bims-ginsta 2025-02-23 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2025–02–23
forty-two papers selected by
Jinrong Hu, National University of Singapore

Force-activated zyxin assemblies coordinate actin nucleation and crosslinking to orchestrate stress fiber repair.
Coupling of cell shape, matrix and tissue dynamics ensures embryonic patterning robustness.
Wnt signaling modulates mechanotransduction in the epidermis to drive hair follicle regeneration.
An Aurora kinase A-BOD1L1-PP2A B56 axis promotes chromosome segregation fidelity.
Local weakening of cell-extracellular matrix adhesion triggers basal epithelial tissue folding.
TGF-β signaling controls neural crest developmental plasticity via SMAD2/3.
SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state.
Combined forces of hydrostatic pressure and actin polymerization drive endothelial tip cell migration and sprouting angiogenesis.
Rho/Rok-dependent regulation of actomyosin contractility at tricellular junctions restricts epithelial permeability in Drosophila.
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype.
Cold and hot fibrosis define clinically distinct cardiac pathologies.
BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress.
Somatic Genomic and Transcriptomic Changes in Single Ischemic Human Heart Cardiomyocytes.
The transmembrane glycoprotein Gpnmb is required for the immune and fibrotic responses during zebrafish heart regeneration.
CTCF/RAD21 organize the ground state of chromatin-nuclear speckle association.
Plasma proteome variation and its genetic determinants in children and adolescents.
AI-based approach to dissect the variability of mouse stem cell-derived embryo models.
Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability.
Mechanism for local attenuation of DNA replication at double-strand breaks.
Noninvasive characterization of oocyte deformability in microconstrictions.
Distinct requirements for PI3K isoforms p110α and p110δ for PIP3 synthesis in mouse oocytes and early embryos.
AMPK activation by glycogen expenditure primes the exit of naïve pluripotency.
Copy number variants and the tangential expansion of the cerebral cortex.
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
Genes of the Fatty Acid Oxidation Pathway are Upregulated in Female as Compared to Male Cardiomyocytes.
Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis.
Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.
Human-correlated genetic models identify precision therapy for liver cancer.
Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
Biomolecular condensation of human IDRs initiates endogenous transcription via intrachromosomal looping or high-density promoter localization.
Intratumour oxidative hotspots provide a niche for cancer cell dissemination.
Compositionally unique mitochondria in filopodia support cellular migration.
Reprogrammable RNA-targeting CRISPR systems evolved from RNA toxin-antitoxins.
Uncovering a gut microbiota-derived metabolite that triggers host cellular senescence.
Roadmap for alleviating the manifestations of ageing in the cardiovascular system.
The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells.
Intrinsically disordered regions as facilitators of the transcription factor target search.
Actin-dependent α-catenin oligomerization contributes to adherens junction assembly.
Centromeres are stress-induced fragile sites.
HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.
Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability.
Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.

Curr Biol. 2025 Feb 11. pii: S0960-9822(25)00072-7. [Epub ahead of print]

Force-activated zyxin assemblies coordinate actin nucleation and crosslinking to orchestrate stress fiber repair.

Donovan Y Z Phua, Xiaoyu Sun, Gregory M Alushin.

  As the cytoskeleton sustains cell and tissue forces, it incurs physical damage that must be repaired to maintain mechanical homeostasis. The LIN-11, Isl-1, and Mec-3 (LIM)-domain protein zyxin detects force-induced ruptures in actin-myosin stress fibers, coordinating downstream repair factors to restore stress fiber integrity through unclear mechanisms. Here, we reconstitute stress fiber repair with purified proteins, uncovering detailed links between zyxin's force-regulated binding interactions and cytoskeletal dynamics. In addition to binding individual tensed actin filaments (F-actin), zyxin's LIM domains form force-dependent assemblies that bridge broken filament fragments. Zyxin assemblies engage repair factors through multivalent interactions, coordinating nucleation of new F-actin by VASP and its crosslinking into aligned bundles by ɑ-actinin. Through these combined activities, stress fiber repair initiates within the cores of micron-scale damage sites in cells, explaining how these F-actin-depleted regions are rapidly restored. Thus, zyxin's force-dependent organization of actin repair machinery inherently operates at the network scale to maintain cytoskeletal integrity.

Keywords:  LIM domain; VASP; actin cytoskeleton; mechanobiology; mechanosensation; mechanotransduction; stress fiber; zyxin; α-actinin

DOI:  https://doi.org/10.1016/j.cub.2025.01.042
Nat Cell Biol. 2025 Feb 18.

Coupling of cell shape, matrix and tissue dynamics ensures embryonic patterning robustness.

Prachiti Moghe, Roman Belousov, Takafumi Ichikawa, Chizuru Iwatani, Tomoyuki Tsukiyama, Anna Erzberger, Takashi Hiiragi.

Tissue patterning coordinates morphogenesis, cell dynamics and fate specification. Understanding how precision in patterning is robustly achieved despite inherent developmental variability during mammalian embryogenesis remains a challenge. Here, based on cell dynamics quantification and simulation, we show how salt-and-pepper epiblast and primitive endoderm (PrE) cells pattern the inner cell mass of mouse blastocysts. Coupling cell fate and dynamics, PrE cells form apical polarity-dependent actin protrusions required for RAC1-dependent migration towards the surface of the fluid cavity, where PrE cells are trapped due to decreased tension. Concomitantly, PrE cells deposit an extracellular matrix gradient, presumably breaking the tissue-level symmetry and collectively guiding their own migration. Tissue size perturbations of mouse embryos and their comparison with monkey and human blastocysts further demonstrate that the fixed proportion of PrE/epiblast cells is optimal with respect to embryo size and tissue geometry and, despite variability, ensures patterning robustness during early mammalian development.

DOI: https://doi.org/10.1038/s41556-025-01618-9
Sci Adv. 2025 Feb 21. 11(8): eadq0638

Wnt signaling modulates mechanotransduction in the epidermis to drive hair follicle regeneration.

Allen S W Oak, Amrit Bagchi, Matthew J Brukman, Joshua Toth, Jamie Ford, Ying Zheng, Arben Nace, Ruifeng Yang, Jen-Chih Hsieh, James E Hayden, Gordon Ruthel, Anisa Ray, Elaine Kim, Vivek B Shenoy, George Cotsarelis.

Most wounds form scars without hair follicles. However, in the wound-induced hair neogenesis (WIHN) model of skin regeneration, wounds regenerate hair follicles if tissue rigidity is optimal. Although WIHN depends on Wnt signaling, whether Wnt performs a mechanoregulatory role that contributes to regeneration remains uncharacterized. Here, we demonstrate that Wnt signaling affects mechanosensitivity at both cellular and tissue levels to drive WIHN. Atomic force microscopy revealed an attenuated substrate rigidity response in epidermal but not dermal cells of healing wounds. Super-resolution microscopy and nanoneedle probing of intracellular compartments in live human keratinocytes revealed that Wnt-induced chromatin remodeling triggers a 10-fold drop in nuclear rigidity without jeopardizing the nucleocytoskeletal mechanical coupling. Mechanistically, Wnt signaling orchestrated a massive reorganization of actin architecture and recruited adherens junctions to generate a mechanical syncytium-a cohesive contractile unit with superior capacity for force coordination and collective durotaxis. Collectively, our findings unveil Wnt signaling's mechanoregulatory role that manipulates the machinery of mechanotransduction to drive regeneration.

