bims-ginsta 2026-04-26 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–04–26
forty-one papers selected by
Jinrong Hu, National University of Singapore

Myosin forces remodel F-actin for mechanosensitive protein recognition.
Piezo1-mediated mechanohydraulic control of cell volume drives cardiac morphogenesis.
mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.
Microtubule dynamics control the direction of cardiomyocyte growth.
Actomyosin contractility is a potent suppressor of mesoderm induction by human pluripotent stem cells.
Patterns of mitochondrial ATP predict tissue folding.
Maladaptive Inflammatory Signaling in Old Mice Impairs Colonic Regeneration by Promoting a Sustained Fetal-Like Epithelial State.
Subcellular mRNA localization patterns across tissues resolved with spatial transcriptomics.
Polyploidy reprograms epithelial cells for motility and phagocytosis via stress signaling.
The proteomic landscape and temporal dynamics of human and mouse gastruloid development.
Slow RNAPII elongation enhances naive pluripotency rewiring while maintaining high replication fork speed.
Dynamic blebbing and absence of organelle transfer during mouse oocyte formation.
A time-resolved atlas of histone modifications during mitotic entry.
Early fibrotic niches establish tumour-permissive microenvironments.
A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.
A conserved hormonal signalling-H2A.Z axis rapidly reorganizes 3D chromatin interactions in adipocyte thermogenesis.
Mechanical load inhibits cancer growth in mouse and human hearts.
Time-resolved single-cell transcriptomics maps zebrafish heart development.
2'3'-cGAMP-induced membrane shearing promotes broad antiphage immunity.
OSK-mediated partial reprogramming induces cardiomyocyte dedifferentiation, overcomes cytokinesis barriers, and promotes post-MI endogenous cardiac regeneration.
Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.
PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.
Quiescent neural stem cells transiently become neuron-like to coordinate long-range reactivation.
A Fkh1/2 binding site array in the WHI5 promoter drives sub-scaling transcription.
p53 safeguards chemical reprogramming of human somatic cells toward pluripotency.
Integrated single-cell whole genome sequencing and spatial transcriptomics reveal intra-tumoral heterogeneity in ovarian cancer.
Somatic cancer variants enriched in Alzheimer's disease microglia-like cells drive inflammatory and proliferative states.
B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.
ATR and TopBP1 oppose to control dormant origin activity and global replication dynamics, providing a first defense against replication stress.
The vault associates with membranes in situ.
rRNA expansion segments mediate ribosome dimerization as a conserved stress response.
Ubiquitination of glycogen and metabolites in cells and tissues.
Transitional Cell States at the Crossroad of Development, Disease, and Repair-Regeneration.
Severe obesity in human HFpEF alters contractile protein function and organization.
Directional guidance to orient Schwann cell alignment in nerve regeneration requires Plexin-B1.
Microtubule organization and molecular architecture of ciliary basal bodies in multiciliated airway cells.
Deciphering the dual effects of transcription on DNA replication elongation by replication-associated Micro-C.
Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation.
TMEM87A suppresses ferroptosis and increases cancer immunotherapy resistance by maintaining the Golgi apparatus pH homeostasis.
From Bump to Pump: Extracellular Matrix Remodeling, Dynamics, and Biomechanics in the Maternal Heart.

Nature. 2026 Apr 22.

Myosin forces remodel F-actin for mechanosensitive protein recognition.

Ayala G Carl, Matthew J Reynolds, Xiaoyu Sun, Pinar S Gurel, Donovan Y Z Phua, Keith Hamilton, Lin Mei, John W Watters, Yasuharu Takagi, Alex J Noble, James R Sellers, Gregory M Alushin.

Cells interface mechanically with their surroundings through cytoskeleton-linked adhesions1,2, which enable them to sense physical cues that instruct development and drive diseases such as cancer3-5. Contractile forces generated by myosin motor proteins6,7 mediate these mechanical signal transduction processes through unknown protein structural mechanisms. Here we show that force generated by myosin elicits structural changes in actin filaments (F-actin) that modulate binding by the mechanosensitive adhesion protein α-catenin8. Using correlative cryo-fluorescence microscopy and cryo-electron tomography, we identify F-actin featuring sinusoidal regions of nanoscale oscillating curvature at cytoskeleton-adhesion interfaces enriched in zyxin, a marker of actin-myosin-generated traction forces9. We introduce a reconstitution system for visualizing F-actin in the presence of myosin forces using cryo-electron microscopy, which reveals morphologically similar F-actin supercoils. In simulations, compressive forces that mimic myosin activity produce supercoils, which can be generated by ensembles of asynchronous motors regardless of their directionality. Three-dimensional reconstruction of supercoils uncovers extensive asymmetric remodelling of the helical lattice of F-actin. This is recognized by α-catenin, which binds cooperatively along individual strands, preferentially engaging interfaces that feature extended inter-subunit distances while simultaneously suppressing rotational deviations to regularize the lattice. In sum, we find that myosin forces can deform F-actin, generating a conformational landscape that is detected and reciprocally modulated by a mechanosensitive protein, providing a direct structural glimpse at active force transduction through the cytoskeleton.

DOI: https://doi.org/10.1038/s41586-026-10398-7
Sci Adv. 2026 Apr 24. 12(17): eaea7025

Piezo1-mediated mechanohydraulic control of cell volume drives cardiac morphogenesis.

