bims-ginsta Biomed News
on Genome instability
Issue of 2025–05–04
forty-two papers selected by
Jinrong Hu, National University of Singapore
  1. Altering metabolism programs cell identity via NAD+-dependent deacetylation.
  2. A transient contractile seam promotes epithelial sealing and sequential assembly of body segments.
  3. ARID5A promotes inflammation and fibrosis during cardiac aging.
  4. Unlocking regeneration: how partial reprogramming resembles tissue healing.
  5. Interphase cell morphology defines the mode, symmetry, and outcome of mitosis.
  6. ARID5A orchestrates cardiac aging and inflammation through MAVS mRNA stabilization.
  7. Epithelial Fibronectin meshwork controls skin regeneration.
  8. Regional differences in progenitor metabolism shape brain growth during development.
  9. Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
  10. Tri-omic single-cell mapping of the 3D epigenome and transcriptome in whole mouse brains throughout the lifespan.
  11. The PCM scaffold enables RNA localization to centrosomes.
  12. Chromosomal instability in human trophoblast stem cells and placentas.
  13. Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation.
  14. NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
  15. Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.
  16. DNA replication in primary hepatocytes without the six-subunit ORC.
  17. Aging promotes reactivation of the Barr body at distal chromosome regions.
  18. Paternal effects on telomere integrity during the sperm-to-embryo transition.
  19. Natural genetic variation quantitatively regulates heart rate and dimension.
  20. Growth of the maternal intestine during reproduction.
  21. Cell cycle duration determines oncogenic transformation capacity.
  22. A cortical pool of LIN-5 (NuMA) controls cytokinetic furrow formation and cytokinesis completion.
  23. The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15.
  24. Chromatin-bound U2AF2 splicing factor ensures exon inclusion.
  25. Moving toward totipotency: the molecular and cellular features of totipotent and naive pluripotent stem cells.
  26. Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division.
  27. RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates.
  28. KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging.
  29. Fast-adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging.
  30. Twinfilin is a nonprocessive depolymerase which synergizes with formin to dramatically accelerate actin filament uncapping by 300-fold.
  31. Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.
  32. Super RNA Pol II domains enhance minor ZGA through 3D interaction to ensure the integrity of major transcriptional waves in late-ZGA mammals.
  33. Prkra dimer senses double-stranded RNAs to dictate global translation efficiency.
  34. Immune-mediated cardiac development and regeneration.
  35. LINE-1 ribonucleoprotein condensates bind DNA to enable nuclear entry during mitosis.
  36. Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
  37. Targeting redox-sensitive MBD2-NuRD condensate in cancer cells.
  38. tRNA modifications tune m6A-dependent mRNA decay.
  39. Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
  40. Stem cells as role models for reprogramming and repair.
  41. Stm1 regulates Ifh1 activity revealing crosstalk between ribosome biogenesis and ribosome dormancy.
  42. Real-time imaging of rotation during synthesis by the replisome.
  1. EMBO J. 2025 Apr 25.
    Altering metabolism programs cell identity via NAD+-dependent deacetylation.
    Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.
      Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
    Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins
    DOI:  https://doi.org/10.1038/s44318-025-00417-0
  2. Nat Commun. 2025 Apr 29. 16(1): 4010
    A transient contractile seam promotes epithelial sealing and sequential assembly of body segments.
    Amélie L Godeau, Miquel Marin-Riera, Elise Trubuil, Svana Rogalla, Guillermo Bengoetxea, Lenka Backová, Thomas Pujol, Julien Colombelli, James Sharpe, Enrique Martin-Blanco, Jérôme Solon.
      In embryos, epithelial sealing proceeds with progressive zipping eventually leading to a scar-free epithelium and ensuring the assembly of body segments in insects and neural tube in mammals. How zipping is mechanically controlled to promote tissue fusion on long distances, remains unclear. Combining physical modeling with genetic and mechanical perturbations, we reveal the existence of a transient contractile seam that generates forces to reduce the zipping angle by force balance, consequently promoting epidermal sealing during Drosophila embryogenesis. The seam is formed by the adhesion of two tissues, the epidermis and amnioserosa, and is stabilized by the tensions generated by the segment boundaries. Once a segment is zipped, the seam disassembles concurrently with the inactivation of the Jun kinase pathway. Thus, we show that epithelial sealing is promoted by a transient actomyosin contractile seam allowing sequential segment assembly.
    DOI:  https://doi.org/10.1038/s41467-025-58566-z
  3. Nat Cardiovasc Res. 2025 Apr 29.
    ARID5A promotes inflammation and fibrosis during cardiac aging.
    Shoval Miyara, Eldad Tzahor.
      
    DOI:  https://doi.org/10.1038/s44161-025-00621-5
  4. Curr Opin Genet Dev. 2025 Apr 30. pii: S0959-437X(25)00043-7. [Epub ahead of print]93 102351
    Unlocking regeneration: how partial reprogramming resembles tissue healing.
    Melissa T Adams, Heinrich Jasper, Lluc Mosteiro.
      Partial reprogramming achieved by the transient expression of the transcription factors (TFs) Oct4, Sox2, Klf4 and C-Myc (abbreviated OSKM) can erase aging and damage features in cells, leading to increased healthspan, lifespan and tissue regeneration. Recent reports suggest that the mechanisms of partial reprogramming may share some similarities with natural dedifferentiation and regeneration. Both processes appear to involve the transient repression of somatic identity through the sequestration of somatic identity TFs to noncanonical sites, which are opened by the high expression of pioneer TFs, leading to transient dedifferentiation into a fetal-like state. Here, we review the reported benefits of partial reprogramming on tissue regeneration and propose a common mechanism of epigenetic remodeling with natural regeneration after tissue injury.
    DOI:  https://doi.org/10.1016/j.gde.2025.102351
  5. Science. 2025 May;388(6746): eadu9628
    Interphase cell morphology defines the mode, symmetry, and outcome of mitosis.
    Holly E Lovegrove, Georgia E Hulmes, Sabrina Ghadaouia, Christopher Revell, Marta Giralt-Pujol, Zain Alhashem, Andreia Pena, Damian D Nogare, Ellen Appleton, Guilherme Costa, Richard L Mort, Christoph Ballestrem, Gareth W Jones, Cerys S Manning, Ajay B Chitnis, Claudio A Franco, Claudia Linker, Katie Bentley, Shane P Herbert.
      During tissue formation, dynamic cell shape changes drive morphogenesis while asymmetric divisions create cellular diversity. We found that the shifts in cell morphology that shape tissues could concomitantly act as conserved instructive cues that trigger asymmetric division and direct core identity decisions underpinning tissue building. We performed single-cell morphometric analyses of endothelial and other mesenchymal-like cells. Distinct morphological changes switched cells to an "isomorphic" mode of division, which preserved pre-mitotic morphology throughout mitosis. In isomorphic divisions, interphase morphology appeared to provide a geometric code defining mitotic symmetry, fate determinant partitioning, and daughter state. Rab4-positive endosomes recognized this code, allowing them to respond to pre-mitotic morphology and segregate determinants accordingly. Thus, morphogenetic shape change sculpts tissue form while also generating cellular heterogeneity, thereby driving tissue assembly.
