optimized LFU treatment parameters increased mouse lifespan and healthspan. These results indicate that mechanically induced pressure waves alone can reverse senescence and aging effects at the cellular and organismal level, providing a non-pharmacological way to treat the effects of aging.
    Keywords:  aging; autophagy; calcium signaling; low frequency ultrasound; rejuvenation; senescence
    DOI:  https://doi.org/10.1111/acel.70008
  15. bioRxiv. 2025 Feb 17. pii: 2025.02.12.637979. [Epub ahead of print]
    Mapping the nanoscale organization of the human cell surface proteome reveals new functional associations and surface antigen clusters.
    Brendan M Floyd, Elizabeth L Schmidt, Nicholas A Till, Jonathan L Yang, Pinyu Liao, Benson M George, Ryan A Flynn, Carolyn R Bertozzi.
      The cell surface is a dynamic interface that controls cell-cell communication and signal transduction relevant to organ development, homeostasis and repair, immune reactivity, and pathologies driven by aberrant cell surface phenotypes. The spatial organization of cell surface proteins is central to these processes. High-resolution fluorescence microscopy and proximity labeling have advanced studies of surface protein associations, but the spatial organization of the complete surface proteome remains uncharted. In this study, we systematically mapped the surface proteome of human T-lymphocytes and B-lymphoblasts using proximity labeling of 85 antigens, identified from over 100 antibodies tested for binding to surface-exposed proteins. These experiments were coupled with an optimized data-independent acquisition mass spectrometry workflow to generate a robust dataset. Unsupervised clustering of the resulting interactome revealed functional modules, including well-characterized complexes such as the T-cell receptor and HLA class I/II, alongside novel clusters. Notably, we identified mitochondrial proteins localized to the surface, including the transcription factor TFAM, suggesting previously unappreciated roles for mitochondrial proteins at the plasma membrane. A high-accuracy machine learning classifier predicted over 6,000 surface protein associations, highlighting functional associations such as IL10RB's role as a negative regulator of type I interferon signaling. Spatial modeling of the surface proteome provided insights into protein dispersion patterns, distinguishing widely distributed proteins, such as CD45, from localized antigens, such as CD226 pointing to active mechanisms of regulating surface organization. This work provides a comprehensive map of the human surfaceome and a resource for exploring the spatial and functional dynamics of the cell membrane proteome.
    DOI:  https://doi.org/10.1101/2025.02.12.637979
  16. Mol Cell. 2025 Feb 26. pii: S1097-2765(25)00111-X. [Epub ahead of print]
    Transcription-coupled AID deamination damage depends on ELOF1-associated RNA polymerase II.
    Pengfei Dai, Yuanqing Tan, Yifeng Luo, Tingting Liu, Yanchao Huang, Yafang Shang, Min Emma Huang, Xiaojing Liu, Senxin Zhang, Yanyan Wang, Qian-Xi Li, Niu Li, Lulu Li, Yining Qin, Junqi Liu, Liu Daisy Liu, Xia Xie, Yanni Cai, Fei Xavier Chen, Xiaoqi Zheng, Leng-Siew Yeap, Jian Wang, Jinchuan Hu, Fei-Long Meng.
      In adaptive immunity, transcription-coupled damage (TCD) is introduced into antibody genes by activation-induced cytidine deaminase (AID) to diversify antibody repertoire. However, the coordination between transcription and DNA damage/repair remains elusive. Here, we find that transcription elongation factor 1 (ELOF1) stabilizes paused RNA polymerase II (RNAPII) at transcription barriers, providing a platform for transcription-coupled DNA damage/repair. Using a genetic screen, we discover that ELOF1 is required for AID targeting and that ELOF1 deficiency results in defective antibody class switch recombination and somatic hypermutation in mice. While downstream transcription-coupled repair factors are dispensable for AID damage, ELOF1 mechanistically facilitates both TCD and repair by stabilizing chromatin-bound RNAPII. In ELOF1-deficient cells, paused RNAPII tends to detach from chromatin and fails to recruit factors to induce or repair DNA damage. Our study places ELOF1 at the center of transcription-coupled DNA metabolism processes and suggests a transition of RNAPII from elongation to a DNA damage/repair scaffold.