Christina Vagena-Pantoula, Konstantinos Kalyviotis, Shuyi Feng, Antoine Sanchez, Igor Kondrychyn, Moe Fukumoto, Xiangbin Pan, Thomas Juan, Didier Y R Stainier, Periklis Pantazis, Li-Kun Phng, Julien Vermot.

Organ morphogenesis is driven by physical forces, yet how mechanical stimuli pattern tissue shape and guide developmental programs remains poorly understood. In zebrafish, endocardial cells (EdCs) within the heart valve-forming region undergo marked volume reduction during early morphogenesis. Here, we uncover a hydraulics-based mechanism by which mechanical forces control EdC volume to direct cardiac development. We show that the mechanosensitive ion channel Piezo1 acts with the calcium-binding protein calmodulin (CaM) and the aquaporin Aqp8a.1 water channel to orchestrate EdC shrinkage. We find that Aqp8a.1 mediates cell volume loss by incorporating into the plasma membrane in response to mechanical stimulation, promoting heart looping and valve formation. Mechanistically, Piezo1 governs Aqp8a.1 through a dual mechanism. First, Piezo1 and CaM drive Aqp8a.1 plasma membrane incorporation, enabling rapid cell volume adjustments. Second, Piezo1 suppresses aqp8a.1 transcription via Notch1b signaling to prevent excessive shrinkage. Together, these findings reveal that mechanotransduction can dictate organ formation through dynamic cell volume regulation, uncovering a fundamental principle of morphogenesis.

DOI: https://doi.org/10.1126/sciadv.aea7025
Sci Signal. 2026 Apr 21. 19(934): eadu5769

mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation.

Keita Uchida, Emily A Scarborough, Elizabeth Pruzinsky, Kathlyene R Stone, Hali Hartman, Daniel P Kelly, Jonathan J Edwards, Izhak Kehat, Benjamin L Prosser.

Cardiomyocytes depend on local translation for growth and can undergo directed growth in length or width in response to different stimuli. Protein synthesis is augmented during concentric hypertrophy, which leads to thickening of the heart muscle by increasing cardiomyocyte width. Protein synthesis is controlled at the translation initiation step, when ribosome loading onto transcripts is regulated by the sequential phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Here, we identified a mode of 4EBP1 phosphorylation that was associated with concentric hypertrophy in cultured cardiomyocytes and mouse hearts. Whereas canonical phosphorylation of 4EBP1 by mTORC1 regulates global protein synthesis rates, mTORC1- and nuclear ERK-dependent phosphorylation of 4EBP1 was specifically activated during concentric but not eccentric hypertrophy. Nuclear ERK-dependent phosphorylation of 4EBP1 at Ser64 was necessary and sufficient to relocalize translation initiation sites closer to the nuclei. ERK activation drove redistribution of ribosomes and nascent translation toward the center of the cardiomyocyte without altering global mRNA distribution, leading to spatially enriched deposition of new sarcomeric protein in the cardiomyocyte interior. Together, these findings demonstrate that global protein synthesis can be spatially regulated by the activation of different kinases in distinct subcellular compartments and identify a mechanism that drives concentric hypertrophy.

DOI: https://doi.org/10.1126/scisignal.adu5769
Science. 2026 Apr 23. eadz1970

Microtubule dynamics control the direction of cardiomyocyte growth.

Emily A Scarborough, Rani M Randell, Keita Uchida, Kathlyene R Stone, Kenneth B Margulies, Benjamin L Prosser.

The adult heart grows by addition of sarcomeres along the length or width of individual cardiomyocytes, yet how directional growth is spatially coordinated remains unclear. Here, we found that microtubule dynamics could act as a toggle to direct cardiomyocyte growth. Increasing microtubule stability drove cellular widening, concomitant with redirecting mRNA export and translation along the width of the cell and reinforcement of the intercalated disc. Conversely, decreasing microtubule stability promoted cellular lengthening, disrupting the intercalated disc and biasing translation and incorporation of new sarcomeric protein toward this structure. Notably, disrupting intercalated disc adhesion was sufficient for cardiomyocyte elongation, yet dispensable for cardiomyocyte widening. Thus, the heart coordinates local translation and structural remodeling to orchestrate bidirectional growth.

DOI: https://doi.org/10.1126/science.adz1970
J Cell Biol. 2026 May 04. pii: e202507103. [Epub ahead of print]225(5):

Actomyosin contractility is a potent suppressor of mesoderm induction by human pluripotent stem cells.

Loic Fort, Vaishna Vamadevan, Wenjun Wang, Ian G Macara.

Activation of WNT signaling in human pluripotent stem cells efficiently drives lateral mesoderm specification and subsequent cardiomyocyte differentiation. Stabilization of the WNT effector β-catenin induces mesodermal genes such as TBXT (Brachyury) and triggers an epithelial-mesenchymal transition (EMT). Although mechanical forces are essential for embryonic development, the role of actomyosin contractility during human mesoderm specification remains unclear. We show that increasing contractility through constitutively active Rho kinase or myosin light-chain kinase unexpectedly blocks β-catenin-dependent mesoderm induction and prevents EMT. In contrast, pharmacological or genetic suppression of contractility enhances Brachyury expression and advances EMT onset by 24 h. While β-catenin signaling alone promotes colony-level contractility, we find that contractility must be reduced prior to WNT activation to promote mesoderm specification, indicating a sensitization effect at the pluripotent state. Mechanistically, reduced tension decreases junctional β-catenin and increases nuclear active β-catenin, identifying actomyosin contractility as a key regulator of lineage commitment following WNT pathway activation.

