bims-ginsta Biomed News
on Genome instability
Issue of 2025–04–13
24 papers selected by
Jinrong Hu, National University of Singapore
  1. Neighbor cells restrain furrowing during Xenopus epithelial cytokinesis.
  2. Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling.
  3. DUX-mediated configuration of p300/CBP drives minor zygotic genome activation independent of its catalytic activity.
  4. Spatial multi-omics reveals cell-type-specific nuclear compartments.
  5. Comprehensive interrogation of synthetic lethality in the DNA damage response.
  6. Perturb-tracing enables high-content screening of multi-scale 3D genome regulators.
  7. A single-cell atlas of spatial and temporal gene expression in the mouse cranial neural plate.
  8. STAT3 signaling enhances tissue expansion during postimplantation mouse development.
  9. Nuclear pores safeguard the integrity of the nuclear envelope.
  10. Placental cytotrophoblast microvillar stabilization is required for cell-cell fusion.
  11. Transcriptional landscapes underlying Notch-induced lineage conversion and plasticity of mammary basal cells.
  12. Multimodal cell maps as a foundation for structural and functional genomics.
  13. Ductal or Ngn3+ cells do not contribute to adult pancreatic islet beta-cell neogenesis in homeostasis.
  14. STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
  15. Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation.
  16. Supra-second tracking and live-cell karyotyping reveal principles of mitotic chromosome dynamics.
  17. Peripheral neural stem cells from the neural tube contribute to multi-organ neurogenesis.
  18. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
  19. Evolutionary Advantage of Cell Size Control.
  20. PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma.
  21. The PIN1-p38-CtIP signalling axis protects stalled replication forks from deleterious degradation.
  22. Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development.
  23. Role of charges in a dynamic disordered complex between an IDP and a folded domain.
  24. Reprogramming site-specific retrotransposon activity to new DNA sites.
  1. Dev Cell. 2025 Apr 04. pii: S1534-5807(25)00157-1. [Epub ahead of print]
    Neighbor cells restrain furrowing during Xenopus epithelial cytokinesis.
    Jennifer Landino, Eileen Misterovich, Lotte van den Goor, Babli Adhikary, Shahana Chumki, Lance A Davidson, Ann L Miller.
      Cytokinesis challenges epithelial tissue homeostasis by generating forces that pull on neighboring cells. Junction reinforcement at the furrow in Xenopus epithelia regulates the speed of furrowing, suggesting that cytokinesis is subject to resistive forces from epithelial neighbors. We show that contractility factors accumulate near the furrow in neighboring cells, and increasing neighbor cell stiffness slows furrowing. Optogenetically increasing contractility in one or both neighbor cells slows furrowing or induces cytokinetic failure. Uncoupling mechanotransduction between dividing cells and their neighbors increases the furrow ingression rate, alters topological cell packing following cytokinesis, and impairs barrier function at the furrow. Computational modeling validates our findings and provides additional insights about epithelial mechanics during cytokinesis. We conclude that forces from the cytokinetic array must be carefully balanced with restraining forces generated by neighbor cells to regulate the speed and success of cytokinesis and maintain epithelial homeostasis.
    Keywords:  Rho GTPase; Xenopus; actin; computational modeling; cytokinesis; epithelium; myosin II; optogenetics; vinculin; ɑ-actinin
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.010
  2. Nat Struct Mol Biol. 2025 Apr 04.
    Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling.
    Pawel Mikulski, Sahar S H Tehrani, Anna Kogan, Izma Abdul-Zani, Emer Shell, Louise James, Brent J Ryan, Lars E T Jansen.
