bims-ginsta Biomed News
on Genome instability
Issue of 2025–07–20
thirty-six papers selected by
Jinrong Hu, National University of Singapore
  1. Spindle checkpoint can secure additional cheating time for selfish expanded centromeres.
  2. Atlas of amnion development during the first trimester of human pregnancy.
  3. The proteostatic landscape of healthy human oocytes.
  4. GATA6 Mediates Endoderm and Mesoderm Progenitor Fate Driven by WNT and NODAL Signaling.
  5. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.
  6. Apical clathrin-coated pits control the location, timing, and scale of microvillar growth.
  7. Ovulation: A cellular symphony in three movements.
  8. Dynamic forces drive cell and organ morphology changes during embryonic development.
  9. Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control.
  10. Master transcription-factor binding sites constitute the core of early replication control elements.
  11. Recent evolution of the developing human intestine affects metabolic and barrier functions.
  12. Highly dynamic mechanical transitions in embryonic cell populations during Drosophila gastrulation.
  13. Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
  14. Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation.
  15. Detecting structural heart disease from electrocardiograms using AI.
  16. Killing wisely: precision senolytics in the age of frailty.
  17. FMRP drives mRNP targets into translationally silenced complexes.
  18. Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury.
  19. Mesenchymal-epithelial transition serves to rapidly, yet transiently, restore the endometrial epithelium during postpartum murine uterine regeneration.
  20. Design of intrinsically disordered region binding proteins.
  21. PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation.
  22. WAVE complex forms linear arrays at negative membrane curvature to instruct lamellipodia formation.
  23. A heterotrimeric protein complex assembles the metazoan V-ATPase upon dissipation of proton gradients.
  24. Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis.
  25. A glycan atlas of the mammalian intestine through ontogeny and inflammation.
  26. Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication.
  27. Decoding protein phosphorylation during oocyte meiotic divisions using phosphoproteomics.
  28. A conserved coupling of transcriptional ON and OFF periods underlies bursting dynamics.
  29. V-ATPase assembly at leaky lysosomes.
  30. Heterochronic parabiosis uncovers AdipoR1 as a critical player in retinal rejuvenation.
  31. Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice.
  32. Specialized high-capacity mitochondria fuel cell invasion.
  33. Interpreting ribosome dynamics during mRNA translation.
  34. TFAP2A+ embryonic progenitor cells undergo fate diversification to give rise to human amnion, germline, and mesoderm.
  35. Midline assembloids reveal regulators of human axon guidance.
  36. TRF1 relies on fork reversal to prevent fragility at human telomeres.
  1. Curr Biol. 2025 Jul 08. pii: S0960-9822(25)00813-9. [Epub ahead of print]
    Spindle checkpoint can secure additional cheating time for selfish expanded centromeres.
    R Zaak Walton, Sebastian J Khan, Warif El Yakoubi, Takashi Akera.
      Expanded centromeric satellite repeats can violate Mendel's law of segregation by preferentially segregating to the egg. In mice, these selfish centromeres enrich microtubule destabilizers at pericentromeres to detach from the spindle and flip toward the egg side of the meiotic spindle, thereby achieving preferential segregation. However, despite the consistent enrichment of destabilizers upon centromere expansion, such enrichment alone is insufficient to drive the preferential retention of expanded centromeres, suggesting a missing component in understanding their non-Mendelian segregation. Here, we propose that prolonged spindle checkpoint activation is crucial for expanded centromeres to cheat the segregation process by providing sufficient time for them to flip toward the egg side. By experimentally manipulating kinetochore size in a species-specific manner, we found that assembling larger kinetochores triggers robust spindle checkpoint activation, leading to anaphase delay and preferential retention of expanded centromeres in the egg. Comparisons across multiple hybrid mouse models revealed that centromeric satellite asymmetry does not consistently lead to kinetochore asymmetry and anaphase delay, explaining why satellite asymmetry does not always result in the preferential retention of larger centromeres. Altogether, this work highlights the significance of checkpoint activation in exploiting the inherent asymmetry in female meiosis and the distinct responses of kinetochore proteins and microtubule destabilizers to centromere expansion.
    Keywords:  centromere; centromere drive; chromosome segregation; female meiosis; kinetochore; meiotic drive; mouse oocyte; spindle checkpoint
    DOI:  https://doi.org/10.1016/j.cub.2025.06.056
  2. Nat Cell Biol. 2025 Jul;27(7): 1175-1185
    Atlas of amnion development during the first trimester of human pregnancy.
    Wenqi Hu, Carmen Sancho-Serra, Carlos W Gantner, Hanna M Szafranska, Nita Solanky, Kate Metcalfe, Roser Vento-Tormo, Magdalena Zernicka-Goetz.
      The amnion is a critical extra-embryonic structure that supports foetal development, yet its ontogeny remains poorly defined. Here, using single-cell transcriptomics, we identified major cell types and subtypes in the human amnion across the first trimester of pregnancy, broadly categorized into epithelial, mesenchymal and macrophage lineages. We uncovered epithelial-mesenchymal and epithelial-immune transitions, highlighting dynamic remodelling during early pregnancy. Our results further revealed key intercellular communication pathways, including BMP4 signalling from mesenchymal to epithelial cells and TGF-β signalling from macrophages to mesenchymal cells, suggesting coordinated interactions that drive amnion morphogenesis. In addition, integrative comparisons across humans, non-human primates and in vitro stem cell-based models reveal that stem cell-based models recapitulate various stages of amnion development, emphasizing the need for careful selection of model systems to accurately recapitulate in vivo amnion formation. Collectively, our findings provide a detailed view of amnion cellular composition and interactions, advancing our understanding of its developmental role and regenerative potential.
    DOI:  https://doi.org/10.1038/s41556-025-01696-9
  3. EMBO J. 2025 Jul 16.
    The proteostatic landscape of healthy human oocytes.
    Gabriele Zaffagnini, Miquel Solé, Juan Manuel Duran, Nikolaos P Polyzos, Elvan Böke.
      Oocytes, female germ cells that develop into eggs, are among the longest-lived cells in the animal body. Recent studies on mouse oocytes highlight unique adaptations in protein homeostasis (proteostasis) within these cells. However, the mechanisms of proteostasis in human oocytes remain virtually unstudied. We present the first large-scale study of proteostatic activity in human oocytes using over 100 freshly donated oocytes from 21 healthy women aged 19-34 years. We analysed the activity and distribution of lysosomes, proteasomes, and mitochondria in both immature and mature oocytes. Notably, human oocytes exhibit nearly twofold lower proteolytic activity than surrounding somatic cells, with further decreases as oocytes mature. Oocyte maturation is also coupled with lysosomal exocytosis and a decrease in mitochondrial membrane potential. We propose that reduced organelle activity preserves key cellular components critical for early embryonic development during the prolonged maturation of human oocytes. Our findings highlight the distinctive biology of human oocytes and the need to investigate human-specific reproductive biology to address challenges in female fertility.