DOI: https://doi.org/10.1083/jcb.202507103
Sci Adv. 2026 Apr 24. 12(17): eaee6175

Patterns of mitochondrial ATP predict tissue folding.

Bezia Lemma, Megan Rothstein, Pengfei Zhang, Bridget Waas, Marcus Kilwein, Safiya Topiwala, Sherry X Zhang, Anvitha Sudhakar, Katharine Goodwin, Elizabeth R Gavis, Ricardo Mallarino, Andrej Kosmrlj, Celeste M Nelson.

The construction of tissue shapes during embryonic development results from patterns of gene expression and mechanical forces fueled by chemical energy from ATP hydrolysis. We find that chemical energy is similarly patterned during apical constriction, which is widely used across the animal kingdom to fold epithelial tissues. Time-lapse imaging, spatial transcriptomics, and measurements of oxygen consumption rate reveal that mitochondrial density, potential, and ATP increase at the apical side of epithelial cells before actomyosin contraction and tissue folding, which is prevented by inhibiting oxidative phosphorylation. Mitochondrial enrichment and apical bias are conserved during apical constriction in flies, chicks, and mice, and these patterns can be used to predict computationally patterns of tissue folding. These findings highlight a spatial dimension of bioenergetics in development.

DOI: https://doi.org/10.1126/sciadv.aee6175
Aging Cell. 2026 May;25(5): e70495

Maladaptive Inflammatory Signaling in Old Mice Impairs Colonic Regeneration by Promoting a Sustained Fetal-Like Epithelial State.

Antonion Korcari, Helen Tauc, Jeff Duggan, Jina Yun, Fabien Wehbe, Spyros Darmanis, Zora Modrusan, Rajita Pappu, David Garfield, Heinrich Jasper, David Castillo-Azofeifa.

  Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake a comprehensive assessment of age-related changes in the mouse colon at single-cell resolution. A survey of immune and epithelial compartments revealed a hyperactivated inflammatory state in the colon of old mice characterized, among other changes, by the induction of an interferon γ (IFNγ) response signature in immune cells. This does not result in increased inflammatory signatures in the epithelium under homeostasis but triggers a disproportionate inflammatory response that disrupts regeneration and epithelial integrity after challenge with the enteropathogen Citrobacter rodentium. Colons of old mice exhibit higher production of IFNγ by T and innate lymphoid cells (ILCs) that are associated with reduced Lgr5+ stem cells and decreased epithelial proliferation. Interestingly, we find that aged intestinal epithelial cells express an elevated regeneration-associated fetal-like gene expression signature that, in turn, renders these cells more sensitive to IFNγ-induced apoptosis. Our findings reveal an age-related imbalance in the interaction between the immune and epithelial compartments in the colon, priming the system for excessive inflammatory responses and the emergence of a hypersensitive epithelial cell state thus derailing proper repair of the intestinal epithelium after injury.

Keywords:  IFNγ; aging; fetal‐like reversion; inflammaging; inflammation; intestine; regeneration; regenerative medicine

DOI:  https://doi.org/10.1111/acel.70495
Nat Commun. 2026 Apr 20.

Subcellular mRNA localization patterns across tissues resolved with spatial transcriptomics.

Roy Novoselsky, Ofra Golani, Tal Barkai, Merav Kedmi, Inna Goliand, Michal Fine, Ilan Kent, Ido Nachmany, Shalev Itzkovitz.

Subcellular RNA localization, including nuclear retention and apical-basal compartmentalization in polarized epithelia plays a central role in post-transcriptional regulation. However, methods for high-throughput mapping of mRNA localization within intact tissue sections remain limited. Here, we apply high-resolution spatial transcriptomics to systematically resolve intracellular mRNA localization across diverse mammalian tissues. We introduce a computational approach that leverages image-derived features to extract subcellular information from spatial data and quantifies transcript localization patterns. Using this framework, we map apical-basal mRNA localization and nuclear retention in gastrointestinal epithelia and in liver hepatocytes. Our analyses reveal conserved and tissue-specific localization signatures. This approach broadens the scope of spatial transcriptomics by enabling routine investigation of intracellular RNA distributions in both healthy and diseased tissues.

DOI: https://doi.org/10.1038/s41467-026-72156-7
J Cell Biol. 2026 May 04. pii: e202507096. [Epub ahead of print]225(5):

Polyploidy reprograms epithelial cells for motility and phagocytosis via stress signaling.

Youfang Zhou, Xianfeng Wang, Xiaochao Tan, Shingo Nara, Yi-Chun Huang, Yoichiro Tamori, Wu-Min Deng.

Polyploidy, an increase in cellular genome content, is a conserved developmental program and a hallmark of malignant cancer, yet its impact on cell behavior remains poorly understood. Here, we show that induction of polyploidy in otherwise diploid cells causes intrinsic stress that reprograms cellular physiology to promote motility-like and phagocytic behaviors. Using the Drosophila wing imaginal disc, we find that induced polyploidy enhances membrane dynamics and triggers dynamic cell behavior through a ROS-JNK stress axis activated by ER stress. These cells also acquire phagocytic activity, engulfing both dead and live neighboring cells in developmental and tumor contexts. This stress-induced reprogramming is conserved in induced poly-aneuploid mammalian cancer cells, linking increased genomic content to metastatic traits. Our findings uncover a conserved role for induced polyploidy in driving stress-responsive and immune cell-like behaviors, revealing how elevated ploidy can reshape epithelial function during development and disease.

