bims-ginsta Biomed News
on Genome instability
Issue of 2025–07–06
twenty papers selected by
Jinrong Hu, National University of Singapore
  1. Conserved signals control self-organization and symmetry breaking of murine bilayered epithelia during development and regeneration.
  2. Condensin II activation by M18BP1.
  3. Repeated extrinsic and anisotropic mechanical inputs promote C. elegans polarized adherens junction elongation.
  4. DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication.
  5. Single-cell long-read Hi-C, scNanoHi-C2, details 3D genome reorganization in embryonic-stage germ cells.
  6. Generation of germinal-vesicle oocytes from mouse embryonic stem cells under an ovarian soma-free condition.
  7. Mechanisms for licensing origins of DNA replication in eukaryotic cells.
  8. Mapping and engineering RNA-driven architecture of the multiphase nucleolus.
  9. The Somatic Mosaicism across Human Tissues Network.
  10. Remodeling of cadherin contacts in embryonic mesenchymal tissues during differential cell migration.
  11. Cell cycle regulation has shaped replication origins in budding yeast.
  12. A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
  13. Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.
  14. WSTF nuclear autophagy regulates chronic but not acute inflammation.
  15. Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging.
  16. High-resolution detection of copy number alterations in single cells with HiScanner.
  17. Mammalian tRNA acetylation determines translation efficiency and tRNA quality control.
  18. Spatial profiling of chromatin accessibility in formalin-fixed paraffin-embedded tissues.
  19. An ex vivo uterine system captures implantation, embryogenesis, and trophoblast invasion via maternal-embryonic signaling.
  20. Transcriptional changes of the extracellular matrix in chronic thromboembolic pulmonary hypertension govern right ventricle remodeling and recovery.
  1. Dev Cell. 2025 Jun 25. pii: S1534-5807(25)00362-4. [Epub ahead of print]
    Conserved signals control self-organization and symmetry breaking of murine bilayered epithelia during development and regeneration.
    Robin P Journot, Mathilde Huyghe, Alexandre Barthelemy, Hugo Couto-Moreira, Tom Deshayes, Louise Harari, Jakub Sumbal, Marisa M Faraldo, Maxime Dubail, Charles Fouillade, Silvia Fre.
      Organ development relies on molecular cues that guide stem cells to differentiate within precise spatial arrangements. After injury, restoring these patterns is key for regeneration. Yet, how tissue geometry shapes cell fate remains unclear. This study employs a comprehensive approach using in vitro organoids, ex vivo embryonic tissue explants, and single-cell quantitative imaging to investigate cell fate acquisition in four murine bilayered epithelia during development and regeneration. The findings identify that tissue architecture serves as the primary driver of cell fate decisions, with symmetry breaking initiated during early cell internalization. Genetic and pharmacological analyses demonstrate that Hippo/YAP and Notch signaling pathways coordinate to link tissue structure with differentiation outcomes. This study identifies the inherent capacity of stem cells to self-organize into multicellular structures, where the precise position of each differentiated cell is critical to instruct their differentiation choices during embryonic development and regeneration.
    Keywords:  Hippo pathway; Notch pathway; binary fate decisions; epithelial stem cells; glandular epithelia; lateral inhibition; pattern establishment; regeneration; self-organization; symmetry breaking
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.007
  2. Mol Cell. 2025 Jul 02. pii: S1097-2765(25)00543-X. [Epub ahead of print]
    Condensin II activation by M18BP1.
    Alessandro Borsellini, Duccio Conti, Erin E Cutts, Rebecca J Harris, Kai Walstein, Andrea Graziadei, Valentina Cecatiello, Tom F Aarts, Ren Xie, Abdelghani Mazouzi, Sushweta Sen, Claire Hoencamp, Richard Pleuger, Sabrina Ghetti, Lina Oberste-Lehn, Dongqing Pan, Tanja Bange, Judith H I Haarhuis, Anastassis Perrakis, Thijn R Brummelkamp, Benjamin D Rowland, Andrea Musacchio, Alessandro Vannini.