    Keywords:  Female Fertility; Human Oocytes; Lysosomes; Mitochondria; Proteostasis
    DOI:  https://doi.org/10.1038/s44318-025-00493-2
  4. bioRxiv. 2025 Jun 25. pii: 2025.06.20.660704. [Epub ahead of print]
    GATA6 Mediates Endoderm and Mesoderm Progenitor Fate Driven by WNT and NODAL Signaling.
    Miriam Gordillo, Rebecca Wu, Kelly M Banks, Neranjan de Silva, Todd Evans.
      During gastrulation, NODAL and WNT signaling drives distinct gene regulatory networks (GRNs) to promote pluripotency exit, specify progenitor fate, and direct lineage differentiation. Here, we employ murine embryonic stem cell directed differentiation toward endoderm and mesoderm lineages to reveal a crucial role of GATA6 during anterior primitive streak-derived progenitor segregation. GATA6 is known to direct by default extra-embryonic endoderm. To promote definitive endoderm fate, GATA6 reinforces the endoderm GRN driven by NODAL while repressing the mesoderm GRN through down-regulation of WNT activity. During progression of mesoderm differentiation, GATA6 induces a switch in the transcriptional output regulated by WNT, promoting lateral mesoderm specification and repression of paraxial mesoderm fate. Thus, this single transcription factor mediates formation of four distinct tissue types, depending on integration of NODAL/WNT activities. Regulation of Eomes and T/Bra expression during anterior primitive streak progression is an essential function of GATA6 during the specification of endoderm or mesoderm fate.
    DOI:  https://doi.org/10.1101/2025.06.20.660704
  5. Nature. 2025 Jul 16.
    Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.
    Andrew McPherson, Ignacio Vázquez-García, Matthew A Myers, Duaa H Al-Rawi, Matthew Zatzman, Adam C Weiner, Samuel Freeman, Neeman Mohibullah, Gryte Satas, Marc J Williams, Nicholas Ceglia, Danguolė Norkūnaitė, Allen W Zhang, Jun Li, Jamie L P Lim, Michelle Wu, Seongmin Choi, Eliyahu Havasov, Diljot Grewal, Hongyu Shi, Minsoo Kim, Roland F Schwarz, Tom Kaufmann, Khanh Ngoc Dinh, Florian Uhlitz, Julie Tran, Yushi Wu, Ruchi Patel, Satish Ramakrishnan, DooA Kim, Justin Clarke, Hunter Green, Emily Ali, Melody DiBona, Nancy Varice, Ritika Kundra, Vance Broach, Ginger J Gardner, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Sarah H Kim, Rachel N Grisham, Ying L Liu, Agnes Viale, Nicole Rusk, Yulia Lakhman, Lora H Ellenson, Simon Tavaré, Samuel Aparicio, Dennis S Chi, Carol Aghajanian, Nadeem R Abu-Rustum, Claire F Friedman, Dmitriy Zamarin, Britta Weigelt, Samuel F Bakhoum, Sohrab P Shah.
      Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1-6. Here we examine the impact of WGD on somatic evolution and immune evasion at single-cell resolution in patient tumours. Using single-cell whole-genome sequencing, we analysed 70 high-grade serous ovarian cancer samples from 41 patients (30,260 tumour genomes) and observed near-ubiquitous evidence that WGD is an ongoing mutational process. WGD was associated with increased cell-cell diversity and higher rates of chromosomal missegregation and consequent micronucleation. We developed a mutation-based WGD timing method called doubleTime to delineate specific modes by which WGD can drive tumour evolution, including early fixation followed by considerable diversification, multiple parallel WGD events on a pre-existing background of copy-number diversity, and evolutionarily late WGD in small clones and individual cells. Furthermore, using matched single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signalling and cGAS-STING pathway activation result from ongoing chromosomal instability, but this is restricted to predominantly diploid tumours (WGD-low). By contrast, predominantly WGD tumours (WGD-high), despite increased missegregation, exhibited cell-cycle dysregulation, STING1 repression, and immunosuppressive phenotypic states. Together, these findings establish WGD as an ongoing mutational process that promotes evolvability and dysregulated immunity in high-grade serous ovarian cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09240-3
  6. Cell Rep. 2025 Jul 16. pii: S2211-1247(25)00779-X. [Epub ahead of print]44(8): 116008
    Apical clathrin-coated pits control the location, timing, and scale of microvillar growth.
    Olivia L Perkins, Alexandra G Mulligan, Evan S Krystofiak, K Elkie Peebles, Rekha N Nagarajan, Leslie M Meenderink, Bryan A Millis, Matthew J Tyska.
      Epithelial cells from diverse systems assemble apical microvilli to mediate biochemical and physical interactions with the external environment. Despite the central importance of these actin-based protrusions in epithelial physiology, how microvilli grow during differentiation remains poorly understood. Here, we report that an epithelial cell's potential for growing microvilli of normal size is limited by an adjacent actin-dependent process: clathrin-mediated endocytosis. Time-lapse imaging of individual microvillar growth events revealed tight spatial and temporal coupling to sites of apical clathrin-mediated endocytosis. Moreover, ultrastructural characterization of differentiating epithelia showed that most nascent microvilli are in contact with an endocytic pit. Finally, inhibition of the Arp2/3 complex, which drives actin polymerization on coated pits, significantly reduced the accumulation of new microvilli on the cell surface. We conclude that clathrin-mediated endocytosis and its associated Arp2/3-based actin nucleation activity control the timing and location of microvillar growth as well as the dimensions of the resulting protrusions.
    Keywords:  CP: Cell biology; actin; bundle; cytoskeleton; differentiation; endocytosis; epithelial; protrusion
    DOI:  https://doi.org/10.1016/j.celrep.2025.116008
  7. Semin Cell Dev Biol. 2025 Jul 12. pii: S1084-9521(25)00044-8. [Epub ahead of print]174 103634
    Ovulation: A cellular symphony in three movements.
    Christopher Thomas.
      Ovulation is a complex and tightly regulated process essential for mammalian reproduction. It involves the coordinated, tissue-scale remodelling of the ovulatory follicle, culminating in the release of a fertilisation-competent egg. Ovulation is triggered by external hormonal cues: rising levels of follicle-stimulating hormone (FSH), followed by a surge in luteinising hormone (LH) from the anterior pituitary. These cues initiate a cascade of downstream events driven by follicle-derived signals, including epidermal growth factor (EGF) and progesterone, which propagate the ovulatory response. Recent advances using ex vivo follicle culture and live imaging in mouse follicles have revealed ovulation as a stepwise, self-contained programme characterised by dynamic spatial and temporal coordination. Notably, the oocyte remains largely stationary during most of ovulation, only moving toward the rupture site minutes before its release. This finding emphasises that ovulation is not defined by egg release alone, but by a prolonged and tightly regulated sequence of cellular and tissue-level events. This review presents ovulation through a temporal framework, metaphorically structured as a symphony performed by the four major follicular cell types. Beginning with an FSH-driven prelude, the symphony progresses through three movements: LH-induced initiation and meiotic resumption; progesterone-driven late events; and finally, follicle rupture and oocyte release. Together, this framework offers a new lens to understand ovulation as a developmental performance marking the transition from reproductive readiness to potential fertilisation and new life.