DOI: https://doi.org/10.1126/sciadv.adq0638
Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00088-9. [Epub ahead of print]44(2): 115317

An Aurora kinase A-BOD1L1-PP2A B56 axis promotes chromosome segregation fidelity.

Thomas J Kucharski, Irma M Vlasac, Tatiana Lyalina, Martin R Higgs, Brock C Christensen, Susanne Bechstedt, Duane A Compton.

  Cancer cells are often aneuploid and frequently display elevated rates of chromosome mis-segregation, called chromosomal instability (CIN). CIN is caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduce the correction efficiency of erroneous K-MT attachments. UMK57, a chemical agonist of the protein MCAK (mitotic centromere-associated kinesin), improves chromosome segregation fidelity in CIN cancer cells by destabilizing K-MT attachments, but cells rapidly develop resistance. To determine the mechanism, we performed unbiased screens, which revealed increased phosphorylation in cells adapted to UMK57 at Aurora kinase A phosphoacceptor sites on BOD1L1 (protein biorientation defective 1-like-1). BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression, and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of Taxol or Aurora kinase A inhibitor.

Keywords:  Aurora; CP: Cancer; CP: Cell biology; kinase; kinetochore; microtubule; mitosis; phosphatase; phosphorylation; spindle

DOI:  https://doi.org/10.1016/j.celrep.2025.115317
EMBO J. 2025 Feb 17.

Local weakening of cell-extracellular matrix adhesion triggers basal epithelial tissue folding.

Andrea Valencia-Expósito, Nargess Khalilgharibi, Ana Martínez-Abarca Millán, Yanlan Mao, María D Martín-Bermudo.

  During development, epithelial sheets sculpt organs by folding, either apically or basally, into complex 3D structures. Given the presence of actomyosin networks and cell adhesion sites on both sides of cells, a common machinery mediating apical and basal epithelial tissue folding has been proposed. However, unlike for apical folding, little is known about the mechanisms that regulate epithelial folding towards the basal side. Here, using the Drosophila wing imaginal disc and combining genetic perturbations and computational modeling, we demonstrate opposing roles for cell-cell and cell-extracellular matrix (ECM) adhesion systems during epithelial folding. While cadherin-mediated adhesion, linked to actomyosin network, regulates apical folding, a localized reduction on integrin-dependent adhesion, followed by changes in cell shape and reorganization of the basal actomyosin cytoskeleton and E-Cadherin (E-Cad) levels, is necessary and sufficient to trigger basal folding. These results suggest that modulation of the cell mechanical landscape through the crosstalk between integrins and cadherins is essential for correct epithelial folding.

Keywords:  Actomyosin; Cadherins; Constricting Forces; Integrins

DOI:  https://doi.org/10.1038/s44318-025-00384-6
Dev Cell. 2025 Feb 18. pii: S1534-5807(25)00059-0. [Epub ahead of print]

TGF-β signaling controls neural crest developmental plasticity via SMAD2/3.

Megan Rothstein, Ana Paula Azambuja, Tatiane Y Kanno, Catriona Breen, Marcos Simoes-Costa.

The neural crest is a highly plastic stem cell population that represents an exception to the germ layer theory. Despite being of ectodermal origin, cranial neural crest cells can differentiate into skeletal derivatives typically formed by mesoderm. Here, we report that SMAD2/3-mediated transforming growth factor β (TGF-β) signaling enhances neural crest developmental potential in the chicken embryo. Our results show that TGF-β signaling modulates neural crest axial identity and directly controls the gene circuits that support skeletal differentiation. Cooperation between TGF-β and low levels of WNT signaling in the embryonic head activates cranial-specific cis-regulatory elements. Activation of TGF-β signaling reprogrammed trunk neural crest cells into adopting an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGF-β signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.

DOI: https://doi.org/10.1016/j.devcel.2025.01.018
Elife. 2025 Feb 19. pii: RP87742. [Epub ahead of print]12

SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state.

Ruben Sebastian-Perez, Shoma Nakagawa, Xiaochuan Tu, Sergi Aranda, Martina Pesaresi, Pablo Aurelio Gomez-Garcia, Marc Alcoverro-Bertran, Jose Luis Gomez-Vazquez, Davide Carnevali, Eva Borràs, Eduard Sabidó, Laura Martin, Malka Nissim-Rafinia, Eran Meshorer, Maria Victoria Neguembor, Luciano Di Croce, Maria Pia Cosma.

  Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment in mice, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. By profiling the chromatin-bound proteome (chromatome) through genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos leads to developmental arrest, reduction of H3K9me3, and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.

Keywords:  2C-like cells; chromatin; developmental biology; embryonic stem cells; mouse; proteomics; regenerative medicine; stem cells

DOI:  https://doi.org/10.7554/eLife.87742
Elife. 2025 Feb 20. pii: RP98612. [Epub ahead of print]13

Combined forces of hydrostatic pressure and actin polymerization drive endothelial tip cell migration and sprouting angiogenesis.

Igor Kondrychyn, Liqun He, Haymar Wint, Christer Betsholtz, Li-Kun Phng.

  Cell migration is a key process in the shaping and formation of tissues. During sprouting angiogenesis, endothelial tip cells invade avascular tissues by generating actomyosin-dependent forces that drive cell migration and vascular expansion. Surprisingly, endothelial cells (ECs) can still invade if actin polymerization is inhibited. In this study, we show that endothelial tip cells employ an alternative mechanism of cell migration that is dependent on Aquaporin (Aqp)-mediated water inflow and increase in hydrostatic pressure. In the zebrafish, ECs express aqp1a.1 and aqp8a.1 in newly formed vascular sprouts in a VEGFR2-dependent manner. Aqp1a.1 and Aqp8a.1 loss-of-function studies show an impairment in intersegmental vessels formation because of a decreased capacity of tip cells to increase their cytoplasmic volume and generate membrane protrusions, leading to delayed tip cell emergence from the dorsal aorta and slower migration. Further inhibition of actin polymerization resulted in a greater decrease in sprouting angiogenesis, indicating that ECs employ two mechanisms for robust cell migration in vivo. Our study thus highlights an important role of hydrostatic pressure in tissue morphogenesis.

Keywords:  actin; angiogenesis; aquaporin; cell migration; developmental biology; hydrostatic pressure; water flow; zebrafish

DOI:  https://doi.org/10.7554/eLife.98612
Curr Biol. 2025 Feb 13. pii: S0960-9822(25)00073-9. [Epub ahead of print]

Rho/Rok-dependent regulation of actomyosin contractility at tricellular junctions restricts epithelial permeability in Drosophila.

Thea Jacobs, Jone Isasti Sanchez, Steven Reger, Stefan Luschnig.