      Condensin I and II promote the drastic spatial rearrangement of the human genome upon mitotic entry. While condensin II is known to initiate this process in early mitosis, what triggers its activation and loading onto chromatin at this juncture remains unclear. Through genetic and proteomic approaches, we identify MIS18-binding protein 1 (M18BP1), a protein required to maintain centromere identity, as the elusive factor required for condensin II localization to chromatin. M18BP1 directly binds condensin II's CAP-G2 subunit. The condensin II antagonist MCPH1 also binds to CAP-G2 and outcompetes M18BP1 during interphase to maintain the genome in its uncondensed state. A switch from MCPH1 to M18BP1 at mitotic onset activates condensin II, thus promoting proper chromosome condensation. Regulation of this M18BP1-condensin interaction thus determines both the uncondensed state of the interphase genome and its compacted state in mitosis.
    Keywords:  AlphA Fold II; M18BP1; SMC complexes; centromeres; chromosome condensation; condensin II; crosslinking mass spectrometry; cryo-EM; haploid genetics; mitosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.014
  3. Dev Cell. 2025 Jul 01. pii: S1534-5807(25)00367-3. [Epub ahead of print]
    Repeated extrinsic and anisotropic mechanical inputs promote C. elegans polarized adherens junction elongation.
    Xinyi Yang, Teresa Ferraro, Kelly Molnar, Julien Pontabry, Sam-Rayden Malanda, Nicola Maghelli, Loïc Royer, Stephan W Grill, Gene Myers, Silvia Grigolon, Michel Labouesse.
      A key challenge in development is understanding how complex organisms physically coordinate the morphogenesis of multiple tissues. Here, using biophysical approaches, we investigate how muscles under the epidermis specifically stimulate the extension of anterior-posterior (AP)-oriented epidermal adherens junctions during late C. elegans embryonic elongation. First, light-sheet imaging shows that asynchronous patterns of muscle contractions drive embryo rotations. In turn, junctions between the lateral and dorso-ventral epidermis repeatedly oscillate between a folded, hypotensed state and an extended, hypertensed state. Second, fluorescence recovery after photobleaching (FRAP) analysis of an E-cadherin::GFP construct shows that muscle contractions stimulate E-cadherin turnover. Moreover, a mechano-chemical model backed by genetic tests suggests that E-cadherin trafficking controls junction elongation due to lower line tension. Altogether, our results illustrate how muscle contractions fluidize epidermal adherens junctions, which, combined with anisotropic tension in the epidermis, drive their polarized extension.
    Keywords:  C. elegans; E-cadherin turnover; FRAP; adherens junction; light-sheet microscopy; mechano-chemical model; morphogenesis; periodic movement; polarity; tissue interactions
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.012
  4. Nat Commun. 2025 Jul 01. 16(1): 5706
    DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication.
    Sara Rodríguez-Acebes, Rodrigo Martín-Rufo, Alicia Gómez-Moya, Scott B Churcher, Alejandro Fernández-Llorente, Guillermo de la Vega-Barranco, Alejandra Perona, Pilar Oroz, Elena Martín-Doncel, Luis Ignacio Toledo, Juan Méndez, Emilio Lecona.
      The replication stress response is an essential pathway that deals with the obstacles that halt the progression of DNA replication forks even during an unperturbed S phase. Basal activation of the ATR and CHK1 kinases prevents the premature firing of origins of replication during S phase, avoiding the activation of an excessive number of replication forks and the appearance of genomic instability. However, the mechanisms that regulate ATR activation in the unperturbed S phase have not been fully determined. Here we present evidence that the AAA ATPase VCP/p97 regulates the presence of the DNA polymerase α/Primase complex (POLA/PRIM) on chromatin, thus limiting its activity and hampering the subsequent activation of ATR by TOPBP1. As a consequence, inhibiting VCP/p97 activates ATR and CHK1 and leads to a cell cycle arrest in G2/M. We propose that the priming activity of POLA/PRIM in the lagging strand is one of the determinants of the basal activation of ATR during an unperturbed S phase and VCP/p97 limits this activation through the extraction of POLA/PRIM from chromatin.
    DOI:  https://doi.org/10.1038/s41467-025-60077-w
  5. Nat Struct Mol Biol. 2025 Jul 04.
    Single-cell long-read Hi-C, scNanoHi-C2, details 3D genome reorganization in embryonic-stage germ cells.
    Jiansen Lu, Wen Li, Fuchou Tang.