      Interferon-γ (IFNγ) transiently activates genes related to inflammation and innate immunity. A subset of targets retain a mitotically heritable memory of prior IFNγ exposure, resulting in hyperactivation upon re-exposure through poorly understood mechanisms. Here, we discover that the transcriptionally permissive chromatin marks H3K4me1, H3K14ac and H4K16ac are established during IFNγ priming and are selectively maintained on a cluster of guanylate-binding protein (GBP) genes in dividing human cells in the absence of transcription. The histone acetyltransferase KAT7 is required for H3K14ac deposition at GBP genes and for accelerated GBP reactivation upon re-exposure to IFNγ. In naive cells, the GBP cluster is maintained in a low-level repressive chromatin state, marked by H3K27me3, limiting priming through a PRC2-dependent mechanism. Unexpectedly, IFNγ priming results in transient accumulation of this repressive mark despite active gene expression. However, during the memory phase, H3K27 methylation is selectively depleted from primed GBP genes, facilitating hyperactivation. Furthermore, we identified a cis-regulatory element that forms transient, long-range contacts across the GBP cluster and acts as a repressor, curbing hyperactivation of previously IFNγ-primed cells. Our results provide insight into the chromatin basis for the long-term transcriptional memory of IFNγ signaling, which might contribute to enhanced innate immunity.
    DOI:  https://doi.org/10.1038/s41594-025-01522-8
  3. Cell Rep. 2025 Apr 08. pii: S2211-1247(25)00315-8. [Epub ahead of print]44(4): 115544
    DUX-mediated configuration of p300/CBP drives minor zygotic genome activation independent of its catalytic activity.
    Lieying Xiao, Hao Jin, Yanna Dang, Panpan Zhao, Shuang Li, Yan Shi, Shaohua Wang, Kun Zhang.
      Maternal-deposited factors initiate zygotic genome activation (ZGA), driving the maternal-to-zygotic transition; however, the coordination between maternal coactivators and transcription factors (TFs) in this process remains unclear. In this study, by profiling the dynamic landscape of p300 during mouse ZGA, we reveal its role in promoting RNA polymerase II (Pol II) pre-configuration at ZGA gene regions and sequentially establishing enhancer activity and regulatory networks. Moreover, p300/CBP-catalyzed acetylation drives Pol II elongation and minor ZGA gene expression by inducing pivotal TFs such as Dux. Remarkably, the supplementation of exogenous Dux rescues ZGA failure and developmental defects caused by the loss of p300/CBP acetylation. DUX functions as a pioneer factor, guiding p300 and Pol II to minor ZGA gene regions and activating them in a manner dependent on the non-catalytic functions of p300/CBP. Together, our findings reveal a mutual dependency between p300/CBP and DUX, highlighting their coordinated role in regulating minor ZGA activation.
    Keywords:  CP: Developmental biology; DUX; RNA polymerase II; ZGA; acetylation; embryo; enhancer; minor ZGA; p300/CBP; preimplantation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115544
  4. Nature. 2025 Apr 09.
    Spatial multi-omics reveals cell-type-specific nuclear compartments.
    Yodai Takei, Yujing Yang, Jonathan White, Isabel N Goronzy, Jina Yun, Meera Prasad, Lincoln J Ombelets, Simone Schindler, Prashant Bhat, Mitchell Guttman, Long Cai.
      The mammalian nucleus is compartmentalized by diverse subnuclear structures. These subnuclear structures, marked by nuclear bodies and histone modifications, are often cell-type specific and affect gene regulation and 3D genome organization1-3. Understanding their relationships rests on identifying the molecular constituents of subnuclear structures and mapping their associations with specific genomic loci and transcriptional levels in individual cells, all in complex tissues. Here, we introduce two-layer DNA seqFISH+, which enables simultaneous mapping of 100,049 genomic loci, together with the nascent transcriptome for 17,856 genes and subnuclear structures in single cells. These data enable imaging-based chromatin profiling of diverse subnuclear markers and can capture their changes at genomic scales ranging from 100-200 kilobases to approximately 1 megabase, depending on the marker and DNA locus. By using multi-omics datasets in the adult mouse cerebellum, we showed that repressive chromatin regions are more variable by cell type than are active regions across the genome. We also discovered that RNA polymerase II-enriched foci were locally associated with long, cell-type-specific genes (bigger than 200 kilobases) in a manner distinct from that of nuclear speckles. Furthermore, our analysis revealed that cell-type-specific regions of heterochromatin marked by histone H3 trimethylated at lysine 27 (H3K27me3) and histone H4 trimethylated at lysine 20 (H4K20me3) are enriched at specific genes and gene clusters, respectively, and shape radial chromosomal positioning and inter-chromosomal interactions in neurons and glial cells. Together, our results provide a single-cell high-resolution multi-omics view of subnuclear structures, associated genomic loci and their effects on gene regulation, directly within complex tissues.