    DOI:  https://doi.org/10.1126/science.adu9628
  6. Nat Cardiovasc Res. 2025 Apr 29.
    ARID5A orchestrates cardiac aging and inflammation through MAVS mRNA stabilization.
    Yanling Fan, Yandong Zheng, Yiyuan Zhang, Gang Xu, Chun Liu, Jianli Hu, Qianzhao Ji, Shuo Zhang, Shuaiqi Fang, Jinghui Lei, Lan-Zhu Li, Xing Wang, Xi Xu, Cui Wang, Si Wang, Shuai Ma, Moshi Song, Wenjian Jiang, Junming Zhu, Yijia Feng, Jiangang Wang, Ying Yang, Guodong Zhu, Xiao-Li Tian, Hongjia Zhang, Weihong Song, Jiayin Yang, Yan Yao, Guang-Hui Liu, Jing Qu, Weiqi Zhang.
      Elucidating the regulatory mechanisms of human cardiac aging remains a great challenge. Here, using human heart tissues from 74 individuals ranging from young (≤35 years) to old (≥65 years), we provide an overview of the histological, cellular and molecular alterations underpinning the aging of human hearts. We decoded aging-related gene expression changes at single-cell resolution and identified increased inflammation as the key event, driven by upregulation of ARID5A, an RNA-binding protein. ARID5A epi-transcriptionally regulated Mitochondrial Antiviral Signaling Protein (MAVS) mRNA stability, leading to NF-κB and TBK1 activation, amplifying aging and inflammation phenotypes. The application of gene therapy using lentiviral vectors encoding shRNA targeting ARID5A into the myocardium not only mitigated the inflammatory and aging phenotypes but also bolstered cardiac function in aged mice. Altogether, our study provides a valuable resource and advances our understanding of cardiac aging mechanisms by deciphering the ARID5A-MAVS axis in post-transcriptional regulation.
    DOI:  https://doi.org/10.1038/s44161-025-00635-z
  7. J Invest Dermatol. 2025 Apr 30. pii: S0022-202X(25)00458-0. [Epub ahead of print]
    Epithelial Fibronectin meshwork controls skin regeneration.
    Soline Estrach, Charles-Maxime Vivier, Lionel Tosello, Floriane S Tissot, Laurence Cailleteau, Ludovic Cervera, Kim B Jensen, Chloé C Féral.
      Adult stem cell fate is tightly balanced by the local microenvironment called niche and sustains tissue regeneration. How niche signals are integrated and regulate regeneration remains largely unexplored. Fibronectin (FN) is a major extracellular matrix component and integrin ligand, which role is well characterized during wound healing. Here, using the hair follicle as a mini organ which regenerates, we discovered a previously unreported role for FN in epidermal regeneration. Hair follicle stem cells (HFSCs) undergo long-term self-renewal and multi-lineage differentiation. We show that FN displays a highly specific enrichment in stem cells at the onset of hair follicle regeneration. We reveal FN tracks along the regenerating hair follicles forming a meshwork. FN conditional deletion in HFSC compartments (Lrig1, K19) leads to impaired stem cell location and fate. Loss of this meshwork is accompanied by hair regeneration blocade. Dermal injection of exogenous FN rescues these phenotypes. Analyzing the molecular mechanisms underlying FN function led us to identify integrin-dependent mechanotransduction as the main player in hair follicle regeneration, via YAP/Taz. Thus, in epithelial cells, fibronectin-integrin-mechanotransduction finely tunes adult stem cell fate and tissue regenerative power.
    Keywords:  fibronectin; hair follicle stem cells; mechanosignaling; meshwork; tissue regeneration
    DOI:  https://doi.org/10.1016/j.jid.2025.04.014
  8. Cell. 2025 Apr 25. pii: S0092-8674(25)00405-2. [Epub ahead of print]
    Regional differences in progenitor metabolism shape brain growth during development.
    Natalia Baumann, Robin J Wagener, Awais Javed, Eleonora Conti, Philipp Abe, Andrea Lopes, Roberto Sansevrino, Adrien Lavalley, Elia Magrinelli, Timea Szalai, Daniel Fuciec, Clothilde Ferreira, Sabine Fièvre, Andreane Fouassier, Davide D'Amico, Oliver Harschnitz, Denis Jabaudon.
      Mammals have particularly large forebrains compared with other brain parts, yet the developmental mechanisms underlying this regional expansion remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late neocortex-enriched mitochondrial protein FAM210B as a key regulator using in vivo gain- and loss-of-function experiments. FAM210B elongates mitochondria and increases lactate production, which promotes progenitor self-replicative divisions and, ultimately, the larger clonal size of their progeny. Together, these findings indicate that spatiotemporal heterogeneity in mitochondrial function regulates regional progenitor cycling behavior and associated clonal neuronal production during brain development.
    Keywords:  brain development; metabolism; mitochondria dynamics; progenitor diversity
    DOI:  https://doi.org/10.1016/j.cell.2025.04.003
  9. Nat Metab. 2025 Apr 28.
    Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
    Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.
      During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.
    DOI:  https://doi.org/10.1038/s42255-025-01289-8
  10. Nat Methods. 2025 Apr 29.
    Tri-omic single-cell mapping of the 3D epigenome and transcriptome in whole mouse brains throughout the lifespan.
    Haoxi Chai, Xingyu Huang, Guangzhou Xiong, Jiaxiang Huang, Katarzyna Karolina Pels, Lingyun Meng, Jin Han, Dongmei Tang, Guanjing Pan, Liang Deng, Qin Xiao, Xiaotao Wang, Meng Zhang, Krzysztof Banecki, Dariusz Plewczynski, Chia-Lin Wei, Yijun Ruan.
      Exploring the genomic basis of transcriptional programs has been a long-standing research focus. Here we report a single-cell method, ChAIR, to map chromatin accessibility, chromatin interactions and RNA expression simultaneously. After validating in cultured cells, we applied ChAIR to whole mouse brains and delineated the concerted dynamics of epigenome, three-dimensional (3D) genome and transcriptome during maturation and aging. In particular, gene-centric chromatin interactions and open chromatin states provided 3D epigenomic mechanism underlying cell-type-specific transcription and revealed spatially resolved specificity. Importantly, the composition of short-range and ultralong chromatin contacts in individual cells is remarkably correlated with transcriptional activity, open chromatin state and genome folding density. This genomic property, along with associated cellular properties, differs in neurons and non-neuronal cells across different anatomic regions throughout the lifespan, implying divergent nuclear mechano-genomic mechanisms at play in brain cells. Our results demonstrate ChAIR's robustness in revealing single-cell 3D epigenomic states of cell-type-specific transcription in complex tissues.
    DOI:  https://doi.org/10.1038/s41592-025-02658-7
  11. Mol Biol Cell. 2025 Apr 30. mbcE25030117
    The PCM scaffold enables RNA localization to centrosomes.
    Junnan Fang, Weiyi Tian, Melissa A Quintanilla, Jordan R Beach, Dorothy A Lerit.