      During mouse development, embryonic-stage germ cells (EGCs) make crucial fate decisions, with female EGCs embarking on meiosis whereas male EGCs enter mitotic arrest until birth. Despite increasing understanding of the reprogramming of epigenetic modifications, the dynamics of three-dimensional (3D) genome structures within individual EGCs remains elusive. Here we present a single-cell input, long-read Hi-C method, termed scNanoHi-C2. We use scNanoHi-C2 to systematically dissect the dynamics of EGC chromatin structures. We find that, despite changes in autosomes similar to spermatogenesis, the X chromosomes of female EGCs show enhanced specific interactions between B compartments. By reconstructing 3D genome models, we observe dynamic chromosome positioning during meiosis, showing that the neighborhood between nonhomologous chromosomes of EGCs is relatively random. Simultaneously, transposable elements undergo dramatic chromatin reorganization and display an asymmetric distribution of Alu/B2 elements around meiotic topologically associated domain boundaries. Moreover, we find that high-order interactions in EGCs at the mitosis stage are mainly enriched in the B compartment, whereas, after the mitosis-to-meiosis transition, enriched high-order interactions shift to refined A compartments, to potentially promote meiotic-specific transcription programs during global genomic condensation. We also reveal an unexpected chromatin structure in mitotic-arrested male EGCs distinct from the previously assumed G0 status, which may prime the unique genome structure for subsequent spermatogenesis. Altogether, our study highlights the potential of scNanoHi-C2 and reveals key features of the chromatin structure reprogramming in EGCs.
    DOI:  https://doi.org/10.1038/s41594-025-01604-7
  6. Dev Cell. 2025 Jun 27. pii: S1534-5807(25)00363-6. [Epub ahead of print]
    Generation of germinal-vesicle oocytes from mouse embryonic stem cells under an ovarian soma-free condition.
    Yoshiaki Nosaka, Masahiro Nagano, Yukihiro Yabuta, Baku Nakakita, So I Nagaoka, Ikuhiro Okamoto, Hiromichi Sasada, Ken Mizuta, Fumiya Umemura, Hiroto Kuma, Yasushi Okochi, Yoshitaka Katou, Bernard de Massy, Azusa Inoue, Akihito Horie, Masaki Mandai, Hiroshi Ohta, Mitinori Saitou.
      In vitro oogenesis provides a platform to elucidate the mechanisms of oocyte development and advance reproductive medicine. The prevalent in vitro oogenesis model requires ovarian somatic cells (OSCs) to support oocyte development; yet, complex three-dimensional oocyte-OSC interactions pose difficulties in systems regulation and mechanistic understanding. Here, we present an OSC-free system of in vitro oogenesis: upon optimized provision of retinoic acid and bone morphogenetic protein on feeders, mouse primordial germ-cell-like cells induced from embryonic stem cells propagate robustly, and enter/progress through meiotic prophase I, generating abundant fetal oocyte-like cells at diplotene arrest. With key cytokines, signaling activators, and antioxidants, they show prominent growth and differentiate into cells comparable to germinal-vesicle oocytes in morphology, transcriptome, and histone modification profiles, with competence to resume meiosis with germinal-vesicle breakdown. By reconstituting major phases of oogenesis with minimal components, our study creates a foundation for OSC-free in vitro oogenesis in mammals, including humans.
    Keywords:  epigenetic programming; in vitro oogenesis; meiosis; mouse pluripotent stem cells; oocyte development; oocyte-like cells; ovarian soma-free; primordial germ cell-like cells
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.008
  7. Nat Struct Mol Biol. 2025 Jun 30.
    Mechanisms for licensing origins of DNA replication in eukaryotic cells.
    Bruce Stillman, John F X Diffley, Janet H Iwasa.
      The initiation of DNA replication in eukaryotic cells begins with the assembly of pre-replicative complexes (pre-RCs) at many sites along each chromosome during the G1 phase of the cell cycle. Pre-RCs license each chromosome for duplication during S phase and mark the origins of DNA replication. In this Review, we discuss and contextualize recent findings identifying the mechanisms of origin recognition and pre-RC assembly mediated by the origin recognition complex (ORC), Cdc6 and the Mcm2-Mcm7 (Mcm2-7) hexamer bound to Cdt1. We also present comprehensive videos that demonstrate the multiple mechanisms for pre-RC assembly and compare the structures of the complexes involved in human and Saccharomyces cerevisiae cells.
    DOI:  https://doi.org/10.1038/s41594-025-01587-5
  8. Nature. 2025 Jul 02.
    Mapping and engineering RNA-driven architecture of the multiphase nucleolus.