    Keywords:  Actomyosin contraction; Corpus; Cumulus expansion; Epidermal growth factor (EGF); Extracellular matrix (ECM) remodelling; Follicle rupture; Follicle-stimulating hormone (FSH); Folliculogenesis; Granulosa cells; Hyaluronic acid; Luteinising, hormone (LH); Luteum; Meiosis; Oogenesis; Ovarian follicle; Ovulation; Progesterone signalling
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103634
  8. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2418111122
    Dynamic forces drive cell and organ morphology changes during embryonic development.
    Raj Kumar Manna, Emma M Retzlaff, Anna Maria Hinman, Yiling Lan, Osama Abdel-Razek, Mike Bates, Heidi Hehnly, Jeffrey D Amack, M Lisa Manning.
      Cells, tissues, and organs must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and in vivo experiments to study a simple organ in the zebrafish embryo called Kupffer's vesicle (KV). Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in KV that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt cell and organ shape during embryo development.
    Keywords:  embryonic development; left–right patterning; mathematical models; morphogenesis; tissue mechanics
    DOI:  https://doi.org/10.1073/pnas.2418111122
  9. Nat Struct Mol Biol. 2025 Jul 11.
    Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control.
    Geraldine Rodschinka, Sergio Forcelloni, Felix M Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D Nedialkova.
      The translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, while defects in translation often have a disproportionate impact in distinct cell types. Here we used inducible CRISPR interference screens to compare the essentiality of genes with functions in mRNA translation in human induced pluripotent stem cells (hiPS cells) and hiPS cell-derived neural and cardiac cells. We find that core components of the mRNA translation machinery are broadly essential but the consequences of perturbing translation-coupled quality control factors are cell type dependent. Human stem cells critically depend on pathways that detect and rescue slow or stalled ribosomes and on the E3 ligase ZNF598 to resolve a distinct type of ribosome collision at translation start sites on endogenous mRNAs with highly efficient initiation. Our findings underscore the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.
    DOI:  https://doi.org/10.1038/s41594-025-01616-3
  10. EMBO J. 2025 Jul 17.
    Master transcription-factor binding sites constitute the core of early replication control elements.
    Jesse L Turner, Laura Hinojosa-Gonzalez, Takayo Sasaki, Satoshi Uchino, Athanasios Vouzas, Mariella S Soto, Abhijit Chakraborty, Karen E Alexander, Cheryl A Fitch, Amber N Brown, Ferhat Ay, David M Gilbert.
      Eukaryotic genomes replicate in a defined temporal order called the replication timing (RT) program. RT is developmentally regulated with the potential to drive cell fate transitions, but mechanisms controlling RT remain elusive. We previously identified "Early Replication Control Elements" (ERCEs), cis-acting elements necessary for early RT, domain-wide transcription, 3D chromatin architecture and compartmentalization in mouse embryonic stem cells (mESCs), but deletions identifying ERCEs were large and encompassed many putative regulatory elements. Here, we show that ERCEs are compound elements, whose RT activity can largely be accounted for by multiple binding sites for diverse master transcription factors (subERCEs). While deletion of subERCEs had large effects on both transcription and replication timing, deleting transcription start sites eliminated nearly all transcription with only moderate effects on replication timing. Our results suggest a model in which subERCEs are a class of transcriptional enhancers that can also organize chromatin domains structurally to support early replication timing, potentially providing a feed-forward loop to drive robust epigenomic change during cell fate transitions.
    Keywords:  Cell Cycle; Cell fate Transitions; Genome Architecture; Replication Timing; Transcription
    DOI:  https://doi.org/10.1038/s44318-025-00501-5
  11. Science. 2025 Jul 17. eadr8628
    Recent evolution of the developing human intestine affects metabolic and barrier functions.
    Qianhui Yu, Umut Kilik, Stefano Secchia, Lukas Adam, Yu-Hwai Tsai, Christiana Fauci, Jasper Janssens, Charlie J Childs, Katherine D Walton, Rubén López-Sandoval, Angeline Wu, Marina Almató Bellavista, Sha Huang, Calen A Steiner, Yannick Throm, Michael James Boyle, Zhisong He, Joep Beumer, Barbara Treutlein, Craig B Lowe, Jason R Spence, J Gray Camp.
      Diet, microbiota, and other exposures place the intestinal epithelium as a nexus for evolutionary change; however, little is known about genomic changes associated with adaptation to a uniquely human environment. Here, we interrogate the evolution of cell types in the developing human intestine by comparing tissue and organoids from humans, chimpanzees, and mice. We find that recent changes in primates are associated with immune barrier function and lipid/xenobiotic metabolism, and that human-specific genetic features impact these functions. Enhancer assays, genetic deletion, and in silico mutagenesis resolve evolutionarily significant enhancers of Lactase (LCT) and Insulin-like Growth Factor Binding Protein 2 (IGFBP2). Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system, and show that great ape organoids provide insight into human biology.
    DOI:  https://doi.org/10.1126/science.adr8628
  12. Nat Commun. 2025 Jul 14. 16(1): 6473
    Highly dynamic mechanical transitions in embryonic cell populations during Drosophila gastrulation.
    Juan Manuel Gomez, Carlo Bevilacqua, Abhisha Thayambath, Jean-Karim Heriche, Maria Leptin, Julio M Belmonte, Robert Prevedel.
      During development, three-dimensional morphology arises from the balance of forces acting on cells and tissues, and their material properties. Cellular forces have been investigated, however the characterisation and specification of cell material properties remains poorly understood. Here, we characterise and spatially map in three dimensions the dynamics of the longitudinal modulus at GHz frequencies to characterise the evolving blastoderm material properties during Drosophila gastrulation utilising line-scan Brillouin microscopy. We find that blastoderm cells undergo rapid and spatially varying changes in their material properties and that these differ in cells with different fates and behaviours. We identify microtubules as potential mechano-effectors, and develop a physical model to understand the role of localised and dynamic changes in material properties during tissue folding. Our work provides the first spatio-temporal description of evolving material properties during organismal morphogenesis, and highlights the potential of Brillouin microscopy for studying the dynamic changes in cell shape and cell material properties simultaneously.
    DOI:  https://doi.org/10.1038/s41467-025-61702-4
  13. Nat Metab. 2025 Jul 14.
    Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
    Simon Andersson, Hien Bui, Arto Viitanen, Daniel Borshagovski, Ella Salminen, Sami Kilpinen, Angelika Gebhart, Emilia Kuuluvainen, Swetha Gopalakrishnan, Nina Peltokangas, Martyn James, Kaia Achim, Eija Jokitalo, Petri Auvinen, Ville Hietakangas, Pekka Katajisto.