      As microtubule-organizing centers, centrosomes direct assembly of the bipolar mitotic spindle required for chromosome segregation and genome stability. Centrosome activity requires the dynamic assembly of pericentriolar material (PCM), the composition and organization of which changes throughout the cell cycle. Recent studies highlight the conserved localization of several mRNAs encoded from centrosome-associated genes enriched at centrosomes, including Pericentrin-like protein (Plp) mRNA. However, relatively little is known about how RNAs localize to centrosomes and influence centrosome function. Here, we examine mechanisms underlying the subcellular localization of Plp mRNA. We find that Plp mRNA localization is puromycin-sensitive, and the Plp coding sequence is both necessary and sufficient for RNA localization, consistent with a co-translational transport mechanism. We identify regions within the Plp coding sequence that regulate Plp mRNA localization. Finally, we show that protein-protein interactions critical for elaboration of the PCM scaffold permit RNA localization to centrosomes. Taken together, these findings inform the mechanistic basis of Plp mRNA localization and lend insight into the oscillatory enrichment of RNA at centrosomes.
    DOI:  https://doi.org/10.1091/mbc.E25-03-0117
  12. Nat Commun. 2025 Apr 25. 16(1): 3918
    Chromosomal instability in human trophoblast stem cells and placentas.
    Danyang Wang, Andrew Cearlock, Katherine Lane, Chongchong Xu, Ian Jan, Stephen McCartney, Ian Glass, Rajiv McCoy, Min Yang.
      The human placenta, a unique tumor-like organ, is thought to exhibit rare aneuploidy associated with adverse pregnancy outcomes. Discrepancies in reported aneuploidy prevalence in placentas stem from limitations in modeling and detection methods. Here, we use isogenic trophoblast stem cells (TSCs) derived from both naïve and primed human pluripotent stem cells (hPSCs) to reveal the spontaneous occurrence of aneuploidy, suggesting chromosomal instability (CIN) as an inherent feature of the trophoblast lineage. We identify potential pathways contributing to the occurrence and tolerance of CIN, such as autophagy, which may support the survival of aneuploid cells. Despite extensive chromosomal abnormalities, TSCs maintain their proliferative and differentiation capacities. These findings are further validated in placentas, where we observe a high prevalence of heterogeneous aneuploidy across trophoblasts, particularly in invasive extravillous trophoblasts. Our study challenges the traditional view of aneuploidy in the placenta and provides insights into the implications of CIN in placental function.
    DOI:  https://doi.org/10.1038/s41467-025-59245-9
  13. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00404-8. [Epub ahead of print]44(5): 115633
    Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation.
    Jiabei Lian, Yachun An, Wenjing Wei, Yao Lu, Xiyu Zhang, Gongping Sun, Haiyang Guo, Longjin Xu, Xuena Chen, Huili Hu.
      Liver regeneration is a well-organized and phase-restricted process that involves chromatin remodeling and transcriptional alterations. However, the specific transcription factors (TFs) that act as key "switches" to initiate hepatocyte regeneration and organoid formation remain unclear. Comprehensive integration of RNA sequencing and ATAC sequencing reveals that ATF3 representing "Initiation_on" TF and ONECUT2 representing "Initiation_off" TF transiently modulate the occupancy of target promoters to license liver cells for regeneration. Knockdown of Atf3 or overexpression of Onecut2 not only reduces organoid formation but also delays tissue-damage repair after PHx or CCl4 treatment. Mechanistically, we demonstrate that ATF3 binds to the promoter of Slc7a5 to activate mTOR signals while the Hmgcs1 promoter loses ONECUT2 binding to facilitate regenerative initiation. The results identify the mechanism for initiating regeneration and reveal the remodeling of transcriptional landscapes and chromatin accessibility, thereby providing potential therapeutic targets for liver diseases with regenerative defects.
    Keywords:  CP: Molecular biology; CP: Stem cell research; chromatin accessibility; hepatocyte organoids; regenerative initiation; transcription factors
    DOI:  https://doi.org/10.1016/j.celrep.2025.115633
  14. Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]
    NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
    Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.
      Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
    Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
  15. Nature. 2025 Apr 30.
    Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.
    Sangkyun Cho, Siyeon Rhee, Christopher M Madl, Arianne Caudal, Dilip Thomas, Hyeonyu Kim, Ana Kojic, Hye Sook Shin, Abhay Mahajan, James W Jahng, Xi Wang, Phung N Thai, David T Paik, Mingqiang Wang, McKay Mullen, Natalie M Baker, Jeremy Leitz, Souhrid Mukherjee, Virginia D Winn, Y Joseph Woo, Helen M Blau, Joseph C Wu.
      Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.
    DOI:  https://doi.org/10.1038/s41586-025-08945-9
  16. Elife. 2025 Apr 30. pii: RP102915. [Epub ahead of print]13
    DNA replication in primary hepatocytes without the six-subunit ORC.
    Róża K Przanowska, Yuechuan Chen, Takayuki-Okano Uchida, Etsuko Shibata, Xiaoxiao Hao, Isaac Segura Rueda, Kate Jensen, Piotr Przanowski, Anthony Trimboli, Yoshiyuki Shibata, Gustavo Leone, Anindya Dutta.
      The six-subunit ORC is essential for the initiation of DNA replication in eukaryotes. Cancer cell lines in culture can survive and replicate DNA replication after genetic inactivation of individual ORC subunits, ORC1, ORC2, or ORC5. In primary cells, ORC1 was dispensable in the mouse liver for endo-reduplication, but this could be explained by the ORC1 homolog, CDC6, substituting for ORC1 to restore functional ORC. Here, we have created mice with a conditional deletion of ORC2, which does not have a homolog. Although mouse embryo fibroblasts require ORC2 for proliferation, mouse hepatocytes synthesize DNA in cell culture and endo-reduplicate in vivo without ORC2. Mouse livers endo-reduplicate after simultaneous deletion of ORC1 and ORC2 both during normal development and after partial hepatectomy. Since endo-reduplication initiates DNA synthesis like normal S phase replication these results unequivocally indicate that primary cells, like cancer cell lines, can load MCM2-7 and initiate replication without ORC.
    Keywords:  cell biology; genetics; genomics; mouse; mouse embryo fibroblasts; mouse liver; primary hepatocytes
    DOI:  https://doi.org/10.7554/eLife.102915
  17. Nat Aging. 2025 May 01.
    Aging promotes reactivation of the Barr body at distal chromosome regions.
    Sarah Hoelzl, Tim P Hasenbein, Stefan Engelhardt, Daniel Andergassen.
      Decades ago, evidence of age-related reactivation of a single gene on the female inactive X chromosome was observed in mice. While stable silencing of the Barr body is crucial for balancing gene dosage between sexes, it remains unclear whether silencing is maintained during aging. Here we used allele-specific multi-omics approaches to capture a comprehensive catalog of genes escaping X chromosome inactivation throughout mouse development and aging. We found substantially elevated escape rates during aging across organs, occurring in multiple distinct cell types and concentrated at distal chromosome regions. Consistently, chromatin accessibility was increased across multiple megabases at chromosome ends, affecting regulatory elements of escapees. As several age-specific escapees are linked to human diseases, their elevated expression in females might contribute to sex-biased disease progression observed during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00856-8
  18. Curr Opin Genet Dev. 2025 Apr 25. pii: S0959-437X(25)00040-1. [Epub ahead of print]93 102348
    Paternal effects on telomere integrity during the sperm-to-embryo transition.