    DOI:  https://doi.org/10.1038/s41586-025-08838-x
  5. Nature. 2025 Apr 09.
    Comprehensive interrogation of synthetic lethality in the DNA damage response.
    John Fielden, Sebastian M Siegner, Danielle N Gallagher, Markus S Schröder, Maria Rosaria Dello Stritto, Simon Lam, Lena Kobel, Moritz F Schlapansky, Stephen P Jackson, Petr Cejka, Marco Jost, Jacob E Corn.
      The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability1,2. Unravelling the complementary interplay between these pathways remains a challenge3,4. Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1-ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.
    DOI:  https://doi.org/10.1038/s41586-025-08815-4
  6. Nat Methods. 2025 Apr 10.
    Perturb-tracing enables high-content screening of multi-scale 3D genome regulators.
    Yubao Cheng, Mengwei Hu, Bing Yang, Tyler B Jensen, Yuan Zhang, Tianqi Yang, Ruihuan Yu, Zhaoxia Ma, Jonathan S D Radda, Shengyan Jin, Chongzhi Zang, Siyuan Wang.
      Three-dimensional (3D) genome organization becomes altered during development, aging and disease, but the factors regulating chromatin topology are incompletely understood and currently no technology can efficiently screen for new regulators of multi-scale chromatin organization. Here, we developed an image-based high-content screening platform (Perturb-tracing) that combines pooled CRISPR screens, a cellular barcode readout method (BARC-FISH) and chromatin tracing. We performed a loss-of-function screen in human cells, and visualized alterations to their 3D chromatin folding conformations, alongside perturbation-paired barcode readout in the same single cells. We discovered tens of new regulators of chromatin folding at different length scales, ranging from chromatin domains and compartments to chromosome territory. A subset of the regulators exhibited 3D genome effects associated with loop extrusion and A-B compartmentalization mechanisms, while others were largely unrelated to these known 3D genome mechanisms. Finally, we identified new regulators of nuclear architectures and found a functional link between chromatin compaction and nuclear shape. Altogether, our method enables scalable, high-content identification of chromatin and nuclear topology regulators that will stimulate new insights into the 3D genome.
    DOI:  https://doi.org/10.1038/s41592-025-02652-z
  7. Elife. 2025 Apr 07. pii: RP102819. [Epub ahead of print]13
    A single-cell atlas of spatial and temporal gene expression in the mouse cranial neural plate.
    Eric R Brooks, Andrew R Moorman, Bhaswati Bhattacharya, Ian S Prudhomme, Max Land, Heather L Alcorn, Roshan Sharma, Dana Pe'er, Jennifer A Zallen.
      The formation of the mammalian brain requires regionalization and morphogenesis of the cranial neural plate, which transforms from an epithelial sheet into a closed tube that provides the structural foundation for neural patterning and circuit formation. Sonic hedgehog (SHH) signaling is important for cranial neural plate patterning and closure, but the transcriptional changes that give rise to the spatially regulated cell fates and behaviors that build the cranial neural tube have not been systematically analyzed. Here, we used single-cell RNA sequencing to generate an atlas of gene expression at six consecutive stages of cranial neural tube closure in the mouse embryo. Ordering transcriptional profiles relative to the major axes of gene expression predicted spatially regulated expression of 870 genes along the anterior-posterior and mediolateral axes of the cranial neural plate and reproduced known expression patterns with over 85% accuracy. Single-cell RNA sequencing of embryos with activated SHH signaling revealed distinct SHH-regulated transcriptional programs in the developing forebrain, midbrain, and hindbrain, suggesting a complex interplay between anterior-posterior and mediolateral patterning systems. These results define a spatiotemporally resolved map of gene expression during cranial neural tube closure and provide a resource for investigating the transcriptional events that drive early mammalian brain development.
    Keywords:  brain development; developmental biology; mouse; mouse embryo; neural plate; neural tube closure; patterning; single-cell RNA sequencing
    DOI:  https://doi.org/10.7554/eLife.102819
  8. Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00277-3. [Epub ahead of print]44(4): 115506
    STAT3 signaling enhances tissue expansion during postimplantation mouse development.
