bims-ginsta Biomed News
on Genome instability
Issue of 2025–07–13
twenty-one papers selected by
Jinrong Hu, National University of Singapore
  1. Retrospective and multifactorial single-cell profiling reveals sequential chromatin reorganization during X inactivation.
  2. Delivering intact, naive, synthetic megabase-scale human DNA into mammalian embryos using SynNICE.
  3. Aging disrupts hepatocyte zonation homeostasis in mice and humans.
  4. Selective remodelling of the adipose niche in obesity and weight loss.
  5. Nonmuscle myosin II regulates presynaptic actin and neuronal mechanobiology in Drosophila.
  6. Muscle growth by sarcomere divisions.
  7. Macrophage-derived oncostatin M repairs the lung epithelial barrier during inflammatory damage.
  8. mRNA 3'UTRs chaperone intrinsically disordered regions to control protein activity.
  9. Coping with uncertainty: Challenges for robust pattern formation in dynamical tissues.
  10. Spatiotemporal mapping of the contractile and adhesive forces sculpting early C. elegans embryos.
  11. Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation.
  12. ER-endosome contacts generate a local environment promoting phagophore formation.
  13. Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy.
  14. Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.
  15. Epidermal Stem Cells Control Periderm Injury Repair via Matrix-Driven Specialization of Intercellular Junctions.
  16. How short peptides disassemble tau fibrils in Alzheimer's disease.
  17. MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
  18. Piezo2+ mechanosensory neurons orchestrate postnatal development through mechano-chemo-transduction of PDGFA signaling.
  19. Curvature feedback for repetitive tissue morphogenesis - Bridging algorithmic principles and self-regulatory systems.
  20. ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
  21. Interaction of Wnt and SHH gradients synchronizes cell cycle exit and differentiation.
  1. Nat Cell Biol. 2025 Jul 10.
    Retrospective and multifactorial single-cell profiling reveals sequential chromatin reorganization during X inactivation.
    Samy Kefalopoulou, Pim M J Rullens, Kim L de Luca, Sandra S de Vries, Tessy Korthout, Alexander van Oudenaarden, Peter Zeller, Jop Kind.
      The regulation of gene expression is governed at multiple levels of chromatin organization. However, how gene regulation is co-ordinated remains relatively unexplored. Here we develop Dam&ChIC, a method that enables retrospective and multifactorial chromatin profiling in single cells. Dam&ChIC employs chromatin labelling in living cells with m6A to acquire a past chromatin state, coupled with an antibody-mediated readout to capture the present chromatin state. Analyses of diverse factor combinations highlight its versatility and superior resolution. By tracking lamina-associated domain inheritance over the cell cycle, we showcase that Dam&ChIC provides retrospective single-cell chromatin data. When applied in random X chromosome inactivation, Dam&ChIC disentangles the temporal order of chromatin remodelling events. Upon mitotic exit and following Xist expression, the inactive X chromosome undergoes extensive genome-lamina detachment, preceding spreading of Polycomb. We anticipate that Dam&ChIC will be instrumental in unravelling the interconnectivity and order of gene-regulatory events underlying cell-state changes during development.
    DOI:  https://doi.org/10.1038/s41556-025-01687-w
  2. Nat Methods. 2025 Jul 10.
    Delivering intact, naive, synthetic megabase-scale human DNA into mammalian embryos using SynNICE.
      
    DOI:  https://doi.org/10.1038/s41592-025-02747-7
  3. Hepatology. 2025 Jul 04.
    Aging disrupts hepatocyte zonation homeostasis in mice and humans.
    Saloni Sinha, Qazi Ali, Tuo Zhang, Duc Huy T-Nguyen, Silvia Hanna, Jason Sethiadi, Erika Hissong, Robert E Schwartz.
       BACKGROUND AND AIMS: Aging-induced degenerative changes in the liver are not inherently pathologic but pose an increased risk for liver diseases. However, the molecular mechanisms underlying aging-induced hepatic dyshomeostasis remain incompletely characterized. Here, we investigate how aging alters liver architecture, cellular communication, and hepatocyte zonation.