    Sung-Ya Lin, Mia T Levine.
      Telomeres are essential nucleoprotein structures that preserve our terminal DNA sequence and protect chromosome ends from fusion. Our vast knowledge of telomeres comes almost entirely from studies of healthy and diseased somatic cells. However, building evidence suggests that the molecules and mechanisms required for telomere integrity in somatic cells are insufficient to preserve telomere integrity during the sperm-to-embryo transition. Here, we review this growing body of work on telomere 'paternal effects', wherein zygotic telomere integrity is determined not by the genotype of the zygote but instead by the genotype of the father. Direct inheritance of sperm-specific proteins establishes paternal telomere epigenetic identity, while direct inheritance of sperm telomere length contributes to telomere length inheritance. Together, these investigations of telomere integrity through the sperm-to-embryo transition reveal potent paternal effects on zygotic telomere functions, with implications for human infertility.
    DOI:  https://doi.org/10.1016/j.gde.2025.102348
  19. Nat Commun. 2025 Apr 30. 16(1): 4062
    Natural genetic variation quantitatively regulates heart rate and dimension.
    Jakob Gierten, Bettina Welz, Tomas Fitzgerald, Thomas Thumberger, Rashi Agarwal, Oliver Hummel, Adrien Leger, Philipp Weber, Kiyoshi Naruse, David Hassel, Norbert Hübner, Ewan Birney, Joachim Wittbrodt.
      The polygenic contribution to heart development and function along the health-disease continuum remains unresolved. To gain insight into the genetic basis of quantitative cardiac phenotypes, we utilize highly inbred Japanese rice fish models, Oryzias latipes, and Oryzias sakaizumii. Employing automated quantification of embryonic heart rates as core metric, we profiled phenotype variability across five inbred strains. We observed maximal phenotypic contrast between individuals of the HO5 and the HdrR strain. HO5 showed elevated heart rates associated with embryonic ventricular hypoplasia and impaired adult cardiac function. This contrast served as the basis for genome-wide mapping. In an F2 segregation population of 1192 HO5 x HdrR embryos, we mapped 59 loci (173 genes) associated with heart rate. Experimental validation of the top 12 candidate genes by gene editing revealed their causal and distinct impact on heart rate, development, ventricle size, and arrhythmia. Our study uncovers new diagnostic and therapeutic targets for developmental and electrophysiological cardiac diseases and provides a novel scalable approach to investigate the intricate genetic architecture of the vertebrate heart.
    DOI:  https://doi.org/10.1038/s41467-025-59425-7
  20. Cell. 2025 Apr 26. pii: S0092-8674(25)00459-3. [Epub ahead of print]
    Growth of the maternal intestine during reproduction.
    Tomotsune Ameku, Anna Laddach, Hannah Beckwith, Alexandra Milona, Loranzie S Rogers, Cornelia Schwayer, Emma Nye, Iain R Tough, Jean-Louis Thoumas, Umesh Kumar Gautam, Yi-Fang Wang, Shreya Jha, Alvaro Castano-Medina, Christopher Amourda, Patric M Vaelli, Sira Gevers, Elaine E Irvine, Leah Meyer, Ivan Andrew, Ka Lok Choi, Bhavik Patel, Alice J Francis, Chris Studd, Laurence Game, George Young, Kevin G Murphy, Bryn Owen, Dominic J Withers, Maria Rodriguez-Colman, Helen M Cox, Prisca Liberali, Martin Schwarzer, Franҫois Leulier, Vassilis Pachnis, Nicholas W Bellono, Irene Miguel-Aliaga.
      
    DOI:  https://doi.org/10.1016/j.cell.2025.04.023
  21. Nature. 2025 Apr 30.
    Cell cycle duration determines oncogenic transformation capacity.
    Danian Chen, Suying Lu, Katherine Huang, Joel D Pearson, Marek Pacal, Phillipos Peidis, Sean McCurdy, Tao Yu, Monika Sangwan, Angela Nguyen, Philippe P Monnier, Daniel Schramek, Liang Zhu, David Santamaria, Mariano Barbacid, Nagako Akeno, Kathryn A Wikenheiser-Brokamp, Rod Bremner.
      Oncogenic mutations are widespread in normal human tissues1. Similarly, in murine chimeras, cells carrying an oncogenic lesion contribute normal cells to adult tissues without causing cancer2-4. How lineages that escape cancer via normal development differ from the minority that succumb is unclear. Tumours exhibit characteristic cancer hallmarks; we therefore searched for hallmarks that differentiate cancer-prone lineages from resistant lineages. Here we show that total cell cycle duration (Tc) predicts transformation susceptibility across multiple tumour types. Cancer-prone Rb- and p107-deficient retina (Rb is also known as Rb1 and p107 is also known as Rbl1) exhibited defects in apoptosis, senescence, immune surveillance, angiogenesis, DNA repair, polarity and proliferation. Perturbing the SKP2-p27-CDK2/CDK1 axis could block cancer without affecting these hallmarks. Thus, cancer requires more than the presence of its hallmarks. Notably, every tumour-suppressive mutation that we tested increased Tc, and the Tc of the cell of origin of retinoblastoma cells was half that of resistant lineages. Tc also differentiated the cell of origin in Rb-/- pituitary cancer. In lung, loss of Rb and p53 (also known as Trp53) transforms neuroendocrine cells, whereas KrasG12D or BrafV600E mutations transform alveolar type 2 cells5-7. The shortest Tc consistently identified the cell of origin, regardless of mutation timing. Thus, relative Tc is a hallmark of initiation that distinguishes cancer-prone from cancer-resistant lineages in several settings, explaining how mutated cells escape transformation without inducing apoptosis, senescence or immune surveillance.
    DOI:  https://doi.org/10.1038/s41586-025-08935-x
  22. J Cell Biol. 2025 Jul 07. pii: e202406059. [Epub ahead of print]224(7):
    A cortical pool of LIN-5 (NuMA) controls cytokinetic furrow formation and cytokinesis completion.
    Kuheli Adhikary, Sukriti Kapoor, Sachin Kotak.
      In animal cells, cleavage furrow formation is controlled by localized activation of the GTPase RhoA at the equatorial membrane using cues transmitted from the spindle. Here, we explore the function of LIN-5, a well-studied protein known for its role in aster separation and spindle positioning in cleavage furrow formation. We show that the cortical pool of LIN-5, recruited by GPR-1/2 and important for cortical force generation, regulates cleavage furrow formation independently of its roles in aster separation and spindle positioning. Instead, our data suggest that enrichment of LIN-5/GPR-1/2 at the polar cortical region is essential to ensure the timely accumulation of contractile ring components-myosin II and Anillin at the equatorial cortex. We additionally define a late cytokinesis role of cortical LIN-5/GPR-1/2 in midbody stabilization and abscission. These results indicate that the cortical LIN-5/GPR-1/2 complex contributes to multiple aspects of cytokinesis independently of its roles in spindle positioning and elongation.