  Cell contacts in epithelia are remodeled to regulate paracellular permeability and to control the passage of migrating cells, but how barrier function is modulated while preserving epithelial integrity is not clear. In the follicular epithelium of Drosophila ovaries, tricellular junctions (TCJs) open transiently in a process termed patency to allow passage of externally produced yolk proteins for uptake by the oocyte. Here, we show that modulation of actomyosin contractility at cell vertices controls TCJ permeability. Before patency, circumferential actomyosin bundles are anchored at apical follicle cell vertices, where tension-sensing junctional proteins, Rho-associated kinase (Rok), and active myosin II accumulate and maintain vertices closed. TCJ opening is initiated by redistribution of myosin II from circumferential bundles to the medial zone, accompanied by decreasing tension on vertices. This transition requires activation of Cofilin-dependent filamentous actin (F-actin) disassembly by the phosphatase Slingshot and myosin II inactivation by myosin light-chain phosphatase and is counteracted by Rok. Accordingly, constitutive activation of myosin or of Rho signaling prevents vertex opening, whereas reduced myosin II or Rok activity causes excessive vertex opening. Thus, the opening of intercellular gaps in the follicular epithelium relies on relaxation of actomyosin contractility rather than active actomyosin-based pulling forces. Conversely, F-actin assembly is required for closing intercellular gaps after patency. Our findings are consistent with a force transduction model in which TCJ integrity is maintained by vertex-anchored contractile actomyosin. We propose that the cell-type-specific organization of actomyosin at cell vertices determines the mode of contractility-dependent regulation of epithelial permeability.

Keywords:  Drosophila; Rho; actin; cell vertex; epithelial permeability; follicle epithelium; myosin; oogenesis; tricellular junction

DOI:  https://doi.org/10.1016/j.cub.2025.01.043
Nat Commun. 2025 Feb 17. 16(1): 1696

Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype.

Joae Joung, Yekang Heo, Yeonju Kim, Jaejin Kim, Haebeen Choi, Taerang Jeon, Yeji Jang, Eun-Jung Kim, Sang Heon Lee, Jae Myoung Suh, Stephen J Elledge, Mi-Sung Kim, Chanhee Kang.

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU. Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.

DOI: https://doi.org/10.1038/s41467-025-56929-0
Cell Syst. 2025 Feb 12. pii: S2405-4712(25)00031-6. [Epub ahead of print] 101198

Cold and hot fibrosis define clinically distinct cardiac pathologies.

Shoval Miyara, Miri Adler, Kfir B Umansky, Daniel Häußler, Elad Bassat, Yalin Divinsky, Jacob Elkahal, David Kain, Daria Lendengolts, Ricardo O Ramirez Flores, Hanna Bueno-Levy, Ofra Golani, Tali Shalit, Michael Gershovits, Eviatar Weizman, Alexander Genzelinakh, Danielle M Kimchi, Avraham Shakked, Lingling Zhang, Jingkui Wang, Andrea Baehr, Zachary Petrover, Rachel Sarig, Tatjana Dorn, Alessandra Moretti, Julio Saez-Rodriguez, Christian Kupatt, Elly M Tanaka, Ruslan Medzhitov, Achim Krüger, Avi Mayo, Uri Alon, Eldad Tzahor.

  Fibrosis remains a major unmet medical need. Simplifying principles are needed to better understand fibrosis and to yield new therapeutic approaches. Fibrosis is driven by myofibroblasts that interact with macrophages. A mathematical cell-circuit model predicts two types of fibrosis: hot fibrosis driven by macrophages and myofibroblasts and cold fibrosis driven by myofibroblasts alone. Testing these concepts in cardiac fibrosis resulting from myocardial infarction (MI) and heart failure (HF), we revealed that acute MI leads to cold fibrosis whereas chronic injury (HF) leads to hot fibrosis. MI-driven cold fibrosis is conserved in pigs and humans. We computationally identified a vulnerability of cold fibrosis: the myofibroblast autocrine growth factor loop. Inhibiting this loop by targeting TIMP1 with neutralizing antibodies reduced myofibroblast proliferation and fibrosis post-MI in mice. Our study demonstrates the utility of the concepts of hot and cold fibrosis and the feasibility of a circuit-to-target approach to pinpoint a treatment strategy that reduces fibrosis. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords:  TIMP1; autocrine loop; cold fibrosis; fibrosis; heart failure; hot fibrosis; macrophage; myocardial infarction; myofibroblast; regeneration

DOI:  https://doi.org/10.1016/j.cels.2025.101198
Nat Commun. 2025 Feb 17. 16(1): 1708

BMP signaling promotes zebrafish heart regeneration via alleviation of replication stress.

Mohankrishna Dalvoy Vasudevarao, Denise Posadas Pena, Michaela Ihle, Chiara Bongiovanni, Pallab Maity, Dominik Geissler, Hossein Falah Mohammadi, Melanie Rall-Scharpf, Julian Niemann, Mathilda T M Mommersteeg, Simone Redaelli, Kathrin Happ, Chi-Chung Wu, Arica Beisaw, Karin Scharffetter-Kochanek, Gabriele D'Uva, Mona Malek Mohammadi, Lisa Wiesmüller, Hartmut Geiger, Gilbert Weidinger.

In contrast to mammals, adult zebrafish achieve complete heart regeneration via proliferation of cardiomyocytes. Surprisingly, we found that regenerating cardiomyocytes experience DNA replication stress, which represents one reason for declining tissue regeneration during aging in mammals. Pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for zebrafish heart regeneration. Manipulation of Bone Morphogenetic Protein (BMP)-Smad signaling using transgenics and mutants showed that BMP signaling alleviates cardiomyocyte replication stress. BMP signaling also rescues neonatal mouse cardiomyocytes, human fibroblasts and human hematopoietic stem and progenitor cells (HSPCs) from replication stress. DNA fiber spreading assays indicate that BMP signaling facilitates re-start of replication forks after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated zebrafish heart regeneration capacity and reveal a conserved role for BMP signaling in promotion of stress-free DNA replication.

DOI: https://doi.org/10.1038/s41467-025-56993-6
Res Sq. 2025 Jan 31. pii: rs.3.rs-5875531. [Epub ahead of print]

Somatic Genomic and Transcriptomic Changes in Single Ischemic Human Heart Cardiomyocytes.

Sangita Choudhury, Nazia Hilal, Zheming An, Maksymilian Prondzynski, Erica Matsui, Debesh Sahu, Shulin Mao, Youngsook Jung, Yingxi Yang, Sonia Epstein, Ming Chen, William Pu, Federica Del Monte, August Huang.