    APPROACH AND RESULTS: Histological analyses of aged (>24-month-old) wild-type mouse livers showed no fibrosis, but a uniform cellular enlargement compared to young (2-month-old) mouse livers. For an unbiased characterization of aging-driven changes, we used single-nucleus RNA sequencing and found that aged livers had altered cell-cell interactions and hepatocyte zonation with zone-specific transcriptomic changes. Immunostaining confirmed aging-induced expansion of ASS1+, CYP2E1+ and GS+ hepatic zones, and an aberrant expression of ASS1+-GS+ "bi-zonal" hepatocytes, causing loss of distinct zonation. Mechanistically, this breakdown was associated with downregulation of key zonation regulators (Ctnnb1, Foxo1, Tcf7l2) and compensatory alterations in Wnt and Rspo3 signaling from NPCs. To assess translational relevance, liver biopsies from young (≤25YO) and aged (>60YO) human donors were analyzed, revealing comparable zonal alterations and supporting the conservation of these aging-associated phenotypes across species.
    CONCLUSION: These findings reveal that aging causes loss of distinct hepatic zonation and alters intercellular communication through widespread transcriptional and architectural remodeling of liver cell types. The emergence of bi-zonal hepatocytes and expansion of hepatic zones in aged livers represent key hallmarks of hepatic aging. Our study provides new insights into mechanisms of liver aging and may inform therapeutic strategies targeting age-associated liver dysfunction.
    Keywords:  Liver; age; hepatic; snRNA-seq; zone
    DOI:  https://doi.org/10.1097/HEP.0000000000001451
  4. Nature. 2025 Jul 09.
    Selective remodelling of the adipose niche in obesity and weight loss.
    Antonio M A Miranda, Liam McAllan, Guianfranco Mazzei, Ivan Andrew, Iona Davies, Meryem Ertugrul, Julia Kenkre, Hiromi Kudo, Joana Carrelha, Bhavik Patel, Sophie Newton, Weihua Zhang, Alice Pollard, Amy Cross, Oliver McCallion, Mikyung Jang, Ka Lok Choi, Scarlett Brown, Yasmin Rasool, Marco Adamo, Mohamed Elkalaawy, Andrew Jenkinson, Borzoueh Mohammadi, Majid Hashemi, Robert Goldin, Laurence Game, Joanna Hester, Fadi Issa, Dylan G Ryan, Patricia Ortega, Ahmed R Ahmed, Rachel L Batterham, John C Chambers, Jaspal S Kooner, Damir Baranasic, Michela Noseda, Tricia Tan, William R Scott.
      Weight loss significantly improves metabolic and cardiovascular health in people with obesity1-3. The remodelling of adipose tissue (AT) is central to these varied and important clinical effects4. However, surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single-nucleus atlas (comprising 171,247 cells from 70 people) investigating the cell types, molecular events and regulatory factors that reshape human AT, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single-nucleus and spatial datasets offer unprecedented insights into the basis of obese AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.
    DOI:  https://doi.org/10.1038/s41586-025-09233-2
  5. J Cell Biol. 2025 Sep 01. pii: e202501211. [Epub ahead of print]224(9):
    Nonmuscle myosin II regulates presynaptic actin and neuronal mechanobiology in Drosophila.
    Biljana Ermanoska, Jonathan Baets, Avital A Rodal.
      Neuromuscular junctions (NMJs) are evolutionarily ancient, specialized contacts between neurons and muscles. They experience lifelong strain, yet the mechanism preserving their integrity under mechanical load remains unclear. Here, we identify a novel actomyosin structure at Drosophila larval NMJs, consisting of a long-lived, low-turnover presynaptic actin core that colocalizes with nonmuscle myosin II (NMII) and becomes disorganized upon manipulating neuronal NMII levels or activity. Intriguingly, neuronal NMII depletion altered postsynaptic NMII levels and organization near synapses, suggesting transsynaptic propagation of actomyosin rearrangements. Under these conditions, integrin adhesion receptors were reduced on both sides of the synapse, indicating disrupted neuron-muscle connections. Notably, axon severing mimics these effects, while axonal stretching reorganizes integrins without disrupting the actin core, suggesting that presynaptic actomyosin and integrin organization are highly sensitive to mechanical cues and dynamically adjust to both loss and gain of tension. Our study reveals a presynaptic actomyosin assembly that maintains mechanical continuity between neurons and muscle, potentially enabling mechanotransduction at the NMJ through integrin-mediated adhesion.