    DOI:  https://doi.org/10.1083/jcb.202406059
  23. EMBO J. 2025 Apr 25.
    The Spc105/Kre28 complex promotes mitotic error correction by outer kinetochore recruitment of Ipl1/Sli15.
    Alexander Dudziak, Richard Pleuger, Jasmin Schmidt, Frederik Hamm, Sharvari Tendulkar, Karolin Jänen, Ingrid R Vetter, Sylvia Singh, Josef Fischböck, Franz Herzog, Stefan Westermann.
      Kinetochores link chromosomes to dynamic microtubules of the mitotic spindle. To ensure equal chromosome segregation, sister chromatids must achieve biorientation. The conserved kinase Aurora B phosphorylates outer kinetochore proteins on attachments lacking tension, allowing the re-establishment of new connections until biorientation is achieved. Aurora B localizes to the centromere as part of the chromosomal passenger complex (CPC), but the underlying recruitment pathways can be eliminated without disrupting biorientation. It therefore remains unclear how the kinase operates during error correction. Here, we identify the conserved Spc105/Kre28 complex as an outer kinetochore receptor of the Aurora kinase Ipl1 and its activator Sli15 in Saccharomyces cerevisiae. We show that mutations in the helix bundle domain of Spc105/Kre28 impair mitotic error correction, resembling the effects of ipl1 or sli15 mutants. The defects can be suppressed by the artificial recruitment of Ipl1. In biochemical experiments, Ipl1/Sli15 directly associates with Spc105/Kre28, and a conserved segment in the Sli15 central domain is crucially involved in the binding mechanism. These results have important implications for the mechanism of tension-dependent error correction during chromosome biorientation.
    Keywords:  Chromosomal Passenger Complex; Chromosome Biorientation; Error Correction; KMN Network; Signaling
    DOI:  https://doi.org/10.1038/s44318-025-00437-w
  24. Mol Cell. 2025 Apr 28. pii: S1097-2765(25)00316-8. [Epub ahead of print]
    Chromatin-bound U2AF2 splicing factor ensures exon inclusion.
    Weifang Wu, Kami Ahmad, Steven Henikoff.
      Most mRNA splicing occurs co-transcriptionally, but it is unclear how splicing factors accurately select exons for inclusion. Using CUT&RUN profiling in K562 cells, we demonstrate that three splicing factors-SF3B1, U2AF1, and U2AF2-bind near active promoters of intron-containing and intronless genes, implying their association with the general transcriptional machinery. RNase A treatment reduces factor binding at promoters, indicating that these proteins interact with nascent transcripts. Strikingly, the U2AF2 protein also accumulates throughout intron-containing gene bodies and requires histone H3-lysine36 trimethylation but not nascent transcripts or persistent RNA polymerase II. Chromatin-bound U2AF2 preferentially binds to exons of highly expressed, exon-dense genes, with greater occupancy at exons skipped after U2AF2 knockdown, suggesting that U2AF2 enhances exon selection accuracy. U2AF2-targeted genes include those encoding splicing factors, where it improves splicing accuracy and efficiency. Our findings provide a mechanistic basis for the homeostatic regulation of efficient co-transcriptional splicing by chromatin-bound U2AF2.
    Keywords:  H3K36me3; RNA polymerase II; SF3B155; U2AF35; U2AF65; co-transcriptional RNA splicing; exon definition
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.013
  25. Hum Reprod Update. 2025 Apr 29. pii: dmaf006. [Epub ahead of print]
    Moving toward totipotency: the molecular and cellular features of totipotent and naive pluripotent stem cells.
    Lingyue Hua, Yuyang Peng, Liying Yan, Peng Yuan, Jie Qiao.
       BACKGROUND: Dissecting the key molecular mechanism of embryonic development provides novel insights into embryogenesis and potential intervention strategies for clinical practices. However, the ability to study the molecular mechanisms of early embryo development in humans, such as zygotic genome activation and lineage segregation, is meaningfully constrained by methodological limitations and ethical concerns. Totipotent stem cells have an extended developmental potential to differentiate into embryonic and extraembryonic tissues, providing a suitable model for studying early embryo development. Recently, a series of ground-breaking results on stem cells have identified totipotent-like cells or induced pluripotent stem cells into totipotent-like cells.
    OBJECTIVE AND RATIONALE: This review followed the PRISMA guidelines, surveys the current works of literature on totipotent, naive, and formative pluripotent stem cells, introduces the molecular and biological characteristics of those stem cells, and gives advice for future research.
    SEARCH METHODS: The search method employed the terms 'totipotent' OR 'naive pluripotent stem cell' OR 'formative pluripotent stem cell' for unfiltered search on PubMed, Web of Science, and Cochrane Library. Papers included were those with information on totipotent stem cells, naive pluripotent stem cells, or formative pluripotent stem cells until June 2024 and were published in the English language. Articles that have no relevance to stem cells, or totipotent, naive pluripotent, or formative pluripotent cells were excluded.
    OUTCOMES: There were 152 records included in this review. These publications were divided into four groups according to the species of the cells included in the studies: 67 human stem cell studies, 70 mouse stem cell studies, 9 porcine stem cell studies, and 6 cynomolgus stem cell studies. Naive pluripotent stem cell models have been established in other species such as porcine and cynomolgus. Human and mouse totipotent stem cells, e.g. human 8-cell-like cells, human totipotent blastomere-like cells, and mouse 2-cell-like cells, have been successfully established and exhibit high developmental potency for both embryonic and extraembryonic contributions. However, the observed discrepancies between these cells and real embryos in terms of epigenetics and transcription suggest that further research is warranted. Our results systematically reviewed the established methods, molecular characteristics, and developmental potency of different naive, formative pluripotent, and totipotent stem cells. Furthermore, we provide a parallel comparison between animal and human models, and offer recommendations for future applications to advance early embryo research and assisted reproduction technologies.
    WIDER IMPLICATIONS: Totipotent cell models provide a valuable resource to understand the underlying mechanisms of embryo development and forge new paths toward future treatment of infertility and regenerative medicine. However, current in vitro cell models exhibit epigenetic and transcriptional differences from in vivo embryos, and many cell models are unstable across passages, thus imperfectly recapitulating embryonic development. In this regard, standardizing and expanding current research on totipotent stem cell models are essential to enhance our capability to resemble and decipher embryogenesis.
    Keywords:  ZGA; embryo development; lineage segregation; naive pluripotency; stem cells; totipotency
    DOI:  https://doi.org/10.1093/humupd/dmaf006
  26. Nat Commun. 2025 Apr 26. 16(1): 3932
    Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division.
    Hien Bui, Simon Andersson, Agustin Sola-Carvajal, Tommaso De Marchi, Eliisa Vähäkangas, Minna Holopainen, Andrew H House, Bohdana M Rovenko, Johanna I Englund, Maria Kasper, Emilia Kuuluvainen, Reijo Käkelä, Ville Hietakangas, Emma Niméus, Pekka Katajisto.