    Takuya Azami, Bart Theeuwes, Mai-Linh Nu Ton, William Mansfield, Luke Harland, Masaki Kinoshita, Berthold Gottgens, Jennifer Nichols.
      Signal transducer and activator of transcription (STAT)3 signaling has been studied extensively using mouse embryonic stem cells. Zygotic deletion of Stat3 enables embryo implantation, but thereafter, mutants resemble non-affected littermates from the previous day until around mid-gestation. This probably results from the loss of serine-phosphorylated STAT3, the predominant form in early postimplantation embryonic tissues associated with mitochondrial activity. Bulk RNA sequencing of isolated mouse epiblasts confirmed developmental delay transcriptionally. Single-cell RNA sequencing revealed the exclusion of derivatives of Stat3 null embryonic stem cells exclusively from the erythroid lineage of mid-gestation chimeras. We show that Stat3 null embryonic stem cells can differentiate into erythroid and hematopoietic lineages in vitro but become outcompeted when mixed with wild-type cells. Our results implicate a role for STAT3 in the temporal control of embryonic progression, particularly in tissues requiring rapid cell division, such as postimplantation epiblast and hematopoietic lineages. Interestingly, mutations in STAT3 are associated with short stature in humans.
    Keywords:  CP: Developmental biology; RNA sequencing; STAT3 signaling; chimeras; developmental delay; erythroid differentiation; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.115506
  9. Nat Cell Biol. 2025 Apr 09.
    Nuclear pores safeguard the integrity of the nuclear envelope.
    Reiya Taniguchi, Clarisse Orniacki, Jan Philipp Kreysing, Vojtech Zila, Christian E Zimmerli, Stefanie Böhm, Beata Turoňová, Hans-Georg Kräusslich, Valérie Doye, Martin Beck.
      Nuclear pore complexes (NPCs) mediate nucleocytoplasmic exchange, which is essential for eukaryotes. Mutations in the central scaffolding components of NPCs are associated with genetic diseases, but how they manifest only in specific tissues remains unclear. This is exemplified in Nup133-deficient mouse embryonic stem cells, which grow normally during pluripotency, but differentiate poorly into neurons. Here, using an innovative in situ structural biology approach, we show that Nup133-/- mouse embryonic stem cells have heterogeneous NPCs with non-canonical symmetries and missing subunits. During neuronal differentiation, Nup133-deficient NPCs frequently disintegrate, resulting in abnormally large nuclear envelope openings. We propose that the elasticity of the NPC scaffold has a protective function for the nuclear envelope and that its perturbation becomes critical under conditions that impose an increased mechanical load onto nuclei.
    DOI:  https://doi.org/10.1038/s41556-025-01648-3
  10. Development. 2025 Apr 01. pii: dev204619. [Epub ahead of print]152(7):
    Placental cytotrophoblast microvillar stabilization is required for cell-cell fusion.
    Wendy K Duan, Sumaiyah Z Shaha, Juan F Garcia Rivas, Bethan L Wilson, Khushali J Patel, Ivan K Domingo, Meghan R Riddell.
      The placenta is an essential organ of pregnancy required for maternal-fetal transport and communication. The surface of the placenta facing the maternal blood is formed by a single giant multinucleate cell: the syncytiotrophoblast. The syncytiotrophoblast is formed and maintained via fusion of progenitor cytotrophoblasts. Cell-cell fusion is a tightly regulated process, and in non-trophoblastic cells is accompanied by stereotypical alterations in cell shape by cells that have attained fusion-competence. The most prominent feature is the formation of actin-based membrane protrusions, but whether stereotypic morphological changes occur in fusion-competent cytotrophoblasts has not been characterized. Using a human placental explant model and trophoblast organoids, we identify microvilliation as a morphological feature that is enriched prior to fusion of cytotrophoblasts. Disruption of microvilli using an inhibitor of the actin-membrane cross-linker protein ezrin blocked cytotrophoblast fusion in both models. We provide evidence that cytotrophoblast microvilli are enriched in early endosomes and a pro-fusogenic protein. Thus, we propose that the polarized assembly of microvillar domains is crucial for mediating efficient syncytiotrophoblast development.