DOI: https://doi.org/10.1083/jcb.202507096
Nat Cell Biol. 2026 Apr 24.

The proteomic landscape and temporal dynamics of human and mouse gastruloid development.

Riddhiman K Garge, Valerie Lynch, Rose Fields, Silvia Casadei, Sabrina Best, Jeremy Stone, Matthew Snyder, Connor Kubo, Arata Wakimoto, Zukai Liu, Chris D McGann, Jay Shendure, Lea M Starita, Nobuhiko Hamazaki, Devin K Schweppe.

The embryo establishes a body plan and primes itself for organogenesis during gastrulation. As gastrulation is challenging to study in vivo, stem-cell-derived 'gastruloids' have emerged as powerful surrogates. Although transcriptomics and imaging have been applied extensively to such embryo models, the dynamics of their proteomes remains largely unknown. Here we apply quantitative proteomics to human and mouse gastruloids at four key stages. We leverage these data to map the expression dynamics of protein complexes, and to nominate cooperative proteins. With matched transcriptome data, we investigate global and stage-specific discordance between the transcriptome and proteome and leverage phosphosite dynamics to nominate kinase-substrate relationships. Finally, we apply co-regulation network analysis to identify genes linked to the Commander complex, the perturbation of which leads to morphological defects in gastruloids. Altogether, our work showcases the potential of applying proteomics to embryo models to advance our understanding of mammalian development in ways challenging through transcriptomics alone.

DOI: https://doi.org/10.1038/s41556-026-01937-5
Sci Adv. 2026 Apr 24. 12(17): eadz6211

Slow RNAPII elongation enhances naive pluripotency rewiring while maintaining high replication fork speed.

Sara Martín-Vírgala, Joana Segura, Alicia Gallego, Ran Tong, Sara Tur-Gracia, Jesús Rafael Rodriguez-Aguilera, Biswajit Das, Javier Isoler-Alcaraz, Carlos Gallego-García, Shraddha Shinde, Magdalena M Maslon, Andrei Chabes, Lothar Schermelleh, María Gómez.

DNA replication and transcription must be intricately coordinated as both machineries navigate the same chromatin landscape to ensure genome stability and proper cell function. Here, we show that altering their elongation rates-specifically, slowed transcriptional elongation alongside rapid replication fork progression-does not elicit replicative stress. Instead, this independent kinetic variation accelerates the acquisition of naive pluripotency during in vitro dedifferentiation, revealing an unexpected link between transcription kinetics and cell plasticity. Mechanistically, we show that the transition to naive pluripotency is accompanied by a distinctive alternative splicing program indicative of reduced RNA polymerase II (RNAPII) elongation. These findings redefine the functional relationship between replication and transcription dynamics and uncover transcriptional velocity as a tunable layer of control over cellular identity transitions.

DOI: https://doi.org/10.1126/sciadv.adz6211
EMBO J. 2026 Apr 21.

Dynamic blebbing and absence of organelle transfer during mouse oocyte formation.

Eishi Aizawa, So Shimamoto, Eriko Kajikawa, Junko Hara, Takaya Abe, Hiroki Shibuya, Tomoya S Kitajima.

Oocyte formation in mammals is a tightly regulated process essential for female fertility, yet the underlying mechanisms remain poorly understood. In this study, we establish an ex vivo culture system that faithfully recapitulates in vivo development and enables long-term live imaging of mouse fetal ovaries. Using high resolution imaging, we capture the dynamic behaviors of germ cells during the development from oogonia to nascent oocytes. We identify pronounced blebbing activity during the mitosis-to-meiosis transition. This behavior is regulated by meiotic initiation signals, underscoring its potential developmental relevance, although its precise role remains unclear. A prevailing model suggests that oocyte formation involves organelle transfer from neighboring germ cells during cyst breakdown. However, through photoconversion-based tracking, we observe no detectable transfer of mitochondria or centrosomes, as organelles remain confined to individual cells. These findings point to alternative mechanisms for cytoplasmic enrichment in oocytes. Our study provides new insights into mammalian oocyte formation and establishes a powerful platform for analyzing germ cell dynamics in real time.

DOI: https://doi.org/10.1038/s44318-026-00780-6
Mol Cell. 2026 Apr 23. pii: S1097-2765(26)00234-0. [Epub ahead of print]

A time-resolved atlas of histone modifications during mitotic entry.

Natalia Y Kochanova, Moonmoon Deb, Marco Borsò, Shaun Webb, Ipek Ustun, Kumiko Samejima, Ignasi Forne, Itaru Samejima, Caitlin Reid, Linfeng Xie, James R Paulson, Axel Imhof, William C Earnshaw.

  Mitotic chromosome formation is essential for faithful chromosome segregation in metazoans. Although condensin complexes are critical for the formation of rod-shaped mitotic chromosomes, histone phosphorylation and deacetylation have been proposed to contribute to a further 2- to 4-fold reduction in mitotic chromatin volume. Here, we employ high-resolution mass spectrometry to determine the kinetics of histone modifications in cell cultures undergoing highly synchronous mitotic entry. Our analysis reveals three temporally distinct programs of histone H3 phosphorylation on T3, S10, and S28 that could differentially regulate the association of readers with chromatin via methyl-phos switching. Mass spectrometry, quantitative chromatin immunoprecipitation sequencing (ChIP-seq), ChIP-qPCR, and immunofluorescence analyses reveal that H3 T3 phosphorylation is a mitosis-specific marker of heterochromatin, whose deposition requires H3K9me3. Finally, we show that histone acetylation undergoes only modest changes as rod-shaped chromosomes form during unperturbed mitotic entry. Thus, deacetylation does not drive mitotic chromosome formation. The mechanism of condensin-independent chromatin compaction in mitosis remains unexplained.