      Selective inheritance of sub-cellular components has emerged as a mechanism guiding stem cell fate after asymmetric cell divisions. Peroxisomes play a crucial role in multiple metabolic processes such as fatty acid metabolism and reactive oxygen species detoxification, but the apportioning of peroxisomes during stem cell division remains understudied. Here, we develop a mouse model and labeling technique to follow the dynamics of distinct peroxisome age-classes, and find that old peroxisomes are inherited by the daughter cell retaining full stem cell potency in mammary and epidermal stem cell divisions. Old peroxisomes carry Glucose-6-phosphate-dehydrogenase, whose specific location on the peroxisomal membrane promotes stem cell function by facilitating peroxisomal ether lipid synthesis. Our study demonstrates age-selective apportioning of peroxisomes in vivo, and unveils how functional heterogeneity of peroxisomes is utilized by asymmetrically dividing cells to metabolically divert the fate of the two daughter cells.
    DOI:  https://doi.org/10.1038/s41467-025-58752-z
  27. Cell. 2025 Apr 23. pii: S0092-8674(25)00404-0. [Epub ahead of print]
    RNA polymerase II partitioning is a shared feature of diverse oncofusion condensates.
    Heankel Lyons, Prashant Pradhan, Gopinath Prakasam, Shubham Vashishtha, Xiang Li, Mikayla Eppert, Christy Fornero, Vanina T Tcheuyap, Kathleen McGlynn, Ze Yu, Dinesh Ravindra Raju, Prasad R Koduru, Chao Xing, Payal Kapur, James Brugarolas, Benjamin R Sabari.
      Condensates regulate transcription by selectively compartmentalizing biomolecules, yet the rules of specificity and their relationship to function remain enigmatic. To identify rules linked to function, we leverage the genetic selection bias of condensate-promoting oncofusions. Focusing on the three most frequent oncofusions driving translocation renal cell carcinoma, we find that they promote the formation of condensates that activate transcription by gain-of-function RNA polymerase II partitioning through a shared signature of elevated π and π-interacting residues and depletion of aliphatic residues. This signature is shared among a broad set of DNA-binding oncofusions associated with diverse cancers. We find that this signature is necessary and sufficient for RNA polymerase II partitioning, gene activation, and cancer cell phenotypes. Our results reveal that dysregulated condensate specificity is a shared molecular mechanism of diverse oncofusions, highlighting the functional role of condensate composition and the power of disease genetics in investigating relationships between condensate specificity and function.
    Keywords:  Pol II-CTD; biomolecular condensates; condensate specificity; oncofusions; selective partitioning; transcription
    DOI:  https://doi.org/10.1016/j.cell.2025.04.002
  28. Nat Aging. 2025 Apr 30.
    KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging.
    Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Elisa Carrasco, José Ignacio Escrig-Larena, Manuel M Gómez de Las Heras, Sandra Delgado-Pulido, Isaac Francos-Quijorna, Eva M Blanco, Álvaro Fernández-Almeida, David Abia, María Josefa Rodríguez, Cristina M Fernández-Díaz, María Beatriz Álvarez-Flores, Ana Ramírez de Molina, Sascha Jung, Antonio Del Sol, Virginia Zorita, Fátima Sánchez-Cabo, Carlos Torroja, María Mittelbrunn.
      Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4+ T cells that accumulate with aging. These age-associated T cells are emerging as relevant players in the onset of inflammaging and tissue senescence. Here, based on information provided by single-cell RNA sequencing data, we present a flow cytometry panel that allows the identification of age-associated T cell subsets in systematic larger analysis in mice. We use this panel to evaluate at the single-cell level mitochondrial and senescence marks in the different age-associated CD4+ T cell subpopulations. Our analysis identifies a subpopulation of regulatory T (Treg) cells that is characterized by the extracellular expression of the co-inhibitory molecule killer cell lectin-like receptor subfamily G member 1 (KLRG1) and accumulates with aging in humans and mice. KLRG1-expressing Treg cells display senescence features such as mitochondrial alterations, increased expression of cell-cycle regulators and genomic DNA damage. Functionally, KLRG1+ Treg cells show a reduced suppressive activity in vivo accompanied by a pro-inflammatory phenotype.
    DOI:  https://doi.org/10.1038/s43587-025-00855-9
  29. Nat Methods. 2025 Apr 29.
    Fast-adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging.
    Chang Qiao, Ziwei Li, Zongfa Wang, Yuhuan Lin, Chong Liu, Siwei Zhang, Yong Liu, Yun Feng, Xiaoyu Yang, Wenfeng Fu, Xue Dong, Jiabao Guo, Wencong Xu, Xinyu Wang, Tao Jiang, Quan Meng, Qinghua Wang, Qionghai Dai, Dong Li.
      Lattice light-sheet microscopy provides a crucial observation window into intra- and intercellular physiology of living specimens but at the diffraction-limited resolution or anisotropic super-resolution with structured illumination. Here we present meta-learning-empowered reflective lattice light-sheet virtual structured illumination microscopy (Meta-rLLS-VSIM), which upgrades lattice light-sheet microscopy to a near-isotropic super resolution of ~120 nm laterally and ~160 nm axially without modifications of the core optical system or loss of other live-cell imaging metrics. Moreover, we devised an adaptive online training approach by synergizing the front-end imaging system and back-end meta-learning framework, which alleviated the demand for training data by tenfold and reduced the total time for data acquisition and model training down to tens of seconds. We demonstrate the versatile functionalities of Meta-rLLS-VSIM by imaging a variety of bioprocesses with ultrahigh spatiotemporal resolution for hundreds of multicolor volumes, delineating the nanoscale distributions, dynamics and interaction patterns of multiple organelles in embryos and eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41592-025-02678-3
  30. Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2501078122
    Twinfilin is a nonprocessive depolymerase which synergizes with formin to dramatically accelerate actin filament uncapping by 300-fold.
    Vishal Reddy, Ankita Arya, Shashank Shekhar.
      For over four decades, our understanding of cellular actin dynamics has been guided by the concept of treadmilling. However, this paradigm has been challenged by the evidence that twinfilin can uncap and promote depolymerization of filament barbed ends, though its precise mechanism remains debated. Using single-molecule microscopy and microfluidics-assisted TIRF imaging, we demonstrate that twinfilin transiently associates with barbed ends for ~0.2 to 0.5 s, acting as a nonprocessive depolymerase that likely removes one or both terminal actin subunits. Furthermore, we show that twinfilin's barbed-end residence time and its ability to uncap CP-capped filaments (both alone and with formin mDia1) are significantly influenced by filament age. The synergistic enhancement in uncapping by twinfilin and mDia1 ranges from 11-fold for newly assembled to ~318-fold for aged actin filaments. These represent the fastest uncapping rates measured in vitro and approach CP turnover rates in vivo. Our study thus reinforces twinfilin's central role as a multifunctional barbed-end regulator which nonprocessively depolymerizes actin filaments, transiently caps barbed ends, and synergizes with formin to destabilize CP, thereby facilitating rapid actin turnover that depends on filament age.