    Keywords:  Cell fusion; Ezrin; Microvilli; Placenta; Trophoblast
    DOI:  https://doi.org/10.1242/dev.204619
  11. EMBO J. 2025 Apr 04.
    Transcriptional landscapes underlying Notch-induced lineage conversion and plasticity of mammary basal cells.
    Candice Merle, Calvin Rodrigues, Atefeh Pourkhalili Langeroudi, Robin Journot, Fabian Rost, Yiteng Dang, Steffen Rulands, Silvia Fre.
      The mammary epithelium derives from multipotent mammary stem cells (MaSCs) that engage into differentiation during embryonic development. However, adult MaSCs maintain the ability to reactivate multipotency in non-physiological contexts. We previously reported that Notch1 activation in committed basal cells triggers a basal-to-luminal cell fate switch in the mouse mammary gland. Here, we report conservation of this mechanism and found that in addition to the mammary gland, constitutive Notch1 signaling induces a basal-to-luminal cell fate switch in adult cells of the lacrimal gland, the salivary gland, and the prostate. Since the lineage transition is progressive in time, we performed single-cell transcriptomic analysis on index-sorted mammary cells at different stages of lineage conversion, generating a temporal map of changes in cell identity. Combining single-cell analyses with organoid assays, we demonstrate that cell proliferation is indispensable for this lineage conversion. We also reveal the individual transcriptional landscapes underlying the cellular plasticity switching of committed mammary cells in vivo with spatial and temporal resolution. Given the roles of Notch signaling in cancer, these results may help to better understand the mechanisms that drive cellular transformation.
    Keywords:  Epithelial Stem Cells; Lineage Conversion; Notch1 Signaling; Plasticity
    DOI:  https://doi.org/10.1038/s44318-025-00424-1
  12. Nature. 2025 Apr 09.
    Multimodal cell maps as a foundation for structural and functional genomics.
    Leah V Schaffer, Mengzhou Hu, Gege Qian, Kyung-Mee Moon, Abantika Pal, Neelesh Soni, Andrew P Latham, Laura Pontano Vaites, Dorothy Tsai, Nicole M Mattson, Katherine Licon, Robin Bachelder, Anthony Cesnik, Ishan Gaur, Trang Le, William Leineweber, Aji Palar, Ernst Pulido, Yue Qin, Xiaoyu Zhao, Christopher Churas, Joanna Lenkiewicz, Jing Chen, Keiichiro Ono, Dexter Pratt, Peter Zage, Ignacia Echeverria, Andrej Sali, J Wade Harper, Steven P Gygi, Leonard J Foster, Edward L Huttlin, Emma Lundberg, Trey Ideker.
      Human cells consist of a complex hierarchy of components, many of which remain unexplored1,2. Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. Self-supervised multimodal data integration resolves 275 molecular assemblies spanning the range of 10-8 to 10-5 m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models3. We explore key applications in structural biology, yielding structures for 111 heterodimeric complexes and an expanded Rag-Ragulator assembly. The map assigns unexpected functions to 975 proteins, including roles for C18orf21 in RNA processing and DPP9 in interferon signalling, and identifies assemblies with multiple localizations or cell type specificity. It decodes paediatric cancer genomes4, identifying 21 recurrently mutated assemblies and implicating 102 validated new cancer proteins. The associated Cell Visualization Portal and Mapping Toolkit provide a reference platform for structural and functional cell biology.
    DOI:  https://doi.org/10.1038/s41586-025-08878-3
  13. EMBO J. 2025 Apr 09.
    Ductal or Ngn3+ cells do not contribute to adult pancreatic islet beta-cell neogenesis in homeostasis.
    Xiuzhen Huang, Huan Zhao, Hui Chen, Zixin Liu, Kuo Liu, Zan Lv, Xiuxiu Liu, Ximeng Han, Maoying Han, Jie Lu, Qiao Zhou, Bin Zhou.
      The adult pancreatic ducts have long been proposed to contain rare progenitors, some of which expressing Ngn3, that generate new beta cells in endocrine-islet homeostasis. Due to their postulated rarity and the lack of definitive markers, the existence or absence of ductal endocrine progenitors remains unsettled despite many studies. Genetic lineage tracing of ductal cells or Ngn3+ cells with currently available CreER drivers has been complicated by off-target labeling of pre-existing beta cells. Here, using dual-recombinase-mediated intersectional genetic strategy and newly-derived Ngn3-2A-CreER and Hnf1b-2A-CreER knock-in drivers, we succeeded in specifically labeling Ngn3-positive cells and Hnf1b-positive ductal cells without marking pre-existing beta cells. These data revealed no evidence of de novo generation of insulin-producing beta cells from ductal cells or endogenous Ngn3-positive cells in the adult pancreas during homeostasis.