Keywords:  chromosome condensation; heterochromatin; histone modification; mitosis

DOI:  https://doi.org/10.1016/j.molcel.2026.03.038
Nature. 2026 Apr 22.

Early fibrotic niches establish tumour-permissive microenvironments.

Erik C Cardoso, Hyeyoung Lee, Frances J England, Hyunjin Cho, Robin Lu, Sagar S Varankar, Moo Suk Park, Natasha Rekhtman, Bon-Kyoung Koo, Benjamin D Simons, Jinwook Choi, Joo-Hyeon Lee.

Pathologic transformation represents a critical yet poorly defined window during which mutant epithelial stem cells actively construct the microenvironment that enables tumour initiation1,2. Here using integrated single-cell, spatial and functional analyses, we define the earliest multicellular events that licence this transition following oncogenic activation in the lung. KrasG12D-mutant alveolar type II cells rapidly adopt regenerative-like states that act as signalling hubs, orchestrating coordinated stromal and immune reprogramming while enhancing epithelial plasticity. Through secretion of amphiregulin, mutant epithelial cells activate EGFR signalling in adjacent fibroblasts, inducing a fibrotic, injury-like programme. Reprogrammed fibroblasts, in turn, expand and reprogramme alveolar macrophages, amplifying inflammatory signalling and reinforcing epithelial plasticity. These reciprocal interactions establish a self-sustaining epithelial-stromal-immune circuit that generates a tumour-permissive niche before malignant outgrowth. Disruption of the amphiregulin-EGFR axis prevents early niche formation and abrogates tumour initiation. Conservation of this programme in KRASG12D-inducible human alveolar organoids and early-stage lung adenocarcinoma tissues identifies epithelial-microenvironment communication as a therapeutically actionable vulnerability and suggests that intercepting niche formation may prevent progression to treatment-resistant disease.

DOI: https://doi.org/10.1038/s41586-026-10399-6
Dev Cell. 2026 Apr 21. pii: S1534-5807(26)00122-X. [Epub ahead of print]

A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.

Silvia Campanario, Mercedes Grima-Terrén, Megan Rommelfanger, Stefania Dell' Orso, Xuesong Feng, Andrés Cisneros, Ignacio Ramírez-Pardo, Aina Calls-Cobos, Benjamin A Yang, Kyung Dae Ko, Esther García-Domínguez, Laura Pena-Couso, Grace Chou, Yuewen Zheng, Nasun Hah, Davide Randazzo, Alberto Pérez-Garcia, Tovah E Markowitz, Jose Milisenda, Iago Pinal-Fernandez, Andrew Mammen, Mari Carmen Gómez-Cabrera, Antonio L Serrano, Eusebio Perdiguero, Vittorio Sartorelli, Joan Isern, Pura Muñoz-Cánoves.

  The molecular basis underlying muscle atrophy, as it occurs during disuse or aging, and activity-induced hypertrophy remain poorly understood. A major challenge has been defining the diverse cellular and niche environments within skeletal muscle, which is mostly composed of multinucleated myofibers. Here, we present a single-nucleus and single-cell transcriptomic atlas, coupled with spatial profiling, of mouse limb skeletal muscle under resting conditions and during experimentally induced atrophy or hypertrophy. We identify condition-dependent shifts in muscle-resident cell populations and fiber-type-specific transcriptional responses. We also uncover extensive remodeling of the neuromuscular junction (NMJ), including the emergence of specialized synaptic myonuclei (SynM) and terminal Schwann cells (tSCs) associated with atrophic or hypertrophic states. High-resolution 3D imaging and spatial transcriptomics confirm these changes at the tissue level. Similar NMJ alterations are observed in denervated and exercised human muscle, supporting the translational relevance of this atlas for studying muscle plasticity and identifying therapeutic targets in muscle-related diseases.

Keywords:  Schwann cell; atrophy; cell atlas; hypertrophy; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1016/j.devcel.2026.03.010
Nat Metab. 2026 Apr 21.

A conserved hormonal signalling-H2A.Z axis rapidly reorganizes 3D chromatin interactions in adipocyte thermogenesis.

Yang Zhang, Rongbin Zheng, Tadataka Tsuji, Chih-Hao Wang, Xiang-Yu Liu, Yu-Hang Xing, Justin Darcy, Matthew D Lynes, Morten Lundh, Rini Arianti, Ferenc Győry, Rui Dong, Brice Emanuelli, Sarah E Johnstone, Miguel N Rivera, Endre Kristóf, C Ronald Kahn, Kaifu Chen, Yu-Hua Tseng.