    Keywords:  actin dynamics; capping protein; formin; twinfilin
    DOI:  https://doi.org/10.1073/pnas.2501078122
  31. Nat Rev Genet. 2025 Apr 25.
    Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.
    Diane D Shao, Andrea J Kriz, Daniel A Snellings, Zinan Zhou, Yifan Zhao, Liz Enyenihi, Christopher Walsh.
      DNA sequencing from bulk or clonal human tissues has shown that genetic mosaicism is common and contributes to both cancer and non-cancerous disorders. However, single-cell resolution is required to understand the full genetic heterogeneity that exists within a tissue and the mechanisms that lead to somatic mosaicism. Single-cell DNA-sequencing technologies have traditionally trailed behind those of single-cell transcriptomics and epigenomics, largely because most applications require whole-genome amplification before costly whole-genome sequencing. Now, recent technological and computational advances are enabling the use of single-cell DNA sequencing to tackle previously intractable problems, such as delineating the genetic landscape of tissues with complex clonal patterns, of samples where cellular material is scarce and of non-cycling, postmitotic cells. Single-cell genomes are also revealing the mutational patterns that arise from biological processes or disease states, and have made it possible to track cell lineage in human tissues. These advances in our understanding of tissue biology and our ability to identify disease mechanisms will ultimately transform how disease is diagnosed and monitored.
    DOI:  https://doi.org/10.1038/s41576-025-00832-3
  32. Cell Genom. 2025 Apr 29. pii: S2666-979X(25)00112-0. [Epub ahead of print] 100856
    Super RNA Pol II domains enhance minor ZGA through 3D interaction to ensure the integrity of major transcriptional waves in late-ZGA mammals.
    Jingcheng Zhang, Hengkuan Li, Linmi Li, Jie Wu, Linjie Song, Xin Liu, Zhangyuan Pan, Chuan Zhou, Wenying Li, Zixiao Liu, Mei Jiao, Mingyang Hu, Zhenyu Dong, Hexu Zhang, Binqiang Shi, Yong Wang, Debao Wang, Benjamin Carter, Shuhong Zhao, Gang Ren, Yunxia Zhao, Yong Zhang.
      Zygotic genome activation (ZGA) occurs at distinct stages across mammals, with mice initiating ZGA at the 2-cell stage and bovines and humans activating the process in the 4- to 8-cell stages. RNA polymerase II (RNA Pol II) gradually initiates ZGA in mice, but regulation in late-ZGA species remains unclear. Here, RNA Pol II profiling in bovine embryos identified strong intergenic clusters that boost minor ZGA gene expression via chromatin interactions and are named super RNA Pol II domains (SPDs). CRISPRi perturbation of SPDs in bovine embryos decreases the expression of minor ZGA genes, whereas the knockdown of these genes disrupts major ZGA and embryogenesis. Rapid enhancement of minor ZGA genes also occurs in human embryos. Alternatively, mouse and porcine oocytes precociously express these minor ZGA genes without SPDs. Thus, SPDs appear to be an adaptation in bovine embryos, promoting minor ZGA gene expression to comparable levels as early-ZGA species, illuminating species-specific regulation of ZGA timing.
    Keywords:  3D interaction; RNA Pol II; SPDs; ZGA pace; interspecies comparison; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.xgen.2025.100856
  33. Mol Cell. 2025 Apr 16. pii: S1097-2765(25)00308-9. [Epub ahead of print]
    Prkra dimer senses double-stranded RNAs to dictate global translation efficiency.
    Tong Lu, Pengcheng Ma, Hailing Fang, Aijun Chen, Jianlin Xu, Xi Kuang, Mingyu Wang, Ling Su, Sen Wang, Yizhuang Zhang, Jiasheng Wang, Boya Yang, De-Li Shi, Yong Zhou, Qianqian Gong, Xiangguo Liu, Bingyu Mao, Ming Shao.
      Double-stranded RNAs (dsRNAs), known as conserved pathogen-associated molecular patterns, activate the integrated stress response via interferon-induced protein kinase R (PKR), leading to global translation inhibition. However, the interferon system is inactive in pluripotent cells, leaving the mechanisms of dsRNA sensing and translational control unclear. In this study, we utilized early zebrafish embryos as a model of pluripotent cells and discovered a PKR-independent blockage of translation initiation by dsRNA stimulation. Prkra dimer was identified as the genuine dsRNA sensor. Upon dsRNA binding, the dimerized dsRNA-binding domain 3 of Prkra becomes activated to sequester the eIF2 complexes from the translation machinery, inhibiting global protein synthesis. This distinctive embryonic stress response restricts RNA virus replication in zebrafish embryos, is conserved in mouse embryonic stem cells, and compensates PKR function in differentiated cells. Therefore, the Prkra-mediated dsRNA sensing and translation control may serve as a common strategy for cells to adapt to environmental stresses.
    Keywords:  PACT/RAX; Prkra; double-stranded RNA; dsRNA sensor; early embryos; embryonic stem cells; translation initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.005
  34. Semin Cell Dev Biol. 2025 May 01. pii: S1084-9521(25)00023-0. [Epub ahead of print]171 103613
    Immune-mediated cardiac development and regeneration.
    Timothy C Byatt, Ehsan Razaghi, Selin Tüzüner, Filipa C Simões.
      The complex interplay between the immune and cardiovascular systems during development, homeostasis and regeneration represents a rapidly evolving field in cardiac biology. Single cell technologies, spatial mapping and computational analysis have revolutionised our understanding of the diversity and functional specialisation of immune cells within the heart. From the earliest stages of cardiogenesis, where primitive macrophages guide heart tube formation, to the complex choreography of inflammation and its resolution during regeneration, immune cells emerge as central orchestrators of cardiac fate. Translating these fundamental insights into clinical applications represents a major challenge and opportunity for the field. In this Review, we decode the immunological blueprint of heart development and regeneration to transform cardiovascular disease treatment and unlock the regenerative capacity of the human heart.
    Keywords:  Cardiac Niche; Development; Heart; Immune Cells; Regeneration
    DOI:  https://doi.org/10.1016/j.semcdb.2025.103613
  35. Sci Adv. 2025 May 02. 11(18): eadt9318
    LINE-1 ribonucleoprotein condensates bind DNA to enable nuclear entry during mitosis.
    Sarah Zernia, Farida Ettefa, Srinjoy Sil, Cas Koeman, Joëlle Deplazes-Lauber, Marvin Freitag, Liam J Holt, Johannes Stigler.
      Long interspersed nuclear element-1 (LINE-1) is an autonomous retrotransposon that makes up a substantial portion of the human genome, contributing to genetic diversity and genome evolution. LINE-1 encodes two proteins, ORF1p and ORF2p, both essential for successful retrotransposition. ORF2p has endonuclease and reverse transcription activity, while ORF1p binds RNA. Many copies of ORF1p assemble onto the LINE-1 RNA to form a ribonucleoprotein (RNP) condensate. However, the function of these condensates in the LINE-1 life cycle remains unclear. Using reconstitution assays on DNA curtains, we show that L1 RNP condensates gain DNA binding activity only when RNA is super-saturated with ORF1p. In cells, L1 RNP condensates bind to chromosomes during mitosis. Mutational analysis reveals that DNA binding is crucial for nuclear entry and LINE-1 retrotransposition activity. Thus, a key function of ORF1p is to form an RNP condensate that gains access to the genome through DNA binding upon nuclear envelope breakdown.