    DOI:  https://doi.org/10.1083/jcb.202501211
  6. Sci Adv. 2025 Jul 11. 11(28): eadw9445
    Muscle growth by sarcomere divisions.
    Clement Rodier, Ian D Estabrook, Eunice HoYee Chan, Gavin Rice, Vincent Loreau, Stefan Raunser, Dirk Görlich, Benjamin M Friedrich, Frank Schnorrer.
      The sarcomere is the elementary contractile unit of muscles. Adult muscle cells are large and chain thousands of sarcomeres into long periodic myofibrils that attach to the skeleton. During development, muscle cells must increase in length to maintain the mechanical connection to the growing skeleton. How muscles add new sarcomeres to facilitate muscle growth is unknown. Using live imaging and high-throughput image analysis, we have now tracked the sarcomere components during the developmental growth of Drosophila muscle and found that individual sarcomeres divide along the myofibril tension axis into daughter sarcomeres. This way, new sarcomeres can be inserted into contractile and mechanically intact myofibrils. We propose that sarcomere division is triggered by tension and local sarcomere damage originating from skeletal growth and muscle contractions. Sarcomere divisions repair damaged sarcomeres, ensure their mechanical integrity, and synchronize sarcomere addition with skeletal growth during animal development.
    DOI:  https://doi.org/10.1126/sciadv.adw9445
  7. Science. 2025 Jul 10. 389(6756): 169-175
    Macrophage-derived oncostatin M repairs the lung epithelial barrier during inflammatory damage.
    Daisy A Hoagland, Patricia Rodríguez-Morales, Alexander O Mann, Alan Y Baez Vazquez, Shuang Yu, Alicia Lai, Harry Kane, Susanna M Dang, Yunkang Lin, Louison Thorens, Shahinoor Begum, Martha A Castro, Scott D Pope, Jaechul Lim, Shun Li, Xian Zhang, Ming O Li, Carla F Kim, Ruaidhrí Jackson, Ruslan Medzhitov, Ruth A Franklin.
      Tissue repair programs must function alongside antiviral immunity to restore the lung epithelial barrier following infection. We found that macrophage-derived oncostatin M (OSM) counteracted the pathological effects of type I interferon (IFN-I) during infection and damage in mice. At baseline, OSM-deficient mice exhibited altered alveolar type II (ATII) epithelial cell states. In response to influenza or viral mimic challenge, mice lacking OSM exhibited heightened IFN-I responses and increased mortality. OSM delivery to the lung induced ATII proliferation and was sufficient to protect deficient mice against morbidity. Furthermore, OSM promoted organoid formation despite the growth-inhibitory effects of IFN-I. These findings identify OSM as an indispensable macrophage-derived growth factor that maintains the homeostasis of lung epithelial cells and promotes their proliferation to overcome IFN-I-mediated immunopathology.
    DOI:  https://doi.org/10.1126/science.adi8828
  8. bioRxiv. 2025 Jul 03. pii: 2025.07.02.662873. [Epub ahead of print]
    mRNA 3'UTRs chaperone intrinsically disordered regions to control protein activity.
    Yang Luo, Yaofeng Zhong, Sudipto Basu, Christine Mayr.
      More than 2,700 human mRNA 3'UTRs have hundreds of highly conserved (HC) nucleotides, but their biological roles are unclear. Here, we show that mRNAs with HC 3'UTRs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. These proteins are only fully active when translated from mRNA templates that include their 3'UTRs, raising the possibility of functional interactions between 3'UTRs and IDRs. Rather than affecting protein abundance or localization, we find that HC 3'UTRs control transcriptional or histone demethylase activity through co-translationally determined protein oligomerization states that are kinetically stable. 3'UTR-dependent changes in protein folding require mRNA-IDR interactions, suggesting that mRNAs act as IDR chaperones. These mRNAs are multivalent, a biophysical RNA feature that enables their translation in network-like condensates, which provide favorable folding environments for proteins with long IDRs. These data indicate that the coding sequence is insufficient for the biogenesis of biologically active conformations of IDR-containing proteins and that RNA can catalyze protein folding.