    Keywords:  AID; ELOF1; class switch recombination; somatic hypermutation; transcription-coupled damage; transcription-coupled repair
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.006
  17. Cell. 2025 Mar 03. pii: S0092-8674(25)00159-X. [Epub ahead of print]
    In-cell structure and snapshots of copia retrotransposons in intact tissue by cryoelectron tomography.
    Sven Klumpe, Kirsten A Senti, Florian Beck, Jenny Sachweh, Bernhard Hampoelz, Paolo Ronchi, Viola Oorschot, Marlene Brandstetter, Assa Yeroslaviz, John A G Briggs, Julius Brennecke, Martin Beck, Jürgen M Plitzko.
      Long terminal repeat (LTR) retrotransposons belong to the transposable elements (TEs), autonomously replicating genetic elements that integrate into the host's genome. Among animals, Drosophila melanogaster serves as an important model organism for TE research and contains several LTR retrotransposons, including the Ty1-copia family, which is evolutionarily related to retroviruses and forms virus-like particles (VLPs). In this study, we use cryo-focused ion beam (FIB) milling and lift-out approaches to visualize copia VLPs in ovarian cells and intact egg chambers, resolving the in situ copia capsid structure to 7.7 Å resolution by cryoelectron tomography (cryo-ET). Although cytoplasmic copia VLPs vary in size, nuclear VLPs are homogeneous and form densely packed clusters, supporting a model in which nuclear import acts as a size selector. Analyzing flies deficient in the TE-suppressing PIWI-interacting RNA (piRNA) pathway, we observe copia's translocation into the nucleus during spermatogenesis. Our findings provide insights into the replication cycle and cellular structural biology of an active LTR retrotransposon.
    Keywords:  Drosophila; LTR retrotransposon; capsid; copia; cryo-ET; cryo-FIB; in situ structural biology; lift-out; piRNA pathway; replication cycle
    DOI:  https://doi.org/10.1016/j.cell.2025.02.003
  18. Nat Aging. 2025 Mar 04.
    The complex interplay between aging and cancer.
    Lucrezia A Trastus, Fabrizio d'Adda di Fagagna.
      Cancer is an age-related disease, but the interplay between cancer and aging is complex and their shared molecular drivers are deeply intertwined. This Review provides an overview of how different biological pathways affect cancer and aging, leveraging evidence mainly derived from animal studies. We discuss how genome maintenance and accumulation of DNA mutations affect tumorigenesis and tissue homeostasis during aging. We describe how age-related telomere dysfunction and cellular senescence intricately modulate tumor development through mechanisms involving genomic instability and inflammation. We examine how an aged immune system and chronic inflammation shape tumor immunosurveillance, fueling DNA damage and cellular senescence. Finally, as animal models are important to untangling the relative contributions of these aging-modulated pathways to cancer progression and to test interventions, we discuss some of the limitations of physiological and accelerated aging models, aiming to improve experimental designs and enhance translation.
    DOI:  https://doi.org/10.1038/s43587-025-00827-z
  19. J Mol Cell Cardiol. 2025 Mar 02. pii: S0022-2828(25)00041-0. [Epub ahead of print]
    Uncoupling protein 3 protects against pathological cardiac hypertrophy via downregulation of aspartate.
    Yajun Wang, Jiliang Tan, Luxiao Li, Shenyan Liu, Xuxia Li, Huitong Shan, Huiyong Yin, Huang-Tian Yang.