    DOI:  https://doi.org/10.1126/sciadv.adt9318
  36. Cell Metab. 2025 Apr 25. pii: S1550-4131(25)00217-7. [Epub ahead of print]
    Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
    Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Jeffrey Milbrandt, David K Imagawa, Dorota Skowronska-Krawczyk, Danica Chen, Gina Lee, Cholsoon Jang, Qin Yang.
      Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.
    Keywords:  NAD(+); aging; kidney; liver; nicotinic acid riboside
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.007
  37. Nat Cell Biol. 2025 Apr 30.
    Targeting redox-sensitive MBD2-NuRD condensate in cancer cells.
    Heyang Wei, Hongdan Zheng, Siqing Wang, Yun Yang, Ruiqian Zhao, Aihong Gu, Ronggui Hu, Fei Lan, Wenyu Wen.
      Transcriptional silencing of hypermethylated tumour suppressor genes is a hallmark of tumorigenesis but the underlying mechanism remains enigmatic. Here we show that methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeller NuRD complex to these gene loci for transcriptional suppression, thus fuelling tumour growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation and consequently impedes tumour progression. We demonstrate that MBD2 condensate is redox sensitive, mediated by C359. Pro-oxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumour suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
    DOI:  https://doi.org/10.1038/s41556-025-01657-2
  38. Cell. 2025 Apr 24. pii: S0092-8674(25)00415-5. [Epub ahead of print]
    tRNA modifications tune m6A-dependent mRNA decay.
    Bastian Linder, Puneet Sharma, Jie Wu, Tosca Birbaumer, Cristian Eggers, Shino Murakami, Roman E Ott, Kai Fenzl, Hannah Vorgerd, Florian Erhard, Samie R Jaffrey, Sebastian A Leidel, Lars M Steinmetz.
      Chemically modified nucleotides in mRNA are critical regulators of gene expression, primarily through interactions with reader proteins that bind to these modifications. Here, we present a mechanism by which the epitranscriptomic mark N6-methyladenosine (m6A) is read by tRNAs during translation. Codons that are modified with m6A are decoded inefficiently by the ribosome, rendering them "non-optimal" and inducing ribosome collisions on cellular transcripts. This couples mRNA translation to decay. 5-Methoxycarbonylmethyl-2-thiouridine (mcm5s2U) in the tRNA anticodon loop counteracts this effect. This unanticipated link between the mRNA and tRNA epitranscriptomes enables the coordinated decay of mRNA regulons, including those encoding oncogenic signaling pathways. In cancer, dysregulation of the m6A and mcm5s2U biogenesis pathways-marked by a shift toward more mcm5s2U-is associated with more aggressive tumors and poor prognosis. Overall, this pan-epitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.
    Keywords:  N(6)-methyladenosine; cancer; epitranscriptome; m(6)A; mRNA decay; mRNA translation; mcm(5)s(2)U; oncogenic signaling; ribosome collisions; tRNA modification
    DOI:  https://doi.org/10.1016/j.cell.2025.04.013
  39. Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]
    Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
    Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.
      Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.
    Keywords:  CCN1; cell death; mitochondria
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
  40. Science. 2025 May;388(6746): eadp2959
    Stem cells as role models for reprogramming and repair.
    Magdalena Götz, Maria-Elena Torres-Padilla.
      Stem cells are a promising source for cellular therapies across many diseases and tissues. Their inherent ability to differentiate into other cell types has been the focus of investigation over decades. This ability is currently being exploited for therapies using strategies to repair or replace damaged tissues and cells or to alleviate immune rejection. Exploring stem cell function has enabled direct reprogramming approaches, for example, through the production of induced pluripotent stem cells and the generation of tissue-specific stem cells. Understanding stem cell function has emerged as an important strategy for repopulating stem cell pools or generating differentiated cells for therapy. Here, we review general principles of mammalian stem cell biology and cellular reprogramming approaches and their use for current and future therapeutic purposes.
    DOI:  https://doi.org/10.1126/science.adp2959
  41. Mol Cell. 2025 May 01. pii: S1097-2765(25)00311-9. [Epub ahead of print]85(9): 1806-1823.e17
    Stm1 regulates Ifh1 activity revealing crosstalk between ribosome biogenesis and ribosome dormancy.
    Eliana Bianco, Martina Bonassera, Federico Uliana, Janny Tilma, Martin Winkler, Sevil Zencir, Alvar Gossert, Michaela Oborská-Oplová, Reinhard Dechant, Jannik Hugener, Vikram Govind Panse, Martin Pilhofer, Benjamin Albert, Philipp Kimmig, Matthias Peter.
      Nutrient abundance boosts ribosome biogenesis, whereas ribosome dormancy factors limit ribosome degradation upon starvation. The equilibrium between the two pathways governs cell growth. In this study, we identified suppressor of Tom1 (Stm1) as a molecular link between ribosome protection and biogenesis in Saccharomyces cerevisiae. While Stm1 was previously described as a dormancy factor, we show that it activates Ifh1, a transcriptional activator of ribosomal protein genes. Stm1 transiently localizes to the nucleolus, where it interacts with pre-ribosomes and directly binds RNA and Ifh1 through its C-terminal intrinsically disordered region (IDR). Although the IDR is dispensable for ribosome protection, its loss compromises cell growth. The IDR is phosphorylated upon nutrient starvation, which disrupts its interaction with Ifh1. Our findings reveal a molecular pathway sensing and adjusting ribosome abundance in response to nutrient availability, reinforcing the relevance of regulated ribosome homeostasis in physiology and disease.
    Keywords:  Ifh1; RGG/GAR motif; RNA-binding; RPG transcription; Stm1; homeostasis; ribosome; ribosome biogenesis; ribosome degradation; ribosome dormancy
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.008
  42. bioRxiv. 2025 Apr 07. pii: 2025.04.01.646591. [Epub ahead of print]
    Real-time imaging of rotation during synthesis by the replisome.
    Thomas M Retzer, Lional T Rajappa, Masateru Takahashi, Samir M Hamdan, Karl E Duderstadt.
      During chromosome replication, unwinding by the helicase and synthesis by the polymerases can lead to overwinding and supercoiling of DNA. The mechanical consequences of these events and resulting local dynamics at the replication fork are not well understood. To address these issues, we developed a transverse DNA flow-stretching approach to spatially resolve the parental, leading and lagging strands in real-time. Using bacteriophage T7 as a model system, this approach revealed bursts of high-speed replisome rotation that support continuous DNA synthesis. Surprisingly, excessive rotation does not reduce replisome speed, but increases pausing, reduces processivity, and increases polymerase exchange. Taken together, our observations reveal intrinsic pathways to overcome challenges posed by unfavorable DNA topologies during DNA replication.
    DOI:  https://doi.org/10.1101/2025.04.01.646591
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