Three-dimensional genome organization underlies gene regulation, yet how acute hormonal signalling reshapes chromatin structure to control metabolism remains unclear. β3-adrenergic receptor (β3-AR) hormonal signalling drives adipocyte thermogenesis. Here, we show three-dimensional genome maps of mouse and primary human brown adipocytes during thermogenesis using Micro-C. We find that β3-AR signalling rapidly reorganizes chromatin loops within 4 h, with dynamically gained loops coupled to thermogenic gene activation in both species. Mechanistically, β3-AR stimulation promotes histone variant H2A.Z deposition to enhance chromatin accessibility at loop anchors, facilitating the recruitment of bridging factor MED1. Loss of H2A.Z compromises loop formation and thermogenic gene activation across species. Brown fat-specific H2A.Z deficiency in mice impairs thermogenic activity and glucose tolerance. Integration with genome-wide association studies links H2A.Z-occupied loops to genetic variants associated with obesity and related metabolic disorders. Together, our findings uncover a cross-species conserved β3-AR signalling-H2A.Z axis that rapidly reorganizes chromatin interactions in adipocyte thermogenesis, providing mechanistic and translational insights into metabolic regulation.

DOI: https://doi.org/10.1038/s42255-026-01510-2
Science. 2026 Apr 23. 392(6796): eads9412

Mechanical load inhibits cancer growth in mouse and human hearts.

Giulio Ciucci, Daniela Lorizio, Nicoletta Bartoloni, Mauricio Budini, Andrea Colliva, Simone Vodret, Anh-Vu Nguyen, Lorenzo Ciacci, Bernhard Texler, Benno Cardini, Rupert Oberhuber, Sofia Bindelli, Ilaria Luciana Carlotta Del Giudice, Roman Vuerich, Francesco Riccitelli, Elena Zago, Henrik Nicolay Finsberg, Mattia Chiesa, Gianluca Lorenzo Perrucci, Rossana Bussani, Furio Silvestri, Manuel Maglione, Gaetano Ivan Dellino, Gianfranco Sinagra, Mauro Giacca, Thomas Eschenhagen, Paolo Golino, Giulio Pompilio, Pier Giuseppe Pelicci, Laura Andolfi, Maurizio Pinamonti, Matteo Dal Ferro, Samuel Wall, Francesco S Loffredo, Serena Zacchigna.

The heart rarely develops cancer, and, at the same time, it lacks regenerative capacity, as cardiomyocytes stop proliferating after birth. This suggests that mechanisms limiting cardiac regeneration may also protect against cancer. In this work, we investigated the role of mechanical load and used in vivo cancer models and ex vivo engineered heart tissues to show that mechanical load reduces cancer cell proliferation in the myocardium. Spatial transcriptomics of human cardiac metastases revealed decreased histone methylation and chromatin compaction. These changes affect chromatin accessibility at proliferation-related loci, with Nesprin-2 identified as a key mechanosensor. Our results uncover how mechanical forces protect the heart from cancer and suggest potential strategies for cancer therapy based on mechanical stimulation.

DOI: https://doi.org/10.1126/science.ads9412
Cell Rep. 2026 Apr 17. pii: S2211-1247(26)00327-X. [Epub ahead of print]45(4): 117249

Time-resolved single-cell transcriptomics maps zebrafish heart development.

Marco Tarasco, Thomas Juan, Yousef Alayoubi, Radha Kulkarni, Annika Schumann, Agatha Ribeiro da Silva, Marga Albu, Manish Dwari, Mirza Dlnija, Stefan Günther, Mario Looso, Didier Y R Stainier.

  Cardiac development is a process where bilateral precursors come together to form a tube that matures into a complex multi-chambered organ. Despite advances in single-cell RNA sequencing technology, a comprehensive analysis of zebrafish heart development from early to late stages is still lacking. We profiled over 34,000 cells from zebrafish hearts spanning ten developmental stages from 25 h to 60 days post-fertilization. We identified and subclustered all known cardiac cell types, revealing distinct proliferation dynamics and uncovering an additional peak in cardiomyocyte proliferation at 14 days post-fertilization. We analyzed the cardiac interactome, focusing on ligand-receptor interactions between the myocardium and endocardium. By investigating later stages, we discovered several marker genes that are enriched in compact or trabecular layer cardiomyocytes including bcam, kcnj14, and kcnj5. We also identified kcnj3b as a specific pacemaker gene. This zebrafish heart atlas enhances our understanding of vertebrate heart development and represents a valuable resource for future studies.

Keywords:  CP: developmental biology; atlas; cardiomyocytes; crosstalk; development; heart; interactome; proliferation; scRNA-seq; transcriptomics; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2026.117249
Cell. 2026 Apr 17. pii: S0092-8674(26)00344-2. [Epub ahead of print]

2'3'-cGAMP-induced membrane shearing promotes broad antiphage immunity.

Yina Gao, Zhaolong Li, Yufei Zhou, Weimin Li, Quanjin Li, Jingge Wang, Miao Shi, Feng Ye, Chunqiu Zhao, Songqing Liu, Qiuyao Jiang, Yun Zhu, Fei Sun, Ang Gao, Pu Gao.

  Cyclic-oligonucleotide-based anti-phage signaling system (CBASS), a central prokaryotic antiviral strategy and evolutionary ancestor of the mammalian cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, relies on cyclic-nucleotide-activated effectors to elicit immunity. The most prevalent effectors are transmembrane (TM) proteins, yet their mechanisms remain unknown. Here, we show how a representative three transmembrane (3TM)-SMODS-associated fused to various effector domains (SAVED) effector couples ligand sensing to membrane disruption. Upon binding 2'3'-cyclic GMP-AMP (cGAMP)-synthesized by bacterial cGAS/DncV-like nucleotidyltransferase (CD-NTase) with features resembling mammalian cGAS-3TM-SAVED assembles stepwise from an apo monomer through a transient dimer into extended filaments. Filament assembly employs 2'3'-cGAMP as molecular glue linking SAVED domains and reorients TM helices and amphipathic hairpins into vertically offset arrays. Both arrays bear opposing hydrophobic and hydrophilic faces, thereby driving vertical lipid shearing. This shearing generates a linear pore array that permeabilizes membranes and triggers cell death. These findings uncover the long-missing mechanism of CBASS TM effectors and establish vertical membrane shearing as an unrecognized principle of membrane disruption across domains of life.