      Metabolic remodeling involving alterations in the substrate utilization is a key feature of cardiac hypertrophy. However, the molecular mechanisms underlying regulation of tricarboxylic acid cycle intermediates by mitochondrial membrane proteins during cardiac hypertrophy have not yet been fully clarified. Mitochondrial uncoupling protein 3 (UCP3), an anion transporter located on the inner mitochondrial membrane, exerts cardioprotective effects against ischemia/reperfusion injury and its insufficiency exacerbates left ventricular (LV) diastolic dysfunction during hypertension. However, its role in pressure overload-induced cardiac hypertrophy remains unknown. Here, we found that UCP3 was downregulated in the mouse LV with transverse aortic constriction (TAC)-induced pathological hypertrophy and in phenylephrine (PE)-stimulated hypertrophic neonatal rat cardiomyocytes (NRCMs). The TAC-induced hypertrophy and LV dysfunction were aggravated in global and cardiac specific knockout of UCP3 (UCP3cKO) mice but improved by cardiac specific overexpression of UCP3 (UCP3cOE). Similar alterations in hypertrophy were observed in PE-treated NRCMs with UCP3-knockdown/overexpression. Moreover, the TAC-increased aspartate and glutamic-oxaloacetic transaminase 2 (GOT2) activity were enhanced in UCP3cKO hearts but reversed in UCP3cOE ones. PE-induced increases of GOT2 activity were enhanced in the UCP3-knockdown NRCMs but attenuated in the UCP3 overexpression ones, accompanied with the downregulation of aspartate. The endogenous interaction of UCP3 and GOT2 was weakened in the PE-treated NRCMs compared with the PE-untreated cells. Furthermore, aspartate supplementation reversed the UCP3 overexpression-attenuated hypertrophy in the PE-stimulated NRCMs. In conclusion, UCP3 expression is downregulated in hypertrophic hearts and cardiomyocytes, whereas the increase of UCP3 mitigates cardiac hypertrophy by downregulation of the enhanced aspartate. These findings provide new knowledge for the function of UCP3 and therapeutic target for cardiac hypertrophy.
    Keywords:  Aspartate; GOT2; Hypertrophy; Metabolism; UCP3
    DOI:  https://doi.org/10.1016/j.yjmcc.2025.03.001
  20. Nature. 2025 Mar 05.
    TIR1-produced cAMP as a second messenger in transcriptional auxin signalling.
    Huihuang Chen, Linlin Qi, Minxia Zou, Mengting Lu, Mateusz Kwiatkowski, Yuanrong Pei, Krzysztof Jaworski, Jiří Friml.
      The phytohormone auxin (Aux) is a principal endogenous developmental signal in plants. It mediates transcriptional reprogramming by a well-established canonical signalling mechanism. TIR1/AFB auxin receptors are F-box subunits of an ubiquitin ligase complex; after auxin perception, they associate with Aux/IAA transcriptional repressors and ubiquitinate them for degradation, thus enabling the activation of auxin response factor (ARF) transcription factors1-3. Here we revise this paradigm by showing that without TIR1 adenylate cyclase (AC) activity4, auxin-induced degradation of Aux/IAAs is not sufficient to mediate the transcriptional auxin response. Abolishing the TIR1 AC activity does not affect auxin-induced degradation of Aux/IAAs but renders TIR1 non-functional in mediating transcriptional reprogramming and auxin-regulated development, including shoot, root, root hair growth and lateral root formation. Transgenic plants show that local cAMP production in the vicinity of the Aux/IAA-ARF complex by unrelated AC enzymes bypasses the need for auxin perception and is sufficient to induce ARF-mediated transcription. These discoveries revise the canonical model of auxin signalling and establish TIR1/AFB-produced cAMP as a second messenger essential for transcriptional reprograming.
    DOI:  https://doi.org/10.1038/s41586-025-08669-w
  21. Cell. 2025 Mar 01. pii: S0092-8674(25)00253-3. [Epub ahead of print]
    Spatiotemporal modeling of molecular holograms.
    Xiaojie Qiu, Daniel Y Zhu, Yifan Lu, Jiajun Yao, Zehua Jing, Kyung Hoi Min, Mengnan Cheng, Hailin Pan, Lulu Zuo, Samuel King, Qi Fang, Huiwen Zheng, Mingyue Wang, Shuai Wang, Qingquan Zhang, Sichao Yu, Sha Liao, Chao Liu, Xinchao Wu, Yiwei Lai, Shijie Hao, Zhewei Zhang, Liang Wu, Yong Zhang, Mei Li, Zhencheng Tu, Jinpei Lin, Zhuoxuan Yang, Yuxiang Li, Ying Gu, David Ellison, Yuancheng Ryan Lu, Qinan Hu, Yuhui Hu, Ao Chen, Longqi Liu, Jonathan S Weissman, Jiayi Ma, Xun Xu, Shiping Liu, Yinqi Bai.
      
    DOI:  https://doi.org/10.1016/j.cell.2025.02.026
  22. Cell Stem Cell. 2025 Feb 27. pii: S1934-5909(25)00046-3. [Epub ahead of print]
    Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature.