    DOI:  https://doi.org/10.1101/2025.07.02.662873
  9. Semin Cell Dev Biol. 2025 Jul 08. pii: S1084-9521(25)00039-4. [Epub ahead of print]173 103629
    Coping with uncertainty: Challenges for robust pattern formation in dynamical tissues.
    Tony Yu-Chen Tsai, Diana Pinheiro.
      An outstanding question in biology is how tissue patterning emerges during development. The concept of positional information, which posits that gradients of morphogens instruct cell fate in a concentration-dependent manner, has been an influential framework to understand pattern formation. Recent studies, however, highlight that developing tissues are highly dynamic, with cellular movements, arising from local mechanical fluctuations or global morphogenetic forces, that often coincide with morphogen signaling and cell fate specification. This calls for a more dynamic understanding of pattern formation by explicitly investigating the interplay between signaling, cell fate and morphogenesis. In this review, we first discuss emerging evidence on the role of cellular movements in modulating signaling dosage and cell fate acquisition. We then examine the biophysical strategies employed by developing tissues to achieve robust patterning despite ongoing cellular dynamics and large-scale morphogenesis. While cellular movements may intuitively be viewed as disruptive to patterning programs, recent evidence suggests that when coupled with cell fate, they can act as a critical mechanism for generating and stabilizing precise tissue patterns during development.
    Keywords:  Cell migration; Cell sorting; Morphogen signaling; Morphogenesis; Pattern formation
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103629
  10. bioRxiv. 2025 Jul 01. pii: 2023.03.07.531437. [Epub ahead of print]
    Spatiotemporal mapping of the contractile and adhesive forces sculpting early C. elegans embryos.
    Kazunori Yamamoto, Sacha Ichbiah, Matthieu Perez, Joana Borrego-Pinto, Fabrice Delbary, Nate Goehring, Hervé Turlier, Guillaume Charras.
      Embryo shape is determined by individual cell mechanics, intercellular interaction strength, and geometrical constraints. Models based on surface tensions at cell interfaces can predict 3D static cellular arrangements within aggregates. However, predicting the dynamics of such arrangements is challenging due to difficulties in measuring temporal changes in tensions. Here, we characterise the spatiotemporal changes in cellular tensions shaping the early nematode embryo using AFM, live microscopy, and tension inference. Using excoriated embryos, we validate a hybrid inference pipeline that calibrates relative inferred tensions temporally using cortical myosin enrichment and absolute tensions using AFM measurements. Applied to embryos within their native shell, we infer a spatiotemporal map of absolute tensions, revealing that ABa, ABp, and EMS compaction is driven by increased tension at free surfaces, while P 2 's initial exclusion is due to high tension at intercellular contacts. We uncover a direct and non-affine contribution of cadherins to cell-cell contact tension, comparable to cadherins' indirect contribution via actomyosin regulation.
    Highlights: P lineage cells have lower cortical tensions than AB lineage cellsEnrichment of Myosin-II at the cell cortex is a good predictor of cell-medium tension but is not sufficient to determine tension at cell-cell contacts.Myosin-informed tension inference allows determination of the spatiotemporal evolution of all surface tensions within the embryo. ABa, ABp, and EMS compact due to high tensions at their cell-medium interfaces compared to their cell-cell interfaces, while P 2 is initially excluded due to high cell-cell contact tensions. Cadherins contribute directly in a non-linear way by reducing cell-cell contact tension by nearly 50%.
    Open Access: For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
    DOI:  https://doi.org/10.1101/2023.03.07.531437
  11. Nat Struct Mol Biol. 2025 Jul 07.
    Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation.
    Luojia Zhang, Yuliya Gordiyenko, Tomos Morgan, Catarina Franco, Ana Tufegdžić Vidaković, Suyang Zhang.