Keywords:  CBASS; CD-NTase; SAVED; antiphage; cGAMP; cGAS; cell death; membrane disruption; membrane shearing

DOI:  https://doi.org/10.1016/j.cell.2026.03.043
J Mol Cell Cardiol. 2026 Apr 19. pii: S0022-2828(26)00056-8. [Epub ahead of print]

OSK-mediated partial reprogramming induces cardiomyocyte dedifferentiation, overcomes cytokinesis barriers, and promotes post-MI endogenous cardiac regeneration.

Yaobin Yan, Yingbo Huang, Changchang Cao, Dandan Li, Yang Che, Qiyuan Wang, Yandan Liu, Qiong Zhang, Yu Hu, Xingzhong Zhang, Li Wang.

  Myocardial infarction (MI) leads to irreversible loss of cardiomyocytes (CMs), owing to the limited regenerative capacity of the adult mammalian heart. Previous studies indicate that the Yamanaka factors (OSKM) can induce CM dedifferentiation and proliferation; however, the inclusion of the proto-oncogene c-Myc poses serious safety concerns for clinical translation. Here, we show that transient overexpression of OSK (OCT4, SOX2, KLF4)-without c-Myc-does not directly trigger CM cell-cycle re-entry. Instead, it initiates a dedifferentiated state marked by sarcomere disassembly. This OSK-induced priming overcomes the cytokinesis barrier in proliferating CMs both in vitro and in vivo, yielding mononuclear CMs with high proliferative potential and ultimately enhancing cardiac repair after MI. Our findings reveal that OSK promotes regeneration primarily by priming dedifferentiation and overcoming cytokinesis bottlenecks, rather than by directly inducing CM S-phase entry, and establish OSK as a novel, safer reprogramming-based strategy for the treatment of MI.

Keywords:  Cardiomyocyte dedifferentiation; Cytokinesis; Myocardial regeneration; Partial reprogramming; Reprogramming factor

DOI:  https://doi.org/10.1016/j.yjmcc.2026.04.005
Nat Genet. 2026 Apr 23.

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.

Genes and Health Research Team

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

DOI: https://doi.org/10.1038/s41588-026-02543-9
Nat Cardiovasc Res. 2026 Apr;5(4): 328-350

PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.

Yao Wei Lu, Zhuomin Liang, Kerry Dorr, Samantha Ruiz, Xiaoran Huang, Denise Fangnibo Hanvi, Sheri M Juntilla, Gisela Beutner, Shuhan Lyu, Haipeng Guo, Tiago Fernandes, Ramon A Espinoza-Lewis, Tingting Wang, Kathryn Li, Xue Li, Gurinder Bir Singh, Yi Wang, Rui Deng, Douglas Cowan, John D Mably, William T Pu, Jessie Huang, George A Porter, Frank Conlon, Hong Chen, Da-Zhi Wang.

Mutations in the AARS2 gene are linked to infantile cardiomyopathy; however, the underlying molecular mechanism remains unknown. Here we report that PCBP1, a poly(rC) binding protein, interacts with the AARS2 transcript to mediate its alternative splicing. Cardiomyocyte-specific deletion of Pcbp1 in mice impairs normal splicing and causes premature termination of Aars2, leading to defects in heart development and postnatal lethality. Similarly, mice with a deletion in Aars2 that mimics a disease-causing splicing lesion display heart developmental abnormalities, reminiscent of those in patients with infantile mitochondrial cardiomyopathy. Mechanistically, loss of Pcbp1 or Aars2 in the heart reduces oxidative phosphorylation, a hallmark of patients with AARS2 mutations. This reduction in mitochondrial-encoded proteome activates mitonuclear communication and the unfolded protein response pathway, thereby inducing a compensatory nuclear-encoded mitochondrial gene program. Our findings provide insights into the PCBP1-AARS2 regulatory axis in mitochondrial cardiomyopathy.

DOI: https://doi.org/10.1038/s44161-026-00798-3
EMBO J. 2026 Apr 24.

Quiescent neural stem cells transiently become neuron-like to coordinate long-range reactivation.

Laura-Yvonne Gherghina, Jocelyn L Y Tang, Leo Otsuki, Leia Judge, Andrea H Brand.

Reactivation of quiescent neural stem cells (NSCs) in the central nervous system (CNS) is a tightly controlled process that generates new neurons and glia to maintain homeostasis or enable repair post-injury, but it remains unclear if reactivation of distinct NSC populations is coupled. Here, we discovered that NSC quiescence exit in Drosophila follows a hierarchical sequence, whereby activation of anterior stem cells in the brain lobes precedes and is required for the timely state-transition of more posterior NSCs in the ventral nerve cord. To achieve this, quiescent NSCs transiently activate neuronal genes. This transient neuronal state is temporary and specific to NSC dormancy, as neuronal genes are switched off after stem cells resume proliferation. Blocking neuronal firing in brain lobe neurons delays the onset of posterior NSC reactivation. Our results reveal long-range communication between quiescent NSCs to coordinate reactivation across the CNS, enabled by a transient, plastic neuron-like state that allows direct interaction with neuronal axons.