    Sofia A Quinodoz, Lifei Jiang, Aya A Abu-Alfa, Troy J Comi, Hongbo Zhao, Qiwei Yu, Lennard W Wiesner, Jordy F Botello, Anita Donlic, Elizabeth Soehalim, Prashant Bhat, Christiane Zorbas, Ludivine Wacheul, Andrej Košmrlj, Denis L J Lafontaine, Sebastian Klinge, Clifford P Brangwynne.
      Biomolecular condensates are key features of intracellular compartmentalization1,2. As the most prominent nuclear condensate in eukaryotes, the nucleolus is a multiphase liquid-like structure in which ribosomal RNAs (rRNAs) are transcribed and processed, undergoing multiple maturation steps to form the small (SSU) and large (LSU) ribosomal subunits3-5. However, how rRNA processing is coupled to the layered organization of the nucleolus is poorly understood owing to a lack of tools to precisely monitor and perturb nucleolar rRNA processing dynamics. Here we developed two complementary approaches to spatiotemporally map rRNA processing and engineer de novo nucleoli. Using sequencing in parallel with imaging, we found that rRNA processing steps are spatially segregated, with sequential maturation of rRNA required for its outward movement through nucleolar phases. By generating synthetic nucleoli in cells using an engineered rDNA plasmid system, we show that defects in SSU processing can alter the ordering of nucleolar phases, resulting in inside-out nucleoli and preventing rRNA outflux, while LSU precursors are necessary to build the outermost layer of the nucleolus. These findings demonstrate how rRNA is both a scaffold and substrate for the nucleolus, with rRNA acting as a programmable blueprint for the multiphase architecture that facilitates assembly of an essential molecular machine.
    DOI:  https://doi.org/10.1038/s41586-025-09207-4
  9. Nature. 2025 Jul;643(8070): 47-59
    The Somatic Mosaicism across Human Tissues Network.
    Somatic Mosaicism across Human Tissues Network
      From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09096-7
  10. Dev Cell. 2025 Jul 03. pii: S1534-5807(25)00364-8. [Epub ahead of print]
    Remodeling of cadherin contacts in embryonic mesenchymal tissues during differential cell migration.
    David Rozema, Christine Fagotto-Kaufmann, Artur Ruppel, Paul Lasko, François Fagotto.
      A fundamental aspect of morphogenesis is the capacity of cells to actively exchange neighbors, which crucially requires remodeling of existing cadherin adhesive contacts. We investigate this process using Xenopus prechordal mesoderm as a model of a mesenchymal tissue, where cell-cell rearrangements are powered by differential migration. Using a reductionist approach, we unveil two concurrent mechanisms. Most cadherins are removed via "peeling," i.e., disruption of the trans bonds and lateral diffusion out of the contact. In parallel, a remnant of cadherins concentrates at the contact, which is resolved by tearing the cytoplasmic link with the cytoskeleton. Myosin is recruited peripheral to the contact, facilitating contact rupture. Manipulating cortical tension indicates that the balance between peeling and condensation mechanisms is sensitive to the magnitude and orientation of forces applied on the contact. This study unravels a new modality of cell contact dynamics likely to be widely relevant for mesenchymal tissues.
    Keywords:  actomyosin cytoskeleton; cadherins; cell-cell adhesion; collective migration; cortical tension; gastrulation; mesenchymal cells; mesoderm; morphogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.009
  11. Nat Struct Mol Biol. 2025 Jun 30.
    Cell cycle regulation has shaped replication origins in budding yeast.
    Chew Theng Lim, Thomas C R Miller, Kang Wei Tan, Saurabh Talele, Anne Early, Philip East, Humberto Sánchez, Nynke H Dekker, Alessandro Costa, John F X Diffley.
      Eukaryotic DNA replication initiates from genomic loci known as origins. At budding yeast origins like ARS1, a double hexamer (DH) of the MCM replicative helicase is assembled by origin recognition complex (ORC), Cdc6 and Cdt1 by sequential hexamer loading from two opposed ORC binding sites. Cyclin-dependent kinase (CDK) inhibits DH assembly, which prevents re-replication by restricting helicase loading to the G1 phase. Here, we show that an intrinsically disordered region (IDR) in the Orc2 subunit promotes interaction between ORC and the first loaded, closed-ring MCM hexamer (the MCM-ORC (MO) intermediate). CDK-dependent phosphorylation of this IDR blocks MO formation and DH assembly. We show that MO stabilizes ORC at lower-affinity binding sites required for second hexamer loading. Origins comprising two high-affinity ORC sites can assemble DH efficiently without MO by independently loading single hexamers. Strikingly, these origins escape CDK inhibition in vitro and in vivo. Our work reveals mechanistic plasticity in MCM loading with implications for understanding how CDK regulation has shaped yeast origin evolution and how natural, strong origins might escape cell cycle regulation. We also identify key steps common to loading pathways, with implications for understanding how MCM is loaded in other eukaryotes.