    Keywords:  Beta Cell Neogenesis; Ngn3; Pancreatic Ductal Cell; Progenitor
    DOI:  https://doi.org/10.1038/s44318-025-00434-z
  14. Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]
    STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
    Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.
      Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.
    Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
  15. Nat Rev Cardiol. 2025 Apr 07.
    Molecular gatekeepers of endogenous adult mammalian cardiomyocyte proliferation.
    Tim Koopmans, Eva van Rooij.
      Irreversible cardiac fibrosis, cardiomyocyte death and chronic cardiac dysfunction after myocardial infarction pose a substantial global health-care challenge, with no curative treatments available. To regenerate the injured heart, cardiomyocytes must proliferate to replace lost myocardial tissue - a capability that adult mammals have largely forfeited to adapt to the demanding conditions of life. Using various preclinical models, our understanding of cardiomyocyte proliferation has progressed remarkably, leading to the successful reactivation of cell cycle induction in adult animals, with functional recovery after cardiac injury. Central to this success is the targeting of key pathways and structures that drive cardiomyocyte maturation after birth - nucleation and ploidy, sarcomere structure, developmental signalling, chromatin and epigenetic regulation, the microenvironment and metabolic maturation - forming a complex regulatory framework that allows efficient cellular contraction but restricts cardiomyocyte proliferation. In this Review, we explore the molecular pathways underlying these core mechanisms and how their manipulation can reactivate the cell cycle in cardiomyocytes, potentially contributing to cardiac repair.
    DOI:  https://doi.org/10.1038/s41569-025-01145-y
  16. Nat Cell Biol. 2025 Apr;27(4): 654-667
    Supra-second tracking and live-cell karyotyping reveal principles of mitotic chromosome dynamics.
    Rumen Stamatov, Sonya Uzunova, Yoana Kicheva, Maria Karaboeva, Tavian Blagoev, Stoyno Stoynov.
      Mitotic chromosome dynamics are essential for the three-dimensional organization of the genome during the cell cycle, but the spatiotemporal characteristics of this process remain unclear due to methodological challenges. While Hi-C methods capture interchromosomal contacts, they lack single-cell temporal dynamics, whereas microscopy struggles with bleaching and phototoxicity. Here, to overcome these limitations, we introduce Facilitated Segmentation and Tracking of Chromosomes in Mitosis Pipeline (FAST CHIMP), pairing time-lapse super-resolution microscopy with deep learning. FAST CHIMP tracked all human chromosomes with 8-s resolution from prophase to telophase, identified 15 out of 23 homologue pairs in single cells and compared chromosomal positioning between mother and daughter cells. It revealed a centrosome-motion-dependent flow that governs the mapping between chromosome locations at prophase and their metaphase plate position. In addition, FAST CHIMP measured supra-second dynamics of intra- and interchromosomal contacts. This tool adds a dynamic dimension to the study of chromatin behaviour in live cells, promising advances beyond the scope of existing methods.
    DOI:  https://doi.org/10.1038/s41556-025-01637-6
  17. Nat Cell Biol. 2025 Apr;27(4): 561-562
    Peripheral neural stem cells from the neural tube contribute to multi-organ neurogenesis.
      
    DOI:  https://doi.org/10.1038/s41556-025-01649-2
  18. Cell. 2025 Apr 04. pii: S0092-8674(25)00286-7. [Epub ahead of print]
    Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
    Erik Malmström, Lars Malmström, Simon Hauri, Tirthankar Mohanty, Aaron Scott, Christofer Karlsson, Carlos Gueto-Tettay, Emma Åhrman, Shahab Nozohoor, Bobby Tingstedt, Sara Regner, Peter Elfving, Leif Bjermer, Andreas Forsvall, Alexander Doyle, Mattias Magnusson, Ingrid Hedenfalk, Päivi Kannisto, Christian Brandt, Emma Nilsson, Lars B Dahlin, Johan Malm, Adam Linder, Emma Niméus, Johan Malmström.