    Charlie J Childs, Holly M Poling, Kevin Chen, Yu-Hwai Tsai, Angeline Wu, Abigail Vallie, Madeline K Eiken, Sha Huang, Caden W Sweet, Ryan Schreiner, Zhiwei Xiao, Ryan C Spencer, Samantha A Paris, Ansley S Conchola, Jonathan W Villanueva, Meghan F Anderman, Emily M Holloway, Akaljot Singh, Roman J Giger, Maxime M Mahe, Claudia Loebel, Michael A Helmrath, Katherine D Walton, Shahin Rafii, Jason R Spence.
      Human intestinal organoids (HIOs) derived from human pluripotent stem cells co-differentiate both epithelial and mesenchymal lineages in vitro but lack important cell types such as neurons, endothelial cells, and smooth muscle, which limits translational potential. Here, we demonstrate that the intestinal stem cell niche factor, EPIREGULIN (EREG), enhances HIO differentiation with epithelium, mesenchyme, enteric neuroglial populations, endothelial cells, and organized smooth muscle in a single differentiation, without the need for co-culture. When transplanted into a murine host, HIOs mature and demonstrate enteric nervous system function, undergoing peristaltic-like contractions indicative of a functional neuromuscular unit. HIOs also form functional vasculature, demonstrated in vitro using microfluidic devices and in vivo following transplantation, where HIO endothelial cells anastomose with host vasculature. These complex HIOs represent a transformative tool for translational research in the human gut and can be used to interrogate complex diseases as well as for testing therapeutic interventions with high fidelity to human pathophysiology.
    Keywords:  HIO; directed differentiation; enteric neruon; human intestinal organoids; intestine; organoids; pluripotent; stem cells; vasculature
    DOI:  https://doi.org/10.1016/j.stem.2025.02.007
  23. Nat Aging. 2025 Mar 06.
    Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
    Haruhito Totani, Takayoshi Matsumura, Rui Yokomori, Terumasa Umemoto, Yuji Takihara, Chong Yang, Lee Hui Chua, Atsushi Watanabe, Takaomi Sanda, Toshio Suda.
      The aging of hematopoietic stem cells (HSCs) substantially alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. In addition, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a distinct marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen understanding of HSC aging and provide additional perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in aging.
    DOI:  https://doi.org/10.1038/s43587-025-00828-y
  24. Sci Adv. 2025 Mar 07. 11(10): eads2998
    Genetically encoded tension heterogeneity sculpts cardiac trabeculation.
    Jinxiu Liang, Peijun Jiang, Shuaifang Yan, Tao Cheng, Shuo Chen, Kexin Xian, Pengfei Xu, Jing-Wei Xiong, Aibin He, Jia Li, Peidong Han.
      The myocardial wall arises from a single layer of cardiomyocytes, some delaminate to create trabeculae while others remain in the compact layer. However, the mechanisms governing cardiomyocyte fate decisions remain unclear. Using single-cell RNA sequencing, genetically encoded biosensors, and in toto live imaging, we observe intrinsic variations in erbb2 expression and its association with trabecular fate. Specifically, erbb2 promotes PI3K activity and recruits the Arp2/3 complex, inducing a polarized accumulation of the actomyosin network to drive cell delamination. Subsequently, the lineage-committed nascent trabeculae trigger Notch activity in neighboring cardiomyocytes to suppress erbb2 expression and reduce cell tension, thereby confining them to the compact layer. Overall, this genetic and cellular interplay governs compact and trabecular cell fate determination to orchestrate myocardial pattern formation.
    DOI:  https://doi.org/10.1126/sciadv.ads2998
  25. Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00176-7. [Epub ahead of print]44(3): 115405
    PIEZO1-dependent mode switch of neuronal migration in heterogeneous microenvironments in the developing brain.
    Naotaka Nakazawa, Gianluca Grenci, Yoshitaka Kameo, Noriko Takeda, Tsuyoshi Sawada, Junko Kurisu, Zhejing Zhang, Kenichi Toma, Taiji Adachi, Keiko Nonomura, Mineko Kengaku.