Heart failure is a multifaceted syndrome contributing significantly to mortality and hospitalization rates among the global population1. One of the prevalent causes of heart failure is ischemic heart disease (IHD), often caused by a blockage in a coronary artery, ultimately leading to the loss of myocardial tissue and contractile force2. The impact of this ischemic ambiance on the cardiomyocyte genome and transcriptome has not been thoroughly studied. During normal aging, cardiomyocytes progressively accumulate somatic mutations faster than many dividing cells, suggesting that internal and external factors specific to cardiomyocytes might influence this accumulation3. In this study, we analyzed single-cell whole-genome and transcriptome data from the left ventricle of 5 individuals with IHD and 10 healthy control individuals. We found that somatic DNA alterations significantly increase in IHD cardiomyocytes, with distinct mutational patterns indicating a disrupted DNA repair system and a cytotoxic environment, potentially associated with increased inflammatory response in the myocardium and a compensatory anti-inflammatory response in IHD. An in vitro iPS-derived hypoxic cardiomyocyte mutational profile indicates similar mutational spectra. Transcriptomic analysis revealed increased expression of EGR1, FOS, and collagen genes in ischemic heart cardiomyocytes, leading to a more fibrotic heart. The aberrant accumulation of DNA alterations and changes in transcriptional patterns in the ischemic heart cardiomyocytes provide insight into the development of IHD.

DOI: https://doi.org/10.21203/rs.3.rs-5875531/v1
Dev Biol. 2025 Feb 19. pii: S0012-1606(25)00049-1. [Epub ahead of print]

The transmembrane glycoprotein Gpnmb is required for the immune and fibrotic responses during zebrafish heart regeneration.

Savita Gupta, Gursimran Kaur Bajwa, Hadil El-Sammak, Kenny Mattonet, Stefan Günther, Mario Looso, Didier Y R Stainier, Rubén Marín-Juez.

  Myocardial infarction occurs when the coronary supply of oxygen and nutrients to part of the heart is interrupted. In contrast to adult mammals, adult zebrafish have a remarkable ability to regenerate their heart after cardiac injury. Several processes are involved in this regenerative response including inflammation, coronary endothelial cell proliferation and revascularization, endocardial expansion, cardiomyocyte repopulation, and transient scar formation. To identify additional regulators of zebrafish cardiac regeneration, we profiled the transcriptome of regenerating coronary endothelial cells at 7 days post cryoinjury (dpci) and observed the significant upregulation of dozens of genes including gpnmb. Gpnmb (glycoprotein non-metastatic melanoma protein B) is a transmembrane glycoprotein implicated in inflammation resolution and tissue regeneration. Transcriptomic profiling data of cryoinjured zebrafish hearts reveal that gpnmb is mostly expressed by macrophages. To investigate gpnmb function during zebrafish cardiac regeneration, we generated a full locus deletion allele. We find that after cardiac cryoinjury, animals lacking gpnmb exhibit neutrophil retention and decreased macrophage recruitment as well as reduced myofibroblast numbers. Moreover, loss of gpnmb impairs coronary endothelial cell regeneration and cardiomyocyte dedifferentiation. Transcriptomic analyses of cryoinjured gpnmb-/- hearts identified enhanced collagen gene expression and the activation of extracellular matrix (ECM) related pathways. Furthermore, gpnmb-/- hearts exhibit larger fibrotic scars revealing additional defects in cardiac regeneration. Altogether, these data indicate that gpnmb, which is mostly expressed by macrophages, modulates inflammation and ECM deposition after cardiac cryoinjury in zebrafish and further highlight the importance of these immune cells during regeneration.

Keywords:  Zebrafish; cardiac regeneration; coronary; gpnmb; macrophages

DOI:  https://doi.org/10.1016/j.ydbio.2025.02.011
Nat Struct Mol Biol. 2025 Feb 21.

CTCF/RAD21 organize the ground state of chromatin-nuclear speckle association.

Ruofan Yu, Shelby Roseman, Allison P Siegenfeld, Zachary Gardner, Son C Nguyen, Khoa A Tran, Eric F Joyce, Rajan Jain, Brian B Liau, Ian D Krantz, Katherine A Alexander, Shelley L Berger.

Recent findings indicate that nuclear speckles, a distinct type of nuclear body, interact with certain chromatin regions in a ground state. Here, we report that the chromatin structural factors CTCF and cohesin are required for full ground-state association between DNA and nuclear speckles. We identified a putative speckle-targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin-nuclear speckle association, disruption of which also impaired induction of speckle-associated genes. Depletion of the cohesin-releasing factor WAPL, which stabilizes cohesin on chromatin, resulted in reinforcement of DNA-speckle contacts and enhanced inducibility of speckle-associated genes. Additionally, we observed disruption of chromatin-nuclear speckle association in patient-derived cells with Cornelia de Lange syndrome, a congenital neurodevelopmental disorder involving defective cohesin pathways. In summary, our findings reveal a mechanism for establishing the ground state of chromatin-speckle association and promoting gene inducibility, with relevance to human disease.

DOI: https://doi.org/10.1038/s41594-024-01465-6
Nat Genet. 2025 Feb 19.

Plasma proteome variation and its genetic determinants in children and adolescents.

Lili Niu, Sara Elizabeth Stinson, Louise Aas Holm, Morten Asp Vonsild Lund, Cilius Esmann Fonvig, Leonardo Cobuccio, Jonas Meisner, Helene Bæk Juel, Joao Fadista, Maja Thiele, Aleksander Krag, Jens-Christian Holm, Simon Rasmussen, Torben Hansen, Matthias Mann.

Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.

DOI: https://doi.org/10.1038/s41588-025-02089-2
Nat Commun. 2025 Feb 19. 16(1): 1772

AI-based approach to dissect the variability of mouse stem cell-derived embryo models.

Paolo Caldarelli, Luca Deininger, Shi Zhao, Pallavi Panda, Changhuei Yang, Ralf Mikut, Magdalena Zernicka-Goetz.

Recent advances in stem cell-derived embryo models have transformed developmental biology, offering insights into embryogenesis without the constraints of natural embryos. However, variability in their development challenges research standardization. To address this, we use deep learning to enhance the reproducibility of selecting stem cell-derived embryo models. Through live imaging and AI-based models, we classify 900 mouse post-implantation stem cell-derived embryo-like structures (ETiX-embryos) into normal and abnormal categories. Our best-performing model achieves 88% accuracy at 90 h post-cell seeding and 65% accuracy at the initial cell-seeding stage, forecasting developmental trajectories. Our analysis reveals that normally developed ETiX-embryos have higher cell counts and distinct morphological features such as larger size and more compact shape. Perturbation experiments increasing initial cell numbers further supported this finding by improving normal development outcomes. This study demonstrates deep learning's utility in improving embryo model selection and reveals critical features of ETiX-embryo self-organization, advancing consistency in this evolving field.

DOI: https://doi.org/10.1038/s41467-025-56908-5
Sci Adv. 2025 Feb 21. 11(8): eadr1453

Disabling leading and lagging strand histone transmission results in parental histones loss and reduced cell plasticity and viability.

Leonie Kollenstart, Alva Biran, Nicolas Alcaraz, Nazaret Reverón-Gómez, Victor Solis-Mezarino, Moritz Völker-Albert, Fion Jenkinson, Valentin Flury, Anja Groth.