      The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent to which different organs and cells impact the plasma proteome in healthy and diseased conditions, we developed a mass-spectrometry-based proteomics strategy to infer the tissue origin of proteins detected in human plasma. We first constructed an extensive human proteome atlas from 18 vascularized organs and the 8 most abundant cell types in blood. The atlas was interfaced with previous RNA and protein atlases to objectively define proteome-wide protein-organ associations to infer the origin and enable the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease-specific quantitative changes of organ-enriched protein panels in six separate patient cohorts, including sepsis, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.
    Keywords:  biomarkers; human proteome atlas; mass spectrometry; organ dysfunction; plasma proteome; plasma proteome dynamics; tissue damage; tissue origin; tissue protein
    DOI:  https://doi.org/10.1016/j.cell.2025.03.013
  19. Phys Rev Lett. 2025 Mar 21. 134(11): 118401
    Evolutionary Advantage of Cell Size Control.
    Spencer Hobson-Gutierrez, Edo Kussell.
      We analyze the advantage of cell size control strategies in growing populations under mortality constraints and show that growth-dependent mortality can select for accurate size control. We determine how mortality, noise, and nongenetic heritability of cell size impact long-term population growth. We derive an analytical expression for the optimal cell size. We demonstrate that size heritability enables selection to act on the distribution of cell sizes in a population to avoid viability thresholds and adapt to size- and growth-dependent mortality landscapes.
    DOI:  https://doi.org/10.1103/PhysRevLett.134.118401
  20. Cell. 2025 Apr 01. pii: S0092-8674(25)00281-8. [Epub ahead of print]
    PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma.
    Bhargab Kalita, Gerard Martinez-Cebrian, Justina McEvoy, Melody Allensworth, Michelle Knight, Alessandro Magli, Rita C R Perlingeiro, Michael A Dyer, Elizabeth Stewart, Brian David Dynlacht.
      Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, fibroblast growth factor (FGF) receptors, tRNA-modifying enzymes, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired oxidative phosphorylation and mitochondrial metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.
    Keywords:  3D/2D-adapted PDX models; Leucine; MYCN; TRMT5; alveolar rhabdomyosarcoma; mitochondrial metabolism; myogenic progenitors; roblitinib; tRNA modifications; tigecycline
    DOI:  https://doi.org/10.1016/j.cell.2025.03.008
  21. Nucleic Acids Res. 2025 Apr 10. pii: gkaf278. [Epub ahead of print]53(7):
    The PIN1-p38-CtIP signalling axis protects stalled replication forks from deleterious degradation.
    Francesca Vivalda, Marco Gatti, Letizia Manfredi, Hülya Dogan, Antonio Porro, Giulio Collotta, Ilaria Ceppi, Christine von Aesch, Vanessa van Ackeren, Sebastian Wild, Martin Steger, Begoña Canovas, Monica Cubillos-Rojas, Antoni Riera, Petr Cejka, Angel R Nebreda, Diego Dibitetto, Sven Rottenberg, Alessandro A Sartori.
      Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signalling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38α stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1-p38α activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1-p38α in fork protection. We further reveal that Brca1-deficient mammary tumour cells that have acquired PARP inhibitor (PARPi) resistance regain chemosensitivity after PIN1 or p38α inhibition. Collectively, our findings identify the PIN1-p38-CtIP signalling pathway as a critical regulator of replication fork integrity.
    DOI:  https://doi.org/10.1093/nar/gkaf278
  22. Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2410520122
    Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development.
    Sara Formichetti, Joana B Serrano, Urvashi Chitnavis, Agnieszka Sadowska, Na Liu, Ana Boskovic, Matthieu Boulard.