      The migration of newborn neurons is essential for brain morphogenesis and circuit formation, yet controversy exists regarding how neurons generate the driving force against strong mechanical stresses in crowded neural tissues. We found that cerebellar granule neurons employ a mechanosensing mechanism to switch the driving forces to maneuver in irregular brain tissue. In two-dimensional (2D) cultures, actomyosin is enriched in the leading process, exerting traction force on the cell soma. In tissue or 3D confinement, however, actomyosin concentrates at the posterior cell membrane, generating contractile forces that assist passage through narrow spaces, working alongside the traction force in the leading process. The 3D migration is initiated by the activation of a mechanosensitive channel, PIEZO1. PIEZO1-induced calcium influx in the soma triggers the PKC-ezrin cascade, which recruits actomyosin and transmits its contractile force to the posterior plasma membrane. Thus, migrating neurons adapt their motility modes in distinct extracellular environments in the developing brain.
    Keywords:  3D confined migration; CP: Developmental biology; CP: Neuroscience; PIEZO1; PKC; actomyosin; brain development; ezrin; mechanosensing; neuronal migration; protein kinase C
    DOI:  https://doi.org/10.1016/j.celrep.2025.115405
  26. Nat Methods. 2025 Mar 03.
    Cell2fate infers RNA velocity modules to improve cell fate prediction.
    Alexander Aivazidis, Fani Memi, Vitalii Kleshchevnikov, Sezgin Er, Brian Clarke, Oliver Stegle, Omer Ali Bayraktar.
      RNA velocity exploits the temporal information contained in spliced and unspliced RNA counts to infer transcriptional dynamics. Existing velocity models often rely on coarse biophysical simplifications or numerical approximations to solve the underlying ordinary differential equations (ODEs), which can compromise accuracy in challenging settings, such as complex or weak transcription rate changes across cellular trajectories. Here we present cell2fate, a formulation of RNA velocity based on a linearization of the velocity ODE, which allows solving a biophysically more accurate model in a fully Bayesian fashion. As a result, cell2fate decomposes the RNA velocity solutions into modules, providing a biophysical connection between RNA velocity and statistical dimensionality reduction. We comprehensively benchmark cell2fate in real-world settings, demonstrating enhanced interpretability and power to reconstruct complex dynamics and weak dynamical signals in rare and mature cell types. Finally, we apply cell2fate to the developing human brain, where we spatially map RNA velocity modules onto the tissue architecture, connecting the spatial organization of tissues with temporal dynamics of transcription.
    DOI:  https://doi.org/10.1038/s41592-025-02608-3
  27. EMBO J. 2025 Feb 28.
    Ubiquitous MEIS transcription factors actuate lineage-specific transcription to establish cell fate.
    Zoulfia Darieva, Peyman Zarrineh, Naomi Phillips, Joshua Mallen, Araceli Garcia Mora, Ian Donaldson, Laure Bridoux, Megan Douglas, Sara F Dias Henriques, Dorothea Schulte, Matthew J Birket, Nicoletta Bobola.
      Control of gene expression is commonly mediated by distinct combinations of transcription factors (TFs). This cooperative action allows the integration of multiple biological signals at regulatory elements, resulting in highly specific gene expression patterns. It is unclear whether combinatorial binding is also necessary to bring together TFs with distinct biochemical functions, which collaborate to effectively recruit and activate RNA polymerase II. Using a cardiac differentiation model, we find that the largely ubiquitous homeodomain proteins MEIS act as actuators, fully activating transcriptional programs selected by lineage-restricted TFs. Combinatorial binding of MEIS with lineage-enriched TFs, GATA, and HOX, provides selectivity, guiding MEIS to function at cardiac-specific enhancers. In turn, MEIS TFs promote the accumulation of the methyltransferase KMT2D to initiate lineage-specific enhancer commissioning. MEIS combinatorial binding dynamics, dictated by the changing dosage of its partners, drive cells into progressive stages of differentiation. Our results uncover tissue-specific transcriptional activation as the result of ubiquitous actuator TFs harnessing general transcriptional activator at tissue-specific enhancers, to which they are directed by binding with lineage- and domain-specific TFs.
    Keywords:  Cardiac Differentiation; Combinatorial Binding; Transcription Factors
    DOI:  https://doi.org/10.1038/s44318-025-00385-5
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