In the process of DNA replication, the first steps in restoring the chromatin landscape involve parental histone recycling and new histone deposition. Disrupting histone recycling to either the leading or lagging strand induces asymmetric histone inheritance, affecting epigenome maintenance and cellular identity. However, the order and kinetics of these effects remain elusive. Here, we use inducible mutants to dissect the early and late consequences of impaired histone recycling. Simultaneous disruption of both leading (POLE4) and lagging strand (MCM2-2A) recycling pathways impairs the transmission of parental histones to newly synthesized DNA, releasing some parental histones to the soluble pool. Subsequently, H3K27me3 accumulates aberrantly during chromatin restoration in a manner preceding gene expression changes. Loss of histone inheritance and the ensuing chromatin restoration defects alter gene expression in embryonic stem cells and challenge differentiation programs and cell viability. Our findings demonstrate the importance of efficient transmission of histone-based information during DNA replication for maintaining chromatin landscapes, differentiation potential, and cellular viability.

DOI: https://doi.org/10.1126/sciadv.adr1453
Nature. 2025 Feb 19.

Mechanism for local attenuation of DNA replication at double-strand breaks.

Robin Sebastian, Eric G Sun, Michael Fedkenheuer, Haiqing Fu, SeolKyoung Jung, Bhushan L Thakur, Christophe E Redon, Gianluca Pegoraro, Andy D Tran, Jacob M Gross, Sara Mosavarpour, Nana Afua Kusi, Anagh Ray, Anjali Dhall, Lorinc S Pongor, Rafael Casellas, Mirit I Aladjem.

DNA double-strand breaks (DSBs) disrupt the continuity of the genome, with consequences for malignant transformation. Massive DNA damage can elicit a cellular checkpoint response that prevents cell proliferation1,2. However, how highly aggressive cancer cells, which can tolerate widespread DNA damage, respond to DSBs alongside continuous chromosome duplication is unknown. Here we show that DSBs induce a local genome maintenance mechanism that inhibits replication initiation in DSB-containing topologically associating domains (TADs) without affecting DNA synthesis at other genomic locations. This process is facilitated by mediators of replication and DSBs (MRDs). In normal and cancer cells, MRDs include the TIMELESS-TIPIN complex and the WEE1 kinase, which actively dislodges the TIMELESS-TIPIN complex from replication origins adjacent to DSBs and prevents initiation of DNA synthesis at DSB-containing TADs. Dysregulation of MRDs, or disruption of 3D chromatin architecture by dissolving TADs, results in inadvertent replication in damaged chromatin and increased DNA damage in cancer cells. We propose that the intact MRD cascade precedes DSB repair to prevent genomic instability, which is otherwise observed when replication is forced, or when genome architecture is challenged, in the presence of DSBs3-5. These observations reveal a previously unknown vulnerability in the DNA replication machinery that may be exploited to therapeutically target cancer cells.

DOI: https://doi.org/10.1038/s41586-024-08557-9
Sci Adv. 2025 Feb 21. 11(8): eadr9869

Noninvasive characterization of oocyte deformability in microconstrictions.

Lucie Barbier, Rose Bulteau, Behnam Rezaei, Thomas Panier, Gaëlle Letort, Elsa Labrune, Marie-Hélène Verlhac, Franck Vernerey, Clément Campillo, Marie-Emilie Terret.

Oocytes naturally present mechanical defects that hinder their development after fertilization. Thus, in the context of assisted reproduction, oocyte selection based on their mechanical properties has great potential to improve the quality of the resulting embryos and the success rate of these procedures. However, using mechanical properties as a quantifiable selective criterion requires robust and nondestructive measurement tools. This study developed a constriction-based microfluidic device that monitors the deformation of mouse oocytes under controlled pressure. The device can distinguish mechanically aberrant oocyte groups from healthy control ones. On the basis of a mathematical model, we propose that deformability measurements infer both oocyte tension and elasticity, elasticity being the most discriminating factor in our geometry. Despite force transmission during oocyte deformation, no long-term damage was observed. This noninvasive characterization of mouse oocyte deformability in microconstrictions allows for a substantial advance in assessing the mechanical properties of mammalian oocytes and has potential application as a quantifiable selective criterion in medically assisted reproduction.

DOI: https://doi.org/10.1126/sciadv.adr9869
Development. 2025 Feb 21. pii: dev.204398. [Epub ahead of print]

Distinct requirements for PI3K isoforms p110α and p110δ for PIP3 synthesis in mouse oocytes and early embryos.

Anne Bourdais, Patricia Viard, Jenny Bormann, Côme Sesboüé, Daniel Guerrier, Nicole Therville, Julie Guillermet-Guibert, John Carroll, Guillaume Halet.

  The PI3K/Akt pathway is thought to regulate key steps of mammalian oogenesis, such as dormant oocyte awakening during follicular activation, meiotic resumption and oocyte maturation. Supporting evidence is however indirect, as oocyte PI3K activation has never been formally demonstrated, and the PI3K isoforms involved have not been revealed. Here, we employed fluorescent PIP3 biosensors to characterize PI3K dynamics in mouse oocytes and we investigated the contribution of PI3K isoform p110α via conditional genetic ablation. Prophase oocytes showed baseline PI3K/Akt activation that could be further stimulated by adding Kit ligand (KitL). Contrary to previous reports, maternal PI3K proved dispensable for oocyte maturation in vitro, yet it was required for PIP3 synthesis in early embryos. We further show that oocyte p110α is not essential for oogenesis and female fertility. Accordingly, our data suggest that KitL activates isoform p110δ for PIP3 synthesis in oocytes. In contrast, constitutive PIP3 synthesis in early embryos is achieved by maternal p110α acting redundantly with p110δ. This study highlights the relevance of PIP3 biosensors in establishing the dynamics, mechanisms and roles of maternal PI3K signaling during mammalian oogenesis.

Keywords:  AKT; Kit; Mouse; Oocyte; PI3K; PIP3

DOI:  https://doi.org/10.1242/dev.204398
EMBO Rep. 2025 Feb 17.

AMPK activation by glycogen expenditure primes the exit of naïve pluripotency.

Seong-Min Kim, Eun-Ji Kwon, Ji-Young Oh, Han Sun Kim, Sunghyouk Park, Goo Jang, Jeong Tae Do, Keun-Tae Kim, Hyuk-Jin Cha.

  Embryonic and epiblast stem cells in pre-and post-implantation embryos are characterized by their naïve and primed states, respectively which represent distinct phases of pluripotency. Thus, cellular transition from naïve-to-primed pluripotency recapitulates a drastic metabolic and cellular remodeling after implantation to adapt to changes in extracellular conditions. Here, we found that inhibition of AMPK occurs during naïve transition with two conventional inhibitors of the MEK1 and GSK3β pathways. The accumulation of glycogen due to iGSK3β is responsible for AMPK inhibition, which accounts for high de novo fatty acid synthesis in naïve (ESCs). The knockout of glycogen synthase 1 in naïve ESCs; GKO, resulting in a drastic glycogen loss, leads to a robust AMPK activation and lowers the level of fatty acids. GKO loses cellular characteristics of naïve ESCs and rapidly transitioned to a primed state. The characteristics of GKO are restored by the simultaneous AMPK KO. These findings suggest that high glycogen in epiblast within pre-implantation blastocyst may act as a signaling molecule for timely activation of AMPK, thus ultimately contributing to transition to post-implantation stage epiblast.