    DOI:  https://doi.org/10.1038/s41594-025-01591-9
  12. Nat Aging. 2025 Jun 30.
    A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
    Tim J Nonninger, Jennifer Mak, Birgit Gerisch, Valentina Ramponi, Kazuto Kawamura, Roberto Ripa, Klara Schilling, Christian Latza, Jonathan Kölschbach, Manuel Serrano, Adam Antebi.
      Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
    DOI:  https://doi.org/10.1038/s43587-025-00911-4
  13. J Cell Biol. 2025 Aug 04. pii: e202407209. [Epub ahead of print]224(8):
    Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.
    Sunyoung Hwang, William Russo, Jaylah Cormier, Jillian Johnson, Sara Martin, Marica Rosaria Ippolito, Sara Cordone, Rui Li, Lihua Julie Zhu, Stefano Santaguida, Eduardo M Torres.
      Lipid synthesis must be precisely regulated to support membrane growth and organelle biogenesis during cell division, yet little is known about how this process is coordinated with other cell cycle events. Here, we show that de novo synthesis of sphingolipids during the S and G2 phases of the cell cycle is essential to increasing nuclear membranes. Indeed, the products of serine palmitoyltransferase (SPT), long-chain bases, localize to the nucleus and are integral components of nuclear membranes in yeast and human cells. Importantly, inhibition of SPT fails to induce cell cycle arrest, causing nuclear membrane collapse and loss of viability in yeast cells. In human cells, this causes abnormal nuclear morphology and genomic instability, evidenced by the increased incidence of nuclear blebs, micronuclei, anaphase bridges, and multipolar mitosis. These results indicate that dysregulated cell division under low sphingolipid availability can drive several disease-associated phenotypes, including aberrant nuclear morphologies and genomic instability.
    DOI:  https://doi.org/10.1083/jcb.202407209
  14. Nature. 2025 Jul 02.
    WSTF nuclear autophagy regulates chronic but not acute inflammation.
    Yu Wang, Vinay V Eapen, Yaosi Liang, Athanasios Kournoutis, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Xianting Li, Xiaoting Zhou, Kathleen E Corey, Kuo Du, Ana Maria Cabral Burkard, Chia-Kang Ho, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Lu Wang, Jihe Liu, Corey Bretz, Aaron P Havas, Zhuo Zhou, Shannan J Ho Sui, Srinivas Vinod Saladi, Ruslan I Sadreyev, Peter D Adams, Robert E Kingston, Anna Mae Diehl, Benjamin Alman, Wolfram Goessling, Zhenyu Yue, Xiao-Fan Wang, Terje Johansen, Zhixun Dou.
      Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09234-1
  15. Nat Commun. 2025 Jul 01. 16(1): 6016
    Lipoic acid functions in Paneth cells to prevent human intestinal stem cell aging.
    Zehong Zhang, Qianyi Wan, Yuedan Zhu, Jinbao Ye, Fang Fu, Xinxin Fan, Haiou Chen, Gang Ren, Wei Jiang, Xiaoxin Guo, Juanyu Zhou, La Yan, Jinhua Yan, Xingzhu Liu, Yu Yuan, Yi Chen, Haiyang Chen.
      Intestinal stem cell (ISC) aging diminishes the regenerative capacity of the intestinal epithelia, but effective therapeutic strategies to counteract human ISC aging remain elusive. Here, we find that the synthesis of α-lipoic acid (ALA) is reduced in old human small intestine. Notably, ALA supplementation inhibits ISC aging and decreases the number of atypical Paneth cells in old human intestinal organoids and in old mouse small intestines. Importantly, we discern that the effect of ALA on mitigating ISC aging is contingent upon the presence of Paneth cells. Inhibiting the mTOR pathway in Paneth cells with ALA or rapamycin significantly increases cyclic ADP ribose (cADPR) secretion and decreases Notum secretion, which, in turn, enhances ISC functions. In this work, our findings substantiate the role of ALA in inhibiting human ISC aging and present a potential therapeutic approach for managing age-related human intestinal diseases.