      Abnormally fast transcription elongation can lead to detrimental consequences such as transcription-replication collisions, altered alternative splicing patterns and genome instability. Therefore, elongating RNA polymerase II (Pol II) requires mechanisms to slow its progression, yet the molecular basis of transcription braking remains unclear. RECQL5 is a DNA helicase that functions as a general elongation factor by slowing down Pol II. Here we report cryo-electron microscopy structures of human RECQL5 bound to multiple transcription elongation complexes. Combined with biochemical analysis, we identify an α-helix of RECQL5 responsible for binding Pol II and slowdown of transcription elongation. We further reveal that the transcription-coupled DNA repair (TCR) complex allows Pol II to overcome RECQL5-induced transcription braking through concerted actions of its translocase activity and competition with RECQL5 for engaging Pol II. Additionally, RECQL5 inhibits TCR-mediated Pol II ubiquitination to prevent activation of the DNA repair pathway. Our results suggest a model in which RECQL5 and the TCR complex coordinately regulate transcription elongation rates to ensure transcription efficiency while maintaining genome stability.
    DOI:  https://doi.org/10.1038/s41594-025-01586-6
  12. Cell Rep. 2025 Jul 09. pii: S2211-1247(25)00764-8. [Epub ahead of print]44(7): 115993
    ER-endosome contacts generate a local environment promoting phagophore formation.
    Juliane Da Graça, Charlotte Thiola, Myckaëla Rouabah, Ida Chiara Guerrera, Naïma El Khallouki, Maryse Romao, Carla Alemany, Dobrawa Amiri, Sarah Dubois, Ashvini Srimoorthy, Francesca Giordano, Graça Raposo, Etienne Morel.
      Autophagy starts with the formation of a double-membrane vacuole called the autophagosome, initiated by a transient structure known as the phagophore. Previous studies reported that phagophore biogenesis primarily occurs at endoplasmic reticulum (ER) omegasome subdomains, but other evidence suggests that the phagophore derives from recycling endosomes. Our study demonstrates the importance of ER-endosome interactions, revealing the dynamic mobilization of endosome-ER contact sites (EERCSs) in response to starvation. We characterize a sequential tethering of Rab5 and Rab11 endosomes to omegasomes, facilitating phagophore biogenesis. Detailed analyses reveal that EERCS-associated molecular machinery creates a confined environment that promotes local Ca2+ accumulation and liquid-liquid phase separation at ER exit sites. This environment primes de novo phagophore formation through a Rab3a-RAB3GAP1/2-mediated nano-vesicle fusion. We propose that EERCS mobilization generates transient cytoplasmic confinement, fostering localized accumulation of components for phagophore biogenesis. Our study reveals a novel role for the ER-endosome interface in the nutrient deprivation response, emphasizing organelle coordination during autophagy initiation.
    Keywords:  CP: Cell biology; ER; autophagy; calcium; endoplasmic reticulum; endosomes; membrane contact sites; phagophore; phase transition; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115993
  13. Sci Transl Med. 2025 Jul 09. 17(806): eadq3516
    Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy.
    Ying-Jie Wang, Kamayani Singh, Adam B Lokman, Siwei Deng, Balaraju Sunitha, Jose Coelho Lima, Julia Beglov, Matthew Kelly, Andrew Blease, Jacky C K Fung, Anan Huang, Moustafa Attar, Lee-Anne Stork, Mahon L Maguire, Jürgen E Schneider, Steve B Marston, Elizabeth J Soilleux, Calliope A Dendrou, Mark Coles, Christopher D Buckley, Jonathan G Seidman, Christine E Seidman, Charles Redwood, Houman Ashrafian, Hugh Watkins.
      Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K (Actc1E99K) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1-knockout (Rag-1KO) mice led to marked exacerbation of adverse cardiac remodeling in the Actc1E99K mice. Detailed characterization of cardiac regulatory T cells (Treg cells) demonstrated a time-dependent increase in Actc1E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic Treg cells reduced cardiac fibrosis and improved systolic dysfunction in Actc1E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti-IL-2 complex (IL-2/c), which specifically induced Treg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in Actc1E99K mice. These data contribute to our understanding of HCM and support the use of Treg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.
    DOI:  https://doi.org/10.1126/scitranslmed.adq3516
  14. PLoS Genet. 2025 Jul 07. 21(7): e1011773
    Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.
    Leonor Miller-Fleming, Wing Hei Au, Laura Raik, Pedro Rebelo-Guiomar, Jasper Schmitz, Ha Yoon Cho, Aron Czako, Alexander J Whitworth.
      Mitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that the Drosophila melanogaster and Saccharomyces cerevisiae Clu/Clu1 proteins form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial proteins by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggest that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.
    DOI:  https://doi.org/10.1371/journal.pgen.1011773
  15. bioRxiv. 2025 Jul 03. pii: 2025.07.02.662640. [Epub ahead of print]
    Epidermal Stem Cells Control Periderm Injury Repair via Matrix-Driven Specialization of Intercellular Junctions.
    Helen Mengze He, Liana C Boraas, Jon M Bell, Xiangyu Gong, Sophia L Iannaccone, Zhang Wen, Michael Mak, Marina Carlson, Kaelyn Sumigray, Stefania Nicoli.
      Epidermal stem cells interact with the extracellular matrix (ECM) to regulate their differentiation and maintain skin architecture. Here, we demonstrate a novel role for basal epidermal stem cells (BECs)-ECM interaction in regulating adhesion molecules expressed by the periderm-the superficial epidermal cells (SECs) of the embryonic bilayered skin. Using the developing zebrafish fin fold, we identify BECs form distinct regions of collagen-versus laminin-enriched basement membranes through integrin-mediated adhesions. Mechanistically, collagen-associated BECs form desmosomes and adherens junctions (AJs) with SECs while laminin-associated BECs display reduced desmosomes but sustain AJs and actomyosin expression with SECs. Notably, we show both in vivo and in a bilayered human keratinocyte model, that laminin, compared to collagen, is sufficient to repress desmosome formation while sustaining AJs specifically at the interlayer cell contacts. In vivo , laminin deficiency enhances desmosome expression across layers and impairs the wound-healing capacity of SECs. This defect was partially rescued by genetic reduction of the desmosome protein Desmoplakin-1a, highlighting the role of ECM-dependent junctional specialization in mediating differences in SEC injury response. Overall, our findings identify that stem cells, through their matrix, establish specialized junctions in the overlying stratified epithelium, which contribute to skin healing properties.
    DOI:  https://doi.org/10.1101/2025.07.02.662640
  16. Nature. 2025 Jul 09.
    How short peptides disassemble tau fibrils in Alzheimer's disease.
    Ke Hou, Peng Ge, Michael R Sawaya, Liisa Lutter, Joshua L Dolinsky, Yuan Yang, Yi Xiao Jiang, David R Boyer, Xinyi Cheng, Justin Pi, Jeffrey Zhang, Jiahui Lu, Romany Abskharon, Shixin Yang, Zhiheng Yu, Juli Feigon, David S Eisenberg.
      Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD)1. Previously, we found that in vitro, the D-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation2. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like ('mock-amyloid') fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09244-z
  17. J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):
    MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
    Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.
      Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.
    Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH
    DOI:  https://doi.org/10.1242/jcs.263701
  18. Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2504103122
    Piezo2+ mechanosensory neurons orchestrate postnatal development through mechano-chemo-transduction of PDGFA signaling.
    Lin Meng, Jifan Feng, Tingwei Guo, Mingyi Zhang, Sa Cha, Peng Chen, Heliya Ziaei, Aaron Harouni, Thach-Vu Ho, Yang Chai.
      Mechanical forces are ubiquitous and essential during vertebrate development, yet how these forces are translated into biochemical signals and regulate development during postnatal organogenesis remains poorly understood. While early embryogenesis relies on cell-autonomous mechanotransduction, the role of sensory innervation-abundant in postnatal stages-has been overlooked. Here, using the postnatal mouse molar development model, a system experiencing sustained mechanical forces and extensive innervation during tooth root formation, we first identify a subpopulation of Piezo2+ mechanosensory neurons in the trigeminal ganglia and reveal these neurons specifically detect tooth root-associated mechanical forces and orchestrate tooth root development via paracrine signaling. Critically, we show that Piezo2 in neurons-not in dental cells-is essential for tooth root morphogenesis, revealing sensory neurons as unexpected master regulators of mesenchymal cell fate. Mechanistically, Piezo2 activation triggers the calcium-dependent secretion of platelet-derived growth factor A, defining the neuronal mechanotransduction pathway that directly converts force into biochemical signals to drive organogenesis. Taken together, our findings demonstrate that Piezo2+ mechanosensory neurons primarily orchestrate mechanical-force-regulated processes during postnatal development. The identification of the PIEZO2-calcium-PDGF axis provides important insight into mechanotransduction by introducing sensory neurons as active architects of tissue development. This work establishes a paradigm in developmental biology, revealing how mechanosensation bridges biomechanics and neurobiology to regulate postnatal organogenesis, with implications for tissue regeneration strategies.