Keywords:  AMPK; Fatty Acids; Glycogen; Pre-implantation Embryo; naïve Pluripotency

DOI:  https://doi.org/10.1038/s44319-025-00384-x
Nat Commun. 2025 Feb 17. 16(1): 1697

Copy number variants and the tangential expansion of the cerebral cortex.

IMAGEN Consortium

The tangential expansion of the human cerebral cortex, indexed by its surface area (SA), occurs mainly during prenatal and early postnatal periods, and is influenced by genetic factors. Here we investigate the role of rare copy number variants (CNVs) in shaping SA, and the underlying mechanisms, by aggregating CNVs across the genome in community-based cohorts (N = 39,015). We reveal that genome-wide CNV deletions and duplications are associated with smaller SA. Subsequent analyses with gene expression in fetal cortex suggest that CNVs influence SA by interrupting the proliferation of neural progenitor cells during fetal development. Notably, the deletion of genes with strong (but not weak) coexpression with neural progenitor genes is associated with smaller SA. Follow up analyses reveal similar mechanisms at play in three clinical CNVs, 1q21.1, 16p11.2 and 22q11.2. Together, this study of rare CNVs expands our knowledge about genetic architecture of human cerebral cortex.

DOI: https://doi.org/10.1038/s41467-025-56855-1
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
Circulation. 2025 Feb 18. 151(7): 511-514

Genes of the Fatty Acid Oxidation Pathway are Upregulated in Female as Compared to Male Cardiomyocytes.

Maya Talukdar, Lukáš Chmátal, Linyong Mao, Daniel Reichart, Danielle S Murashige, Helen Skaletsky, Daniel M DeLaughter, Zoltan Arany, Jonathan G Seidman, Christine E Seidman, David C Page.



Keywords:  metabolism; sex characteristics

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.071973
Nat Commun. 2025 Feb 14. 16(1): 1394

Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis.

Oscar Maiques, Marta C Sallan, Roman Laddach, Pahini Pandya, Adrian Varela, Eva Crosas-Molist, Jaume Barcelo, Olivia Courbot, Yanbo Liu, Vittoria Graziani, Youssef Arafat, Joanne Sewell, Irene Rodriguez-Hernandez, Bruce Fanshawe, Yaiza Jung-Garcia, Paul Rc Imbert, Eloise M Grasset, Jean Albrengues, Maria Santacana, Anna Macià, Jordi Tarragona, Xavier Matias-Guiu, Rosa M Marti, Sophia Tsoka, Cedric Gaggioli, Jose L Orgaz, Gilbert O Fruhwirth, Fredrik Wallberg, Kai Betteridge, Constantino Carlos Reyes-Aldasoro, Syed Haider, Andrejs Braun, Sophia N Karagiannis, Alberto Elosegui-Artola, Victoria Sanz-Moreno.

The extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and alignment, with unique radial fibre orientation at the distal invasive front correlating with amoeboid invasive features. Using patient samples and murine models, we find that metastases recapitulate ECM features of the primary tumour. Ex vivo culture of murine cancer cells isolated from the different tumour regions reveals a spatial cytoskeletal and transcriptional memory. Several in vitro models recapitulate the in vivo ECM organisation showing that increased matrix induces 3D confinement supporting Rho-ROCK-Myosin II activity, while radial orientation enhances directional invasion. Spatial transcriptomics identifies a mechano-inflammatory program associated with worse prognosis across multiple tumour types. These findings provide mechanistic insights into how ECM organization shapes local invasion and distant metastasis.

DOI: https://doi.org/10.1038/s41467-025-56299-7
Cell Stem Cell. 2025 Feb 13. pii: S1934-5909(25)00011-6. [Epub ahead of print]

Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.

Frances J England, Ignacio Bordeu, Minn-E Ng, JaeHak Bang, Bumsoo Kim, Jinwook Choi, Erik C Cardoso, Bon-Kyoung Koo, Benjamin D Simons, Joo-Hyeon Lee.

  Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.

Keywords:  AT2 clone dynamics; NF-κB activation; cell fate plasticity; cell plasticity; clonal modeling; lineage tracing; lung cancer; lung stem cells; regeneration program; stem cell competition; tumor ecosystem dynamics; tumor evolution

DOI:  https://doi.org/10.1016/j.stem.2025.01.011
Nature. 2025 Feb 19.

Human-correlated genetic models identify precision therapy for liver cancer.

Miryam Müller, Stephanie May, Holly Hall, Timothy J Kendall, Lynn McGarry, Lauriane Blukacz, Sandro Nuciforo, Anastasia Georgakopoulou, Thomas Jamieson, Narisa Phinichkusolchit, Sandeep Dhayade, Toshiyasu Suzuki, Júlia Huguet-Pradell, Ian R Powley, Leah Officer-Jones, Rachel L Pennie, Roger Esteban-Fabró, Albert Gris-Oliver, Roser Pinyol, George L Skalka, Jack Leslie, Matthew Hoare, Joep Sprangers, Gaurav Malviya, Agata Mackintosh, Emma Johnson, Misti McCain, John Halpin, Christos Kiourtis, Colin Nixon, Graeme Clark, William Clark, Robin Shaw, Ann Hedley, Thomas M Drake, Ee Hong Tan, Matt Neilson, Daniel J Murphy, David Y Lewis, Helen L Reeves, John Le Quesne, Derek A Mann, Leo M Carlin, Karen Blyth, Josep M Llovet, Markus H Heim, Owen J Sansom, Crispin J Miller, Thomas G Bird.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide1,2. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations3, with hepatocytes the most likely cell of origin2. However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies4. Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations5,6. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC7. Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

DOI: https://doi.org/10.1038/s41586-025-08585-z
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]

Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.

Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.

  Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

Keywords:  MPST; ergothioneine; exercise; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
Nucleic Acids Res. 2025 Feb 08. pii: gkaf056. [Epub ahead of print]53(4):

Biomolecular condensation of human IDRs initiates endogenous transcription via intrachromosomal looping or high-density promoter localization.

Jing Li, Shizhe Liu, Sunghwan Kim, Jacob Goell, Zachary Allen Drum, John Patrick Flores, Alex J Ma, Barun Mahata, Mario Escobar, Alex Raterink, Jeong Hyun Ahn, Erik R Terán, Rosa Selenia Guerra-Resendez, Yuhao Zhou, Bo Yu, Michael R Diehl, Gang Greg Wang, Anna-Karin Gustavsson, Douglas H Phanstiel, Isaac B Hilton.