    DOI:  https://doi.org/10.1038/s41467-025-61070-z
  16. Nat Commun. 2025 Jul 01. 16(1): 5477
    High-resolution detection of copy number alterations in single cells with HiScanner.
    Yifan Zhao, Lovelace J Luquette, Alexander D Veit, Xiaochen Wang, Ruibin Xi, Vinayak V Viswanadham, Yuwei Zhang, Diane D Shao, Christopher A Walsh, Hong Wei Yang, Mark D Johnson, Peter J Park.
      Improvements in single-cell whole-genome sequencing (scWGS) assays have enabled detailed characterization of somatic copy number alterations (CNAs) at the single-cell level. Yet, current computational methods are mostly designed for detecting chromosome-scale changes in cancer samples with low sequencing coverage. Here, we introduce HiScanner (High-resolution Single-Cell Allelic copy Number callER), which combines read depth, B-allele frequency, and haplotype phasing to identify CNAs with high resolution. In simulated data, HiScanner consistently outperforms state-of-the-art methods across various CNA types and sizes. When applied to high-coverage scWGS data from 65 cells across 11 neurotypical human brains, HiScanner shows a superior ability to detect smaller CNAs, uncovering distinct CNA patterns between neurons and oligodendrocytes. We also generated low-coverage scWGS data from 179 cells sampled from the same meningioma patient at two time points. For this serial dataset, integration of CNAs with point mutations revealed evolutionary trajectories of tumor cells. These findings show that HiScanner enables accurate characterization of frequency, clonality, and distribution of CNAs at the single-cell level in both non-neoplastic and neoplastic cells.
    DOI:  https://doi.org/10.1038/s41467-025-60446-5
  17. Nat Commun. 2025 Jul 01. 16(1): 5496
    Mammalian tRNA acetylation determines translation efficiency and tRNA quality control.
    Na Liu, Bingxue Liu, Chun-Rui Ma, Zixin Cai, Jin-Tao Wang, Zi-Qing Chai, Nanlin Zhu, Ting Shao, Yue-Lei Chen, Yu Lin, Yirong Wang, Hong Xu, Xiao-Long Zhou.
      Acetylation is a conserved and pivotal RNA modification. Acetylation of tRNA occurs at C12 (ac4C12) in eukaryotic tRNAs. Yeast ac4C12 prevents tRNASer from rapid tRNA decay (RTD) at higher temperatures. However, the biological function of ac4C12 in higher eukaryotes remains unexplored. Moreover, whether mammalian cells contain an RTD pathway is unclear. Here, we deleted Thumpd1, the indispensable factor for ac4C12 biogenesis, in NIH/3T3 cells. Loss of ac4C12 significantly reduced tRNA aminoacylation and translational efficiency physiologically, in particular, of those enriched with Ser/Leu codons with two U/A nucleotides. Remarkably, ac4C12 hypomodification selectively generated rapid tRNALeu(CAG) turnover under heat stress. We demonstrated that tRNALeu(CAG) was degraded by a mammalian RTD (mRTD) mechanism, consisting of Xrn1/Xrn2-mediated 5'-3' exonuclease digestion and intracellular pAp level control by Bpnt1/Bpnt2. Our results reveal both the pivotal roles of ac4C12 in translation and a mRTD pathway for tRNA quality control under heat stress in mammalian cells.
    DOI:  https://doi.org/10.1038/s41467-025-60723-3
  18. Nat Commun. 2025 Jul 01. 16(1): 5945
    Spatial profiling of chromatin accessibility in formalin-fixed paraffin-embedded tissues.
    Pengfei Guo, Yufan Chen, Liran Mao, Angelysia Cardilla, Chin Nien Lee, Yan Cui, Dengge Jin, Yucong Hua, Xiaowei Xu, Yanxiang Deng.