    Keywords:  PDGF signaling; PIEZO2; mechanosensation; sensory nerves; tooth root development
    DOI:  https://doi.org/10.1073/pnas.2504103122
  19. Semin Cell Dev Biol. 2025 Jul 04. pii: S1084-9521(25)00043-6. [Epub ahead of print]173 103633
    Curvature feedback for repetitive tissue morphogenesis - Bridging algorithmic principles and self-regulatory systems.
    Emmanuel Vikran, Tsuyoshi Hirashima.
      Tissue patterning during organ development consists of intricate morphogenetic processes, driven by the interplay of physical and genetic cues among constituent cells. Despite its complexity, these processes can be decomposed into fundamental morphogenetic motifs that appear repeatedly in a spatiotemporally organized manner, giving rise to diverse organ architectures. Recent studies have highlighted tissue-scale curvature as critical information for constitutive cells, which enables it to bridge mechanical and biochemical signals. In this review, we discuss the regulatory principles underlying the roles of tissue curvature in morphogenesis along with recent insights from earlier studies. Here, we focus on the dual role of tissue curvature as an instructive signal that directs collective cell behavior and as a dynamic property modulated by cellular activities. First, we introduce the concept of morphogenetic motifs and provide examples from developmental processes in various organ systems. Next, we discuss how cells collectively respond to two distinct curvature types, lateral and topographical, and examine the mechanisms by which cells sense these curvatures from a mechanobiological perspective. Finally, we highlight the repetitive terminal bifurcation in developing murine lung epithelium, illustrating how curvature-driven feedback loops, mediated through mechano-chemical multicellular couplings, ensure robust morphogenetic cycles. By integrating geometric, mechanical, and chemical cues, curvature feedback emerges as a framework for self-organized morphogenesis, providing fresh perspectives on the recurrent properties and robustness of development.
    Keywords:  Curvature sensing; Mechanobiology; Morphogenetic motif; Pattern formation; Tissue curvature
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103633
  20. Science. 2025 Jul 10. 389(6756): 157-162
    ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
    Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.
      Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.
    DOI:  https://doi.org/10.1126/science.adn2804
  21. bioRxiv. 2025 Jul 01. pii: 2025.06.29.660399. [Epub ahead of print]
    Interaction of Wnt and SHH gradients synchronizes cell cycle exit and differentiation.
    Ruiqi Li, Yiqun Jiang, Sarah Platt, Kevin A Peterson, Hainan Lam, Sarah Van, Chae Ho Lim, Jonathan Levinsohn, Eva-Larue Barber, David Wang, M Mark Taketo, Yuval Kluger, Peggy Myung.
      How signals coordinate cellular proliferation with differentiation to regulate cell fate transitions is poorly understood. Hair follicle dermal condensates (DCs) emerge in developing skin from an acute cell fate transition in which cell cycle exit and molecular differentiation occur simultaneously. Here, we show that the coincident levels of Wnt and Hedgehog signals synchronize these two processes and when uncoupled, trigger them discordantly, resulting in asynchronous arrest and fuzzy cell fate borders. We use an innovative computational approach to dissect out independent processes from scRNA-sequencing data to show that high Wnt activity alone elicits cell cycle exit through a Hedgehog mediator, Gli3. Furthermore, Hedgehog induces DC genes in a Wnt-dependent manner while cell-autonomously accelerating Wnt activity, effectively synchronizing cell cycle exit with DC gene expression. These results show that the interaction of signal gradients can balance proliferation with differentiation to regulate cell fate transitions, revealing a tunable logic to tissue patterning.
    DOI:  https://doi.org/10.1101/2025.06.29.660399
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