Protein intrinsically disordered regions (IDRs) are critical gene-regulatory components and aberrant fusions between IDRs and DNA-binding/chromatin-associating domains cause diverse human cancers. Despite this importance, how IDRs influence gene expression, and how aberrant IDR fusion proteins provoke oncogenesis, remains incompletely understood. Here we develop a series of synthetic dCas9-IDR fusions to establish that locus-specific recruitment of IDRs can be sufficient to stimulate endogenous gene expression. Using dCas9 fused to the paradigmatic leukemogenic NUP98 IDR, we also demonstrate that IDRs can activate transcription via localized biomolecular condensation and in a manner that is dependent upon overall IDR concentration, local binding density, and amino acid composition. To better clarify the oncogenic role of IDRs, we construct clinically observed NUP98 IDR fusions and show that, while generally non-overlapping, oncogenic NUP98-IDR fusions convergently drive a core leukemogenic gene expression program in donor-derived human hematopoietic stem cells. Interestingly, we find that this leukemic program arises through differing mechanistic routes based upon IDR fusion partner; either distributed intragenic binding and intrachromosomal looping, or dense binding at promoters. Altogether, our studies clarify the gene-regulatory roles of IDRs and, for the NUP98 IDR, connect this capacity to pathological cellular programs, creating potential opportunities for generalized and mechanistically tailored therapies.

DOI: https://doi.org/10.1093/nar/gkaf056
Nat Cell Biol. 2025 Feb 21.

Intratumour oxidative hotspots provide a niche for cancer cell dissemination.

Yoshifumi Ueda, Shigeki Kiyonaka, Laura M Selfors, Keisuke Inoue, Hiroshi Harada, Tomohiro Doura, Kunishige Onuma, Makoto Uchiyama, Ryuhei Kurogi, Yuji Yamada, Jiacheng H Sun, Reiko Sakaguchi, Yuki Tado, Haruki Omatsu, Harufumi Suzuki, Mike Aoun, Takahiro Nakayama, Taketoshi Kajimoto, Tetsuya Yano, Rikard Holmdahl, Itaru Hamachi, Masahiro Inoue, Yasuo Mori, Nobuaki Takahashi.

Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial-mesenchymal transition through p38-MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation.

DOI: https://doi.org/10.1038/s41556-025-01617-w
Curr Biol. 2025 Feb 14. pii: S0960-9822(25)00125-3. [Epub ahead of print]

Compositionally unique mitochondria in filopodia support cellular migration.

Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen, Jonathan R Friedman.

  Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.

Keywords:  MCU; MICOS; MYO19; calcium; cristae; filopodia; migration; mitochondria; organelle

DOI:  https://doi.org/10.1016/j.cub.2025.01.062
Cell. 2025 Feb 12. pii: S0092-8674(25)00103-5. [Epub ahead of print]

Reprogrammable RNA-targeting CRISPR systems evolved from RNA toxin-antitoxins.

Shai Zilberzwige-Tal, Han Altae-Tran, Soumya Kannan, Max E Wilkinson, Samuel Chau-Duy-Tam Vo, Daniel Strebinger, KeHuan K Edmonds, Chun-Chen Jerry Yao, Kepler S Mears, Sergey A Shmakov, Kira S Makarova, Rhiannon K Macrae, Eugene V Koonin, Feng Zhang.

  Despite ongoing efforts to study CRISPR systems, the evolutionary origins giving rise to reprogrammable RNA-guided mechanisms remain poorly understood. Here, we describe an integrated sequence/structure evolutionary tracing approach to identify the ancestors of the RNA-targeting CRISPR-Cas13 system. We find that Cas13 likely evolved from AbiF, which is encoded by an abortive infection-linked gene that is stably associated with a conserved non-coding RNA (ncRNA). We further characterize a miniature Cas13, classified here as Cas13e, which serves as an evolutionary intermediate between AbiF and other known Cas13s. Despite this relationship, we show that their functions substantially differ. Whereas Cas13e is an RNA-guided RNA-targeting system, AbiF is a toxin-antitoxin (TA) system with an RNA antitoxin. We solve the structure of AbiF using cryoelectron microscopy (cryo-EM), revealing basic structural alterations that set Cas13s apart from AbiF. Finally, we map the key structural changes that enabled a non-guided TA system to evolve into an RNA-guided CRISPR system.

Keywords:  CRISPR; Cas13; RNA-guided mechanism; bacterial immunity; toxin-antitoxin system

DOI:  https://doi.org/10.1016/j.cell.2025.01.034
Nat Aging. 2025 Feb 17.

Uncovering a gut microbiota-derived metabolite that triggers host cellular senescence.

DOI: https://doi.org/10.1038/s43587-025-00831-3
Nat Rev Cardiol. 2025 Feb 19.

Roadmap for alleviating the manifestations of ageing in the cardiovascular system.

Luca Liberale, Simon Tual-Chalot, Simon Sedej, Stefano Ministrini, Georgios Georgiopoulos, Myriam Grunewald, Magnus Bäck, Marie-Luce Bochaton-Piallat, Reinier A Boon, Gustavo Campos Ramos, Menno P J de Winther, Konstantinos Drosatos, Paul C Evans, Jane F Ferguson, Sofia K Forslund-Startceva, Claudia Goettsch, Mauro Giacca, Judith Haendeler, Marinos Kallikourdis, Daniel F J Ketelhuth, Rory R Koenen, Patrick Lacolley, Esther Lutgens, Pasquale Maffia, Satomi Miwa, Claudia Monaco, Fabrizio Montecucco, Giuseppe Danilo Norata, Elena Osto, Gavin D Richardson, Niels P Riksen, Oliver Soehnlein, Ioakim Spyridopoulos, Sophie Van Linthout, Gemma Vilahur, Jolanda J Wentzel, Vicente Andrés, Lina Badimon, Athanase Benetos, Christoph J Binder, Ralf P Brandes, Filippo Crea, David Furman, Vera Gorbunova, Tomasz J Guzik, Joseph A Hill, Thomas F Lüscher, María Mittelbrunn, Alessio Nencioni, Mihai G Netea, João F Passos, Kimon S Stamatelopoulos, Nektarios Tavernarakis, Zoltan Ungvari, Joseph C Wu, James L Kirkland, Giovanni G Camici, Stefanie Dimmeler, Guido Kroemer, Mahmoud Abdellatif, Konstantinos Stellos.

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.

DOI: https://doi.org/10.1038/s41569-025-01130-5
Cell Rep. 2025 Feb 11. pii: S2211-1247(25)00057-9. [Epub ahead of print] 115286

The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells.

May Nakajima-Koyama, Mio Kabata, Joonseong Lee, Yuko Sogabe, Satoko Sakurai, Akira Hirota, Mizuki Kimura, Tomonori Nakamura, Yusuke Imoto, Kohei Kometani, Yoko Hamazaki, Yasuaki Hiraoka, Mitinori Saitou, Eisuke Nishida, Takuya Yamamoto.

  While the intestinal epithelium has the highest cellular turnover rates in the mammalian body, it is also considered one of the tissues most resilient to aging-related disorders. Here, we reveal an innate protective mechanism that safeguards intestinal stem cells (ISCs) from environmental conditions in the aged intestine. Using in vivo phenotypic analysis, transcriptomics, and in vitro intestinal organoid studies, we show that age-dependent activation of interferon-γ (IFN-γ) signaling and inactivation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling are responsible for establishing an equilibrium of Lgr5+ ISCs-between active and quiescent states-to preserve the ISC pool during aging. Furthermore, we show that differentiated cells have different sensitivities to each of the two signaling pathways, which may induce aging-related, functional, and metabolic changes in the body. Thus, our findings reveal an exquisitely balanced, age-dependent signaling mechanism that preserves stem cells at the expense of differentiated cells.