      Formalin-fixed paraffin-embedded (FFPE) samples represent a vast, untapped resource for epigenomic research, yet molecular tools for deep analysis of these specimens remain limited. We introduce spatial FFPE-ATAC-seq, an approach for in situ profiling chromatin accessibility within archived tissues. This approach overcomes formalin-induced crosslinking challenges, allowing high-resolution mapping of chromatin landscapes while preserving tissue architecture. Applying spatial FFPE-ATAC-seq to mouse and human tissues, including brain and thymus, reveals intricate spatial organization and distinct cell types in alignment with tissue morphology. Integration with single-cell RNA sequencing validates the precision of our chromatin profiles in identifying key cell types and regulatory elements. We further apply this method to human melanoma, comprehensively characterizing chromatin accessibility across both tumor and non-tumor regions. This method significantly expands the toolkit for epigenomic research, unlocking the potential of an extensive collection of archived FFPE samples for studying gene regulation and disease mechanisms with spatial context.
    DOI:  https://doi.org/10.1038/s41467-025-60882-3
  19. Nat Commun. 2025 Jul 01. 16(1): 5755
    An ex vivo uterine system captures implantation, embryogenesis, and trophoblast invasion via maternal-embryonic signaling.
    Takehiro Hiraoka, Shizu Aikawa, Daisuke Mashiko, Tatsuya Nakagawa, Hiroki Shirai, Yasushi Hirota, Hiroshi Kimura, Masahito Ikawa.
      Embryo implantation remains challenging to study because of its inaccessibility in situ despite its essentiality and clinical significance. Although recent studies on long-term culture of authentic and model embryos have provided significant advances in elucidating embryogenesis in vitro, they, without the uterus, cannot genuinely replicate implantation. Here, we have recapitulated bona fide implantation ex vivo at more than 90% efficiency followed by embryogenesis and trophoblast invasion using authentic mouse embryos and uterine tissue. We utilized air-liquid interface culture method with originally developed devices manufactured with polydimethylsiloxane. Notably, the system replicated the robust induction of a maternal implantation regulator COX-2 at the attachment interface, which was accompanied by trophoblastic AKT activation, suggesting a possible signaling that mediates maternal COX-2 and embryonic AKT1 that accelerates implantation. By expanding the ex vivo findings, embryonic AKT1 transduction ameliorated defective implantation of uterine origin by a COX-2 inhibitor in vivo. The system, proposing a potentially standard platform of embryogenesis, offers a concise, reproducible, and scalable screening system, suggesting significant implications for developmental biology and therapeutic strategies for recurrent implantation failure in assisted reproductive technology.
    DOI:  https://doi.org/10.1038/s41467-025-60610-x
  20. Nat Cardiovasc Res. 2025 Jul 04.
    Transcriptional changes of the extracellular matrix in chronic thromboembolic pulmonary hypertension govern right ventricle remodeling and recovery.
    Leili Jafari, Christoph B Wiedenroth, Steffen D Kriechbaum, Dimitri Grün, Prakash Chelladurai, Stefan Guenther, Carsten Kuenne, Alicia M Späth, Anoop V Cherian, Christian Troidl, Jochen Wilhelm, Stanislav Keranov, Till Keller, Baktybek Kojonazarov, Ralph T Schermuly, Stefan Guth, Oliver Dörr, Holger Nef, Mario Boehm, Edda Spiekerkoetter, Przemyslaw Leszek, Zoltan V Varga, Peter Ferdinandy, Hossein A Ghofrani, Peter Dorfmüller, Norbert Weißmann, Christian W Hamm, Eckhard Mayer, Werner Seeger, Christoph Liebetrau, Soni Savai Pullamsetti.
      Chronic thromboembolic pulmonary hypertension (CTEPH) leads to progressive right ventricular (RV) dysfunction. Pulmonary endarterectomy (PEA) is an established treatment for these patients; however, the molecular mechanisms underlying RV remodeling and recovery remain poorly understood. Here we show that RNA sequencing and histological analysis of RV free wall and septal biopsies from patients with CTEPH reveal extracellular matrix enrichment and cytoskeletal remodeling before PEA. These changes were consistent across an exploratory and confirmatory cohort. Post-PEA samples showed reversal of both histological and transcriptional abnormalities. Key signaling molecules-ANKRD1, IL7R and SERPINE1-were implicated in fibrotic and proliferative pathways, as confirmed in human tissues and experimental models. Our findings identify a reversible gene expression and structural remodeling signature in the RV, linking hemodynamic unloading with molecular recovery. These insights suggest potential therapeutic targets to modulate maladaptive RV remodeling in CTEPH and improve outcomes beyond surgical intervention.
    DOI:  https://doi.org/10.1038/s44161-025-00672-8
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