      Cellular metabolism is a key regulator of cell fate1, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues2,3. In the small intestine, intestinal stem cells (ISCs)4 produce metabolically distinct progeny5, including their Paneth cell (PC) niche6. Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISCmito-O), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISCmito-O mitochondria produce more α-ketoglutarate, driving ten-eleven translocation-mediated epigenetic changes that promote PC formation. In vivo α-ketoglutarate supplementation enhanced PC turnover and niche renewal, aiding recovery from chemotherapy-induced damage in aged mice. Our results reveal a subpopulation of ISCs whose old mitochondria metabolically regulate cell fate, and provide proof of principle for metabolically promoted replacement of specific aged cell types in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01325-7
  14. Sci Immunol. 2025 Jul 18. 10(109): eadq3066
    Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation.
    Nagisa Yoshida, Anna Appios, Qian Li, Joseph P Hutton, George Wood, Martin Potts, Julia Aleksandrowicz, Enrico R Barrozo, Freya Dover, Holly Anderson, Katie Stephens, Irving L M H Aye, Jake R Thomas, Hannah C M Schenk, Adam M Bourke, Catherine E Aiken, Ashley Moffett, Andrew Sharkey, Anna V Protasio, Kjersti M Aagaard, James R Edgar, Betty Y W Chung, Naomi McGovern.
      Hofbauer cells (HBCs) are extraembryonic macrophages generated de novo within the human placenta. In this study, we explored how the properties of HBCs change throughout gestation. Our analysis revealed transcriptomic differences between first-trimester and term HBCs, with many of the altered genes linked to immune responses. As pregnancy progresses, HBCs exhibit a marked decrease in phagosome maturation and acidification. We show that the differences between first-trimester and term HBCs are important in the context of infection with Listeria monocytogenes, a pathogen that crosses the placenta and replicates within macrophages. Specifically, we observed reduced colony-forming units and diminished actin recruitment by L. monocytogenes in first-trimester HBCs compared with term HBCs. Our findings indicate that the ability of L. monocytogenes to escape from vacuoles is impaired within first-trimester HBCs. Thus, the changes in HBC biology across pregnancy are important in shaping their interactions with L. monocytogenes.
    DOI:  https://doi.org/10.1126/sciimmunol.adq3066
  15. Nature. 2025 Jul 16.
    Detecting structural heart disease from electrocardiograms using AI.
    Timothy J Poterucha, Linyuan Jing, Ramon Pimentel Ricart, Michael Adjei-Mosi, Joshua Finer, Dustin Hartzel, Christopher Kelsey, Aaron Long, Daniel Rocha, Jeffrey A Ruhl, David vanMaanen, Marc A Probst, Brock Daniels, Shalmali D Joshi, Olivier Tastet, Denis Corbin, Robert Avram, Joshua P Barrios, Geoffrey H Tison, I-Min Chiu, David Ouyang, Alexander Volodarskiy, Michelle Castillo, Francisco A Roedan Oliver, Paloma P Malta, Siqin Ye, Gregg F Rosner, Jose M Dizon, Shah R Ali, Qi Liu, Corey K Bradley, Prashant Vaishnava, Carol A Waksmonski, Ersilia M DeFilippis, Vratika Agarwal, Mark Lebehn, Polydoros N Kampaktsis, Sofia Shames, Ashley N Beecy, Deepa Kumaraiah, Shunichi Homma, Allan Schwartz, Rebecca T Hahn, Martin Leon, Andrew J Einstein, Mathew S Maurer, Heidi S Hartman, John Weston Hughes, Christopher M Haggerty, Pierre Elias.
      Early detection of structural heart disease is critical to improving outcomes, but widespread screening remains limited by the cost and accessibility of imaging tools such as echocardiography1,2. Recent advances in machine learning applied to heart rhythm recordings have shown promise in identifying disease3,4, although previous work has been limited by development in narrow populations or targeting only select heart conditions5. Here we introduce a deep learning model, EchoNext, trained on more than 1 million heart rhythm and imaging records across a large and diverse health system to detect many forms of structural heart disease. The model demonstrated high diagnostic accuracy in internal and external validation, outperforming cardiologists in a controlled evaluation and showing consistent performance across different care settings and racial and/or ethnic groups. The models were prospectively evaluated in a clinical trial of patients without previous cardiac imaging, successfully identifying previously undiagnosed heart disease. These findings support the potential of artificial intelligence to expand access to heart disease screening at scale. To enable further development and transparency, we have publicly released model weights and a large, annotated dataset linking heart rhythm data to imaging-based diagnoses.
    DOI:  https://doi.org/10.1038/s41586-025-09227-0
  16. Genes Dev. 2025 Jul 15.
    Killing wisely: precision senolytics in the age of frailty.
    Valentin J A Barthet, Scott W Lowe.
      Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies has catalyzed efforts to develop therapeutics that preferentially kill senescent cells (also known as "senolytics"). However, clinical translation from bench to bedside remains challenging due to senescent state heterogeneity, limited biomarkers, off-target toxicities, and the frailty of aged patients. Small molecule senolytics, although promising, often lack defined mechanisms of action and pose safety concerns that may constrain their use in older adults. Emerging precision approaches, including those that exploit surface markers and leverage engineered immune therapies, offer a rational and potentially more selective path forward. Here we highlight recent advances in senescence profiling and targeted clearance strategies, emphasizing the need for therapies designed with both biological complexity and the needs of aging populations in mind.
    Keywords:  aging; senescence; senolytics
    DOI:  https://doi.org/10.1101/gad.353134.125
  17. Mol Cell. 2025 Jul 08. pii: S1097-2765(25)00512-X. [Epub ahead of print]
    FMRP drives mRNP targets into translationally silenced complexes.
    Tatsuaki Kurosaki, Hana Cho, Elizabeth T Abshire, Christoph Pröschel, Shuhei Mitsutomi, Hanae Sato, Eric A J Simko, Christopher S Fraser, Hitomi Sakano, Lynne E Maquat.
      Fragile X syndrome (FXS) results from a deficiency of the ubiquitously expressed RNA-binding protein fragile X protein (FMRP). While FMRP-mediated translational repression has been attributed primarily to ribosome stalling, using immunoprecipitations and polysome profiling of non-polar- and polar-cell lysates and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses, we show that mammalian FMRP largely represses translation initiation by associating with granule constituents to preclude 40S ribosomal subunit binding. We demonstrate that FMRP associates with its target mRNAs by binding directly to eukaryotic translation initiation factor 4E (eIF4E) at the 5' cap in competition with eIF4G1 and that ataxin-2-like promotes FMRP binding to the transcribed body. The KH1 + KH2 domains of FMRP are critical for the co-immunoprecipitation of eIF4E, mRNA targets, ataxin-2-like, and PABPC1. Our findings supplement FMRP-mediated ribosome-stalling data, suggesting that FMRP largely mediates the sequestration of its mRNA targets from translation initiation and degradation in a network of FMRP molecules that simultaneously associate with cap-bound eIF4E, GC-rich mRNA regions, and poly(A)-bound PABPC1.
    Keywords:  FMRP; Fragile X syndrome; LC-MS/MS; PABPC1; ataxin-2-like; eIF4E; embryonic human cortical neurons; mRNP; post-natal mouse cortex; translational repression
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.012
  18. Cell Stem Cell. 2025 Jul 04. pii: S1934-5909(25)00231-0. [Epub ahead of print]
    Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury.