      The main form of intracellular protein glycosylation (O-GlcNAc) is reversible and has been mapped on thousands of cytoplasmic and nuclear proteins, including RNA polymerase II, transcription factors, and chromatin modifiers. The O-GlcNAc modification is catalyzed by a single enzyme known as O-GlcNAc Transferase, that is required for mammalian early development. Yet, neither the regulatory function of protein O-GlcNAcylation in the embryo nor the embryonic O-GlcNAc proteome have been documented. Here, we devised a strategy to enzymatically remove O-GlcNAc from preimplantation embryonic nuclei, where this modification accumulates coincidently with embryonic genome activation (EGA). Unexpectedly, the depletion of nuclear O-GlcNAc to undetectable levels has no impact on EGA, but dampens the transcriptional upregulation of the translational machinery, and triggers a spindle checkpoint response. These molecular alterations were phenotypically associated with a developmental delay starting from early cleavage stages and persisting after embryo implantation, establishing a link between nuclear glycosylation and the pace of embryonic development.
    Keywords:  O-GlcNAc; embryonic genome activation; gene expression; preimplantation development
    DOI:  https://doi.org/10.1073/pnas.2410520122
  23. Nat Commun. 2025 Apr 04. 16(1): 3242
    Role of charges in a dynamic disordered complex between an IDP and a folded domain.
    Katrine Bugge, Andrea Sottini, Miloš T Ivanović, Freia S Buus, Daniel Saar, Catarina B Fernandes, Fabienne Kocher, Jacob H Martinsen, Benjamin Schuler, Robert B Best, Birthe B Kragelund.
      Protein complexes involving intrinsically disordered proteins (IDPs) cover a continuum from IDPs that fully fold upon binding to IDPs that remain fully disordered in the complex. Here we demonstrate a case of charge-driven interactions of a folded domain with an oppositely charged IDP that remains completely disordered in the complex. Using the negatively charged and fully disordered prothymosin α and the positively charged and folded globular domain of histone H1.0, we show that they form a low-micromolar-affinity complex without fixed relative orientations or persistent contacts between specific residues. Using 25 charge variants of the globular domain, we find that the binding affinity can be modulated both by net charge and charge clustering on the folded domain, indicating some selectivity in highly charged complexes. Our results highlight that a folded protein can provide a charged surface onto which an oppositely charged IDP can bind while retaining disorder. We expect that more such complexes exist.
    DOI:  https://doi.org/10.1038/s41467-025-58374-5
  24. Nature. 2025 Apr 09.
    Reprogramming site-specific retrotransposon activity to new DNA sites.
    Christopher W Fell, Lukas Villiger, Justin Lim, Masahiro Hiraizumi, Dario Tagliaferri, Matthew T N Yarnall, Anderson Lee, Kaiyi Jiang, Alisan Kayabolen, Rohan N Krajeski, Cian Schmitt-Ulms, Harsh Ramani, Sarah M Yousef, Nathaniel Roberts, Christopher A Vakulskas, Hiroshi Nishimasu, Omar O Abudayyeh, Jonathan S Gootenberg.
      Retroelements have a critical role in shaping eukaryotic genomes. For instance, site-specific non-long terminal repeat retrotransposons have spread widely through preferential integration into repetitive genomic sequences, such as microsatellite regions and ribosomal DNA genes1-6. Despite the widespread occurrence of these systems, their targeting constraints remain unclear. Here we use a computational pipeline to discover multiple new site-specific retrotransposon families, profile members both biochemically and in mammalian cells, find previously undescribed insertion preferences and chart potential evolutionary paths for retrotransposon retargeting. We identify R2Tg, an R2 retrotransposon from the zebra finch, Taeniopygia guttata, as an orthologue that can be retargeted by payload engineering for target cleavage, reverse transcription and scarless insertion of heterologous payloads at new genomic sites. We enhance this activity by fusing R2Tg to CRISPR-Cas9 nickases for efficient insertion at new genomic sites. Through further screening of R2 orthologues, we select an orthologue, R2Tocc, with natural reprogrammability and minimal insertion at its natural 28S site, to engineer SpCas9H840A-R2Tocc, a system we name site-specific target-primed insertion through targeted CRISPR homing of retroelements (STITCHR). STITCHR enables the scarless, efficient installation of edits, ranging from a single base to 12.7 kilobases, gene replacement and use of in vitro transcribed or synthetic RNA templates. Inspired by the prevalence of nLTR retrotransposons across eukaryotic genomes, we anticipate that STITCHR will serve as a platform for scarless programmable integration in dividing and non-dividing cells, with both research and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41586-025-08877-4
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