Keywords:  CP: Stem cell research; ERK/MAPK signaling pathway; IFN-γ signaling pathway; aging; intestinal stem cells

DOI:  https://doi.org/10.1016/j.celrep.2025.115286
Nat Rev Genet. 2025 Feb 21.

Intrinsically disordered regions as facilitators of the transcription factor target search.

Felix Jonas, Yoav Navon, Naama Barkai.

Transcription factors (TFs) contribute to organismal development and function by regulating gene expression. Despite decades of research, the factors determining the specificity and speed at which eukaryotic TFs detect their target binding sites remain poorly understood. Recent studies have pointed to intrinsically disordered regions (IDRs) within TFs as key regulators of the process by which TFs find their target sites on DNA (the TF target search). However, IDRs are challenging to study because they can confer specificity despite low sequence complexity and can be functionally conserved despite rapid sequence divergence. Nevertheless, emerging computational and experimental approaches are beginning to elucidate the sequence-function relationship within the IDRs of TFs. Additional insights are informing potential mechanisms underlying the IDR-directed search for the DNA targets of TFs, including incorporation into biomolecular condensates, facilitating TF co-localization, and the hypothesis that IDRs recognize and directly interact with specific genomic regions.

DOI: https://doi.org/10.1038/s41576-025-00816-3
Nat Commun. 2025 Feb 20. 16(1): 1801

Actin-dependent α-catenin oligomerization contributes to adherens junction assembly.

Regina B Troyanovsky, Indrajyoti Indra, Sergey M Troyanovsky.

Classic cadherins, specifically E-cadherin in most epithelial cells, are transmembrane adhesion receptors, whose intracellular region interacts with proteins, termed catenins, forming the cadherin-catenin complex (CCC). The cadherin ectodomain generates 2D adhesive clusters (E-clusters) through cooperative trans and cis interactions, while catenins anchor the E-clusters to the actin cytoskeleton. How these two types of interactions are coordinated in the formation of specialized cell-cell adhesions, adherens junctions (AJ), remains unclear. Here, we focus on the role of the actin-binding domain of α-catenin (αABD) by showing that the interaction of the αABD with actin generates actin-bound linear CCC oligomers (CCC/actin strands) incorporating up to six CCCs. This actin-driven CCC oligomerization, which is cadherin ectodomain independent, preferentially occurs along the actin cortex enriched with key basolateral proteins, myosin-1c, scribble, and DLG1. In cell-cell contacts, the CCC/actin strands integrate with the E-clusters giving rise to the composite oligomers, E/actin clusters. Targeted inactivation of strand formation by point mutations emphasizes the importance of this oligomerization process for blocking intercellular protrusive membrane activity and for coupling AJs with the actomyosin-derived tensional forces.

DOI: https://doi.org/10.1038/s41467-025-57079-z
Curr Biol. 2025 Feb 14. pii: S0960-9822(25)00118-6. [Epub ahead of print]

Centromeres are stress-induced fragile sites.

Daniel Kolbin, Maëlle Locatelli, John Stanton, Katie Kesselman, Aryan Kokkanti, Jinghan Li, Elaine Yeh, Kerry Bloom.

  Centromeres are unique loci on eukaryotic chromosomes and are complexed with centromere-specific histone H3 molecules (CENP-A in mammals, Cse4 in yeast). The centromere provides the binding site for the kinetochore that captures microtubules and provides the mechanical linkage required for chromosome segregation. Centromeres encounter fluctuations in force as chromosomes jockey for position on the metaphase spindle. We have developed biological assays to examine the response of centromeres to high force. Torsional stress is induced on covalently closed DNA circles from supercoiling. Plasmid-borne centromeres with single-nucleotide inactivating mutations exhibit a high conversion frequency to plasmid dimer species. Conversion to dimers is dependent on the activity of the Rad1 single-strand endonuclease, indicative of unwinding a region of the centromere sequence in the absence of a functional kinetochore. To determine the region of unwinding, we used conditionally functional dicentric chromosomes to exert tension. Centromere DNA is exquisitely sensitive to cleavage following activation of the dicentric chromosome. Cleavage is dependent on the action of Rad1, highlighting the propensity of centromeres to unwind in response to supercoiling or mechanical stress. These studies provide mechanistic insights into the evolution of AT-rich pericentromere DNA throughout phylogeny and suggest a mechanism for stress-induced error correction at the centromere.

Keywords:  CENP-A nucleosome; DSB; Rad1 nuclease; centromere DNA; fragile sites; supercoiling tension

DOI:  https://doi.org/10.1016/j.cub.2025.01.055
Cell. 2025 Feb 12. pii: S0092-8674(25)00098-4. [Epub ahead of print]

HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.

Skyler Y Blume, Ankur Garg, Yolanda Martí-Mateos, Ayush D Midha, Brandon T L Chew, Baiwei Lin, Cecile Yu, Ryan Dick, Patrick S Lee, Eva Situ, Richa Sarwaikar, Eric Green, Vyas Ramanan, Gijsbert Grotenbreg, Maarten Hoek, Christopher Sinz, Isha H Jain.

  We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.

Keywords:  Leigh syndrome; hemoglobin; hyperoxia; hypoxia; mitochondrial disease; oxygen; red blood cells; therapy

DOI:  https://doi.org/10.1016/j.cell.2025.01.029
Nat Commun. 2025 Feb 19. 16(1): 1599

Spatio-temporal control of mitosis using light via a Plk1 inhibitor caged for activity and cellular permeability.

Victoria von Glasenapp, Ana C Almeida, Dalu Chang, Ivana Gasic, Nicolas Winssinger, Monica Gotta.

The ability to control the activity of kinases spatially and temporally is essential to elucidate the role of signalling pathways in development and physiology. Progress in this direction has been hampered by the lack of tools to manipulate kinase activity in a highly controlled manner in vivo. Here we report a strategy to modify BI2536, the well characterized inhibitor of the conserved and essential mitotic kinase Polo-like kinase 1 (Plk1). We introduce the same coumarin photolabile protecting group (PPG) at two positions of the inhibitor. At one position, the coumarin prevents the interaction with Plk1, at the second it masks an added carboxylic acid, important for cellular retention. Exposure to light results in removal of both PPGs, leading to the activation of the inhibitor and its trapping inside cells. We demonstrate the efficacy of the caged inhibitor in three-dimensional spheroid cultures: by uncaging it with a single light pulse, we can inhibit Plk1 and arrest cell division, a highly dynamic process, with spatio-temporal control. Our design can be applied to other small molecules, providing a solution to control their activity in living cells with unprecedented precision.

DOI: https://doi.org/10.1038/s41467-025-56746-5
Nature. 2025 Feb 19.

Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.

Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.

Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.

DOI: https://doi.org/10.1038/s41586-025-08590-2