    Shawn Goyal, Cynthia X Guo, Ojas Singh, Adrienne Ranger, Caitlin F Harrigan, Justin Meade, Alexander Luchak, Derek K Tsang, Herbert Y Gaisano, Nan Gao, Scott A Yuzwa, Jeffrey L Wrana, Dana J Philpott, Scott D Gray-Owen, Stephen E Girardin.
      ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory nuclear factor κB (NF-κB) signaling and tumor necrosis factor (TNF)-dependent ISC apoptosis, which initiated a transforming growth factor β (TGF-β)- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. In vivo, revSC emergence following irradiation or dextran-sodium-sulfate-induced injury was blunted in Tifa-/- mice. Together, our work reveals that ALPK1-TIFA signaling contributes to ISC turnover in response to bacterial detection in the intestine.
    Keywords:  Alpk1; CLU; Tifa; innate immunity; intestine; regeneration; revival stem cell
    DOI:  https://doi.org/10.1016/j.stem.2025.06.009
  19. bioRxiv. 2025 May 09. pii: 2025.05.05.652287. [Epub ahead of print]
    Mesenchymal-epithelial transition serves to rapidly, yet transiently, restore the endometrial epithelium during postpartum murine uterine regeneration.
    Zidao Wang, Kimberly M Davenport, Susanta K Behura, Amanda L Patterson.
      The uterus is a remarkable organ in its ability to undergo extensive tissue damage during menstruation and parturition, yet achieves efficient, scar-free repair. Coordinated regulation of this regenerative process is essential for uterine homeostasis and fertility; however, the underlying mechanisms remain incompletely understood. Here, we demonstrate that mesenchymal-epithelial transition (MET) contributed to postpartum endometrial re-epithelialization using Pdgfrα CreERT2/+ ; Rosa26-tdTomato fl/+ lineage tracing mice. Flow cytometry revealed a marked increase in mesenchymal-derived (MD) epithelial cells during active tissue repair. Notably, these cells were transient, undergoing clearance primarily via apoptosis following completed epithelial restoration. We also identified a migratory population of transitional cells of mesenchymal origin within the mesometrial stroma that incorporated into the luminal epithelium, consistent with an active MET program. Single-nucleus RNA sequencing (snRNA-seq) revealed that MD epithelial cells exhibited gene expression profiles associated with cell adhesion and cytoskeletal remodeling, while transitional cells were enriched for genes involved in junctional assembly and actin dynamics. MET-associated genes were significantly upregulated in both transitional and MD epithelial populations. Cell-cell communication analysis highlighted WNT, BMP, and EPHA signaling as candidate regulators of MET during regeneration. Together, these findings provide confirmation of MET as a physiologic mechanism of postpartum endometrial epithelial repair and uncover a coordinated signaling network that facilitates this process. Perturbations in MET may contribute to pathologies such as endometriosis or endometrial cancer, underscoring the importance of understanding mesenchymal-epithelial plasticity in both normal and disease states.
    Significance: The mammalian endometrium undergoes repeated injury and repair during menstruation (women) and pregnancy (most eutherians), yet exhibits a remarkable capacity for rapid, scar-free healing that mediates infection, inflammation and hemorrhage. Despite its clinical relevance, the molecular regulation of endometrial regeneration remains poorly defined. Using a transgenic lineage-tracing mouse model, we identified mesenchymal-derived (MD) epithelial and transitional cells during the regenerative window and revealed a critical role for mesenchymal-epithelial transition (MET) in this process. Single-nucleus RNA sequencing further uncovered functional characteristics of these cells and highlighted WNT, BMP, and EPHA signaling as potential regulators of MET. These findings provide new insight into the cellular and molecular framework of endometrial regeneration and have important implications for diseases involving aberrant tissue repair.
    DOI:  https://doi.org/10.1101/2025.05.05.652287
  20. Science. 2025 Jul 17. 389(6757): eadr8063
    Design of intrinsically disordered region binding proteins.
    Kejia Wu, Hanlun Jiang, Derrick R Hicks, Caixuan Liu, Edin Muratspahić, Theresa A Ramelot, Yuexuan Liu, Kerrie McNally, Sebastian Kenny, Andrei Mihut, Amit Gaur, Brian Coventry, Wei Chen, Asim K Bera, Alex Kang, Stacey Gerben, Mila Ya-Lan Lamb, Analisa Murray, Xinting Li, Madison A Kennedy, Wei Yang, Zihao Song, Gudrun Schober, Stuart M Brierley, John O'Neill, Michael H Gelb, Gaetano T Montelione, Emmanuel Derivery, David Baker.
      Intrinsically disordered proteins and peptides play key roles in biology, but a lack of defined structures and high variability in sequence and conformational preferences have made targeting such systems challenging. We describe a general approach for designing proteins that bind intrinsically disordered protein regions in diverse extended conformations with side chains fitting into complementary binding pockets. We used the approach to design binders for 39 highly diverse unstructured targets, including polar targets, and obtained designs with 100-picomolar to 100-nanomolar affinities in 34 cases, testing ~22 designs per target. The designs function in cells and as detection reagents and are specific for their intended targets in all-by-all binding experiments. Our approach is a major step toward a general solution to the intrinsically disordered protein and peptide recognition problem.
    DOI:  https://doi.org/10.1126/science.adr8063
  21. Elife. 2025 Jul 14. pii: RP104076. [Epub ahead of print]14
    PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation.
    Li He, Jiayu Wen, Qi Dai.
      BMP signaling acts as an instructive cue in various developmental processes such as tissue patterning, stem cell proliferation, and differentiation. However, it is not fully understood how this signaling pathway generates different cell-specific outputs. Here, we have identified PRDM16 as a key co-factor for BMP signaling in the mouse brain. PRDM16 contributes to a repressive role of BMP signaling on neural stem cell (NSC) proliferation. We demonstrate that PRDM16 regulates the genomic distribution of BMP pathway transcription factors, the SMAD4/pSMAD complex, preventing the activation of cell proliferation genes. When Prdm16 is lost, the SMAD complex relocates to nearby genomic regions, leading to abnormal upregulation of BMP target genes. This function of PRDM16 is also required for the specification of choroid plexus (ChP) epithelial cells. Through a single-cell resolution fluorescent in situ approach, we have observed that genes co-repressed by SMAD and PRDM16, such as Wnt7b and several cell cycle regulators, become overexpressed in Prdm16 mutant ChP. Our findings elucidate a mechanism through which SMAD4 and pSMAD1/5/8 repress gene expression. Moreover, our study suggests a regulatory circuit composed of BMP and Wnt signaling, along with PRDM16, in controlling stem cell behaviors.
    Keywords:  BMP signaling; PRDM16; Wnt signaling; choroid plexus; developmental biology; mouse; regenerative medicine; stem cell proliferation; stem cells
    DOI:  https://doi.org/10.7554/eLife.104076
  22. J Cell Biol. 2025 Sep 01. pii: e202410098. [Epub ahead of print]224(9):
    WAVE complex forms linear arrays at negative membrane curvature to instruct lamellipodia formation.
    Muziyue Wu, Raj Kumar Sadhu, Kirstin Meyer, Ziqi Tang, Paul Marchando, Derek N Woolfson, Nir S Gov, Orion D Weiner.
      Different actin nucleation-promoting factors (NPFs) orchestrate different patterns of cell protrusions, likely reflecting their distinct patterns of self-organization. Here, we leveraged in vivo biochemical approaches to investigate how the WAVE complex instructs the formation of sheet-like lamellipodia. We show that the WAVE complex is a core constituent of a linear multilayered protein array at the plasma membrane, expected for an NPF that builds sheet-like actin-based protrusions. Negative membrane curvature is both necessary and sufficient for WAVE complex linear membrane association in the presence of upstream activators (Rac, Arf1/6, and PIP3) and the PRDs of both WAVE2 and Abi2, providing a potential mechanistic basis for templating of lamellipodia and their emergent behaviors, including barrier avoidance. Through computational modeling, we demonstrate that WAVE complex's linear organization and preference for negative curvature both play important roles in robust lamellipodia formation. Our data reveal key features of mesoscale WAVE complex patterning and highlight an integral relation between NPF self-organization and cell morphogenesis.
    DOI:  https://doi.org/10.1083/jcb.202410098
  23. Nat Struct Mol Biol. 2025 Jul 11.
    A heterotrimeric protein complex assembles the metazoan V-ATPase upon dissipation of proton gradients.
    Christopher Nardone, Julian Mintseris, Dingwei He, Justine C Rutter, Benjamin L Ebert, Steven P Gygi, Tom Rapoport.
      Organelles such as lysosomes and synaptic vesicles are acidified by V-ATPases, which consist of a cytosolically oriented V1 complex that hydrolyzes ATP and a membrane-embedded VO complex that pumps protons. In yeast, V1-VO association is facilitated by the RAVE (regulator of H+-ATPase of the vacuolar and endosomal membrane) complex, but how higher eukaryotes assemble V-ATPases remains unclear. Here we identify a metazoan RAVE complex (mRAVE) whose structure and composition are notably divergent from the ancestral counterpart. mRAVE consists of DMXL1 or DMXL2, WDR7 and the central linker ROGDI. DMXL1 and DMXL2 interact with subunits A and D of the inactive, isolated V1. On dissipation of proton gradients, mRAVE binds to V1 and VO, forming a supercomplex on the membrane. mRAVE then catalyzes V1-VO assembly, enabling lysosomal acidification, neurotransmitter loading into vesicles and ATG16L1 recruitment for LC3/ATG8 conjugation onto single membranes. Our findings provide a molecular basis for neurological disorders caused by mRAVE mutations.
    DOI:  https://doi.org/10.1038/s41594-025-01610-9
  24. bioRxiv. 2025 Jun 12. pii: 2025.06.10.656791. [Epub ahead of print]
    Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis.
    José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masillioni, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.
      The transition from benign to malignant growth is a pivotal yet poorly understood step in cancer progression that marks the shift from a pathologically inert condition to a clinically lethal disease. Here, we integrate lineage tracing, single-cell and spatial transcriptomics to visualize the molecular, cellular and tissue-level events that promote or restrain malignancy during the tumor initiation in mouse models of pancreatic ductal adenocarcinoma (PDAC). We identify a discrete progenitor-like population of KRAS -mutant cells that co-activates oncogenic and tumor-suppressive programs-including p53, CDKN2A, and SMAD4-engaging senescence-like responses and remodeling their microenvironment, ultimately assembling a niche that mirrors invasive PDAC. KRAS inhibition depletes progenitor-like cells and dismantles their niche. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state as the convergence point of cancer-driving mutations, plasticity, and tissue remodeling-revealing a critical window for intercepting malignancy at its origin.
    DOI:  https://doi.org/10.1101/2025.06.10.656791
  25. bioRxiv. 2025 May 28. pii: 2025.03.06.641959. [Epub ahead of print]
    A glycan atlas of the mammalian intestine through ontogeny and inflammation.
    Steven J Siegel, Daniel Pomerantz, Jamie Heimburg-Molinaro, Shaikh Danish Mahmood, Joshua R Korzenik, Richard D Cummings, Seth Rakoff-Nahoum.
      The muco-epithelial interface in the mammalian gut is composed of a mucus and epithelial lining fundamental to barrier function, microbe-host interactions, and intestinal homeostasis. This barrier is heavily glycosylated by O-linked sugars covalently linked to mucin glycoproteins, and N-linked sugars that coat epithelial surface proteins. Gut O- and N-glycans are thought to play central roles in barrier function, host defense, nutrition and attachment for commensals and pathogens, immunoregulation and cell-cell interactions. However, the precise nature of the glycans and how glycan composition changes through development, as a function of diet, and during inflammation, remains incompletely understood. Here, we apply O- and N-glycomic platforms to profile glycans on mucus and intestinal epithelium. By mapping individual glycan species spatially and temporally we identify 57 O- and 18 N-glycans in the mouse intestine, and observe that fucosylation and sialylation varies according to intestinal region and developmental stage. We identify a subset of glycans regulated by the gut microbiome, and observe a constriction of the glycan repertoire during inflammation in both mice and humans. Together, these results provide an atlas of individual intestinal glycans and their dynamic range through ontogeny and inflammation, and represent a significant resource for our understanding of the role of intestinal glycans in health and disease and glycan-focused therapies for intestinal inflammation and shaping the gut microbiome.
    Highlights: - Individual glycans vary across gut region and developmental stage- Terminal fucose and sialic acid residues vary across space and time- The microbiome influences gut glycan composition early in life- Gut inflammation in mice and humans converge on a restricted glycan repertoire.
    eTOC blurb: Microbes colonizing the mammalian intestines encounter mucus and an epithelial layer highly decorated by glycans. Siegel et al. use glycomics to map these sugars in high resolution across gut region, microbial colonization, development and inflammation in both humans and mice.
    DOI:  https://doi.org/10.1101/2025.03.06.641959
  26. Cell Metab. 2025 Jul 07. pii: S1550-4131(25)00304-3. [Epub ahead of print]
    Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication.
    Jason C L Tong, Charlotte Frazer-Morris, Ali H Shilleh, Katrina Viloria, Anne de Bray, Adithya Muraleedaran Nair, Paul R V Johnson, Rebecca Spiers, Ahmad Kobiita, Oladapo E Olaniru, Shanta J Persaud, Robert Hauffe, André Kleinridders, Carsten Schultz, C Bruce Verchere, Canqi Cui, Jonathan E Campbell, Malgorzata Cyranka, Alexey Epanchintsev, Carina Ämmälä, Johannes Broichhagen, David J Hodson.
      Pancreatic alpha cells modulate beta cell function in a paracrine manner through the release of glucagon. However, the detailed molecular architecture underlying alpha-to-beta cell regulation remains poorly characterized. Here, we show that the glucagon-like peptide-1 receptor (GLP1R) is enriched as nanodomains on beta cell membranes that contact alpha cells, in keeping with increased single-molecule transcript expression. At low glucose, beta cells next to alpha cells directly sense micromolar glucagon release by pre-internalizing GLP1R. Pre-internalized GLP1R is associated with earlier beta cell Ca2+ responses to high glucose, which are then propagated across the islet. Beta cells adjacent to alpha cells are more secretory than beta cells next to other beta cells. Localized GLP1R signaling occurs in vitro and in vivo, is operative in the post-prandial state, and GLP1R contacts decrease between beta cells and alpha cells during metabolic stress. Thus, we detail a regulated pathway through which glucagon modulates insulin release.
    Keywords:  Ca(2+); GLP1R; alpha cell; beta cell; diabetes; glucagon; insulin; islet; pancreas; signaling
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.009
  27. Elife. 2025 Jul 17. pii: RP104255. [Epub ahead of print]13
    Decoding protein phosphorylation during oocyte meiotic divisions using phosphoproteomics.
    Leonid Peshkin, Enrico Maria Daldello, Elizabeth S Van Itallie, Matthew Sonnett, Johannes Kreuzer, Wilhelm Haas, Marc W Kirschner, Catherine Jessus.
      Oocyte meiotic divisions represent a critical process in sexual reproduction, as a diploid non-dividing oocyte is transformed into a haploid fertilizable egg, as a prelude for the subsequent embryonic divisions and differentiation. Although cell differentiation and proliferation are governed by transcription, oocyte maturation and early embryonic divisions depend entirely on changes in protein abundance and post-translational modifications. Here, we analyze the abundance and phosphorylation of proteins during Xenopus oocyte meiotic maturation. We reveal significant shifts in protein stability, related to spindle assembly, DNA replication, and RNA-binding. Our analysis pinpoints broad changes in phosphorylation correlating with key cytological meiotic milestones, noteworthy changes in membrane trafficking, nuclear envelope disassembly, and modifications in microtubule dynamics. Additionally, specific phosphorylation events target regulators of protein translation, Cdk1 and the Mos/MAPK pathway, thereby providing insight into the dynamics of Cdk1 activity, as related to the meiotic cell cycle. This study sheds light on the orchestration of protein dynamics and phosphorylation events during oocyte meiotic divisions, providing a rich resource for understanding the molecular pathways orchestrating meiotic progression in the frog, and most likely applicable to other vertebrate species.
    Keywords:  biochemistry; cell biology; chemical biology; meiotic maturation; oocyte; phosphoproteome; xenopus
    DOI:  https://doi.org/10.7554/eLife.104255
  28. Nat Struct Mol Biol. 2025 Jul 15.
    A conserved coupling of transcriptional ON and OFF periods underlies bursting dynamics.
    Po-Ta Chen, Michal Levo, Benjamin Zoller, Thomas Gregor.
      Transcription commonly occurs in bursts, with alternating productive (ON) and quiescent (OFF) periods determining mRNA production rates. However, how bursting dynamics regulate transcription is not well understood. Here, we conduct real-time measurements of endogenous transcriptional bursting with single-mRNA sensitivity. Using the diverse transcriptional activities present in early Drosophila embryos, we find stringent relationships between bursting parameters. Specifically, ON and OFF durations are tightly coupled, and each level of gene activity is associated with a characteristic combination of these periods. Lowly transcribing alleles primarily adjust OFF periods (burst frequency), while highly transcribing alleles tune ON periods (burst size). These relationships persist across developmental stages, body-axis positions, cis-regulatory or trans-regulatory perturbations and bursting dynamics observed in other species. Our findings suggest a mechanistic constraint that governs bursting dynamics, challenging the view that regulatory processes independently control distinct parameters.
    DOI:  https://doi.org/10.1038/s41594-025-01615-4
  29. Nat Struct Mol Biol. 2025 Jul 11.
    V-ATPase assembly at leaky lysosomes.
    Alf Håkon Lystad.
      
    DOI:  https://doi.org/10.1038/s41594-025-01612-7
  30. Sci Adv. 2025 Jul 18. 11(29): eadv6642
    Heterochronic parabiosis uncovers AdipoR1 as a critical player in retinal rejuvenation.
    Yidan Liu, Xiuxing Liu, Jianjie Lv, Qi Zhang, Zhenlan Yang, Xuhao Chen, Chenyang Gu, Chun Zhang, Yehong Zhuo, Wenru Su.
      Aging induces substantial structural and functional decline in the retina, yet the molecular drivers of this process remain elusive. In this study, we used heterochronic parabiosis (HP) combined with single-cell RNA sequencing to generate comprehensive transcriptomic profiles of murine retinas from young, aged, and HP pairs, aiming to identify antiaging targets. Our analysis revealed extensive transcriptional alterations across retinal cell types with aging. HP experiments demonstrated that systemic factors from young mice rejuvenated aged retinas and alleviated senescent phenotypes, while aged blood accelerated aging in young mice. Integrative analysis pinpointed adiponectin receptor 1 (AdipoR1) and the downstream adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway as central to the molecular mechanisms underlying retinal rejuvenation. Treatment with the AdipoR1 agonist AdipoRon reversed retinal aging. Mechanistically, AdipoR1-AMPK activation promoted mitochondrial function, contributing to the restoration of youthful cellular phenotypes. Together, our study identifies AdipoR1 as a therapeutic target for retinal aging and provides insights into the molecular programs driving retinal rejuvenation.
    DOI:  https://doi.org/10.1126/sciadv.adv6642
  31. J Mol Cell Cardiol. 2025 Jul 10. pii: S0022-2828(25)00116-6. [Epub ahead of print]206 11-26
    Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice.
    Collin K Wells, Daniel C Nguyen, Robert E Brainard, Lindsey A McNally, Maleesha De Silva, Kenneth R Brittian, Lauren Garrett, Madison S Taylor, Yania Martinez-Ondaro, Caitlin Howard, Snigdha Suluru, Sujith Dassanayaka, Tamer M A Mohamed, Richa Singhal, Andrew A Gibb, Pawel K Lorkiewicz, Joseph B Moore, Steven P Jones, Bradford G Hill.
      Fibroblasts are crucial for cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the infarcted heart. We found that two enzymes that could facilitate a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2) and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart after MI. Although Pck2 deletion had no effect on post-MI remodeling, fibroblast-specific switching of Pkm2 to Pkm1 (fbPkm2 → 1) mitigated ventricular dilation, wall thinning, and losses in ejection fraction caused by MI. Despite these salutary effects, fbPkm2 → 1 switching did not alter cardiac fibrosis in vivo, nor did it affect collagen production, cytokine or chemokine secretion, myofibroblast differentiation markers, or transcriptional regulation in vitro. Nevertheless, Pkm2 → 1 splice variant switching increased myofibroblast contractile activity as well as influenced the metabolic phenotype of fibroblasts, as shown by increased pyruvate kinase activity, higher mitochondrial respiratory capacity, and elevation in glycolytic intermediate abundance. Despite these changes, Pkm2 → 1 switching had relatively minor effects on glucose carbon fate, as determined by stable isotope-resolved metabolomics. Nevertheless, these metabolic data demonstrate that cardiac fibroblasts exhibit minimal glucose-supported de novo glycine synthesis in vitro, yet possess high hexosamine and glucuronate biosynthetic pathway activity. Collectively, these findings reveal that fibroblast PKM isoforms influence post-MI remodeling, highlighting pyruvate kinase as a potential therapeutic target.
    Keywords:  Extracellular matrix; Fibrosis; Glycolysis; Heart failure; Metabolism
    DOI:  https://doi.org/10.1016/j.yjmcc.2025.07.005
  32. bioRxiv. 2025 May 03. pii: 2025.05.02.651978. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Caitlin Su, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive, and how an invading cell produces high ATP levels to power invasion is understudied. By generating 20 endogenously tagged mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP to fuel invasion. These ETC-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through a Src kinase directs microtubule polarization, which facilitates metaxin adaptor complex dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP by generating and localizing high-capacity mitochondria. This might be common strategy used by other cells to meet energy demanding processes.
    DOI:  https://doi.org/10.1101/2025.05.02.651978
  33. J Biol Chem. 2025 Jul 10. pii: S0021-9258(25)02319-1. [Epub ahead of print] 110469
    Interpreting ribosome dynamics during mRNA translation.
    Saori Uematsu, Shu-Bing Qian.
      Translation takes a central position in gene expression, its swift response to environmental stress is evolutionarily conserved. Upon chemical damage to the messenger RNA (mRNA) or the lack of building blocks, the ribosome stalls during elongation and halts the production line. Even under normal growth conditions, the translation machinery encounters constant hinderances such as varied codon composition or nascent chains with distinct features. However, it is challenging to define these kinetics experimentally partly due to the inherent variations of ribosome behavior during mRNA translation. To ensure the flow of ribosomal traffic, cells employ several mechanisms to circumvent the traffic jam. When the roadblock is not resolved timely, trailing ribosomes can collide with stalled ribosomes. However, the boundary between physiological queuing and pathological collision is often blurred, representing a fundamental gap in our understanding of ribosome dynamics. To cope with translational barriers, several signaling pathways are activated to adjust the rate of global translation and rescue the local stalled ribosome. Deficiencies of cellular response to translational stress have been associated with a wide array of human diseases. In this review, we focus on fundamental aspects of the ribosome dynamics during mRNA translation. We provide an overview of causes, outcomes, and cellular responses to ribosome stalling and collision on mRNA. We highlight questions that may clarify the biological roles of distinct ribosome behavior during mRNA translation and emphasize the mechanistic connection between altered ribosome dynamics and human diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110469
  34. bioRxiv. 2025 Jun 27. pii: 2025.06.26.661839. [Epub ahead of print]
    TFAP2A+ embryonic progenitor cells undergo fate diversification to give rise to human amnion, germline, and mesoderm.
    Auriana Arabpour, Jonathan Adam DiRusso, Qiu Ya Wu, Mark Larsen, Young Sun Hwang, Elsie Jacobson, Thi Xuan Ai Pham, Nicole Agranonik, Megan Sparrow, Vernon Leander Monteiro, Zenya Rebecca Bian, Nicolas Pelaez-Restrepo, Antuca Callejas-Marin, Vincent Pasque, Kathrin Plath, Amander T Clark.
      Amnion, germline and mesoderm specification at the posterior end of the human embryo occur around the same time in vivo . Similarly, in vitro generation of germline and amnion is associated with mesoderm induction regardless of differentiation platform. Yet, the lineage relationships between amnion, germline and mesoderm remains unresolved. By adding Basement Membrane Extract (BME) to the media, we demonstrate emergence of TFAP2A+/SOX2-epithelial progenitor cells which develop in response to BMP receptor signaling. We track the order of embryonic events that take place from this progenitor pool revealing that amnion-like cells (AMLCs) and primordial germ cell (PGC)-like cells (PGCLCs) are specified first. Shortly after, gastrulating mesoderm-like cells (MeLCs) arise that undergo an epithelial to mesenchymal transition (EMT). These results highlight the interconnected role of basement membrane deposition and BMP receptor signaling in the specification of human germline, amnion and mesoderm from TFAP2A+ embryonic progenitors.
    DOI:  https://doi.org/10.1101/2025.06.26.661839
  35. Science. 2025 Jul 17. 389(6757): 282-289
    Midline assembloids reveal regulators of human axon guidance.
    Massimo M Onesto, Neal D Amin, Chenjie Pan, Xiaoyu Chen, Ji-Il Kim, Noah Reis, Sabina Kanton, Alfredo M Valencia, Zuzana Hudacova, James P McQueen, Marc Tessier-Lavigne, Sergiu P Pașca.
      Organizers orchestrate cell patterning and axon guidance in the developing nervous system. Although nonhuman models have led to fundamental discoveries about floor plate (FP)-mediated midline organization, an experimental model of the human FP would enable insights into human neurodevelopment and midline connectivity. Here, we developed organoids resembling human FP (hFpOs) and assembled them with human spinal cord organoids (hSpOs) to generate midline assembloids (hMAs). We demonstrate that hFpOs promote ventral patterning, commissural axon guidance, and bilateral connectivity. To investigate midline regulators, we profiled the hFpO secretome, identifying 27 human-enriched genes compared with mouse. In an arrayed CRISPR screen of hMAs, we discovered that loss of GALNT2 and PLD3 impaired FP-mediated guidance of axons. This platform holds promise for revealing aspects of human-specific neurobiology and disease.
    DOI:  https://doi.org/10.1126/science.adq7934
  36. Nat Commun. 2025 Jul 11. 16(1): 6439
    TRF1 relies on fork reversal to prevent fragility at human telomeres.
    Mélina Vaurs, Eloïse Claude, Elia Zanella, Joana Rodrigues, Joe Nassour, Jan Karlseder, Claus M Azzalin, Ylli Doksani, Anabelle Decottignies.
      Telomeres pose challenges during replication, with converging forks unlikely to resolve issues. Depleting TRF1 results in fragile telomeres, yet its exact role in telomere replication remains unclear. In our cellular model, insufficient TRF1 density at long telomeres leads to telomere fragility that is alleviated by restoring telomeric TRF1 levels. Our findings indicate that TRF1 mitigates lagging strand telomere fragility through fork reversal in a process involving telomerase activity, rather than merely alleviating fork barriers. Additionally, TFIIH, a crucial partner of TRF1, aids in restarting replication on the leading strand after fork reversal. When fork reversal is compromised, PrimPol-mediated repriming rescues fragility at leading strand telomeres, revealing a new role for this enzyme in human telomere replication. Lastly, our findings indicate that the TRF1-mediated decrease in telomere fragility is dependent on RNA:DNA hybrids, likely facilitating fork restart.
    DOI:  https://doi.org/10.1038/s41467-025-61828-5
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