DOI: https://doi.org/10.1038/s44318-026-00775-3
Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00382-7. [Epub ahead of print]45(5): 117304

A Fkh1/2 binding site array in the WHI5 promoter drives sub-scaling transcription.

Jacob Kim, Shicong Xie, Lucas Fuentes Valenzuela, Jordan Xiao, Mike C Lanz, Xin Gao, Matthew Swaffer, Corbin E Mitchell, Seth M Rubin, Kurt Schmoller, Jan M Skotheim.

  Cells maintain size homeostasis by coupling growth to division. In budding yeast, newborn cells contain similar amounts of the G1/S inhibitor Whi5, which is diluted as cells grow in G1 to promote cell cycle entry. Similar Whi5 amounts at birth arise from size-independent (sub-scaling) WHI5 mRNA production during S/G2/M and equal partitioning of Whi5 at division. Although chromatin association explains equal partitioning at division, the basis of sub-scaling transcription remained unclear. By systematically mutating the WHI5 promoter, we identify a core region from -126 to -75 bp upstream of the start codon that is responsible for sub-scaling. This sequence contains a repeating array of binding sites for the Fkh1/2 transcription factor. Mutating these sites, deleting FKH1 or FKH2, or disrupting Fkh1/2 dimerization weakens WHI5 sub-scaling. Together with structural predictions and a mathematical model of cooperative Fkh binding, our results suggest that sub-scaling WHI5 transcription is regulated by a Fkh1/2 heteropolymer that binds an array of sites in its core promoter.

Keywords:  CP: cell biology; CP: genomics; G1/S transition; Whi5 dilution; cell cycle control; cell size control; cooperative DNA binding; forkhead transcription factors; size scaling; sub-scaling transcription

DOI:  https://doi.org/10.1016/j.celrep.2026.117304
Cell. 2026 Apr 17. pii: S0092-8674(26)00339-9. [Epub ahead of print]

p53 safeguards chemical reprogramming of human somatic cells toward pluripotency.

Lin Cheng, Yanglu Wang, Zhihan Yang, Jingxiao Cao, Fangqi Peng, Tianlong Lan, Ruoqi Cheng, Tianxing Liu, Ziqing Xia, Jingyang Guan, Cheng Li, Shicheng Sun, Hongkui Deng.

  Cell fate manipulation is powerful for generating desired cell types through reprogramming. However, reprogramming induces dramatic changes in cell states and identities, which can be risky, necessitating strict regulation to ensure safety and efficiency. p53 is essential for genome stability; however, it functionally opposes oncogenes comprising the Yamanaka factors. Delicately balancing p53 activity for efficient reprogramming has proven challenging. Here, we demonstrate that p53 is essential for chemical reprogramming, unlike its inhibitory role in transcription factor-mediated reprogramming. Unexpectedly, suppressing p53 impairs the generation of chemically induced pluripotent stem cells (CiPSCs). p53 prevents excessive epithelial-to-mesenchymal transition during the early reprogramming stages. Retinoic acid signaling activation promotes CiPSC generation by leveraging p53's anti-metastatic function via BTG2. Cell proliferation ability is sustained in the presence of p53 expression by regulating p21 with chemicals. p53 preservation shows practical advantages in securing genome integrity; thus, chemical reprogramming is promising for delicately balancing p53 activity and achieving efficient reprogramming for cell fate manipulation.

Keywords:  BTG2; CiPSCs; cell fate manipulation; chemical reprogramming; epithelial-mesenchymal transition; genome integrity; p53; pluripotency

DOI:  https://doi.org/10.1016/j.cell.2026.03.038
Cancer Res Commun. 2026 Apr 20.

Integrated single-cell whole genome sequencing and spatial transcriptomics reveal intra-tumoral heterogeneity in ovarian cancer.

Rania Bassiouni, Yuxin Jin, Lee D Gibbs, Jing Qian, Solomon O Rotimi, Heather Miller, Michelle G Webb, Seeta Rajpara, Javier Arias-Stella, David W Craig, Lynda Roman, John D Carpten.

The mortality rate of ovarian cancer remains disproportionately high compared to its incidence. This is partly due to a high level of intra-tumoral heterogeneity, driven by genomic instability, that promotes disease recurrence and treatment failure. In this study, we describe degrees of heterogeneity revealed by single-cell whole genome sequencing and spatial transcriptomics of five late-stage, treatment-naïve primary epithelial ovarian carcinomas, including high grade serous and clear cell subtypes. All samples exhibited widespread copy number aberrations, with greatest intra-specimen diversification in regions of copy number gain. Diversification was also associated with whole genome doubling in all samples. In two samples, we identify persistent, clonal pseudo-diploid cells evolutionarily consistent with a pre-malignant phenotype. In multi-clonal samples, we interpret clonal evolution in the context of single cell copy number, loss of heterozygosity analysis, and somatic mutations, and correlate these with tissue histology and gene expression programs. In one high grade serious carcinoma, we identify functionally consequential copy number alterations that contribute to molecular diversity, cell proliferation, and inflammation in a minor clone that persisted without major expansion alongside a more complex major clone. In another clear cell carcinoma, we describe a complex evolutionary history including a spontaneous functional reversion of a CTNNB1 driver mutation in a secondary clone, which correlated with a switch in oncogenic expression programs. These examples highlight various consequences of genomic instability on clonal heterogeneity and plasticity in ovarian cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0795
Cell. 2026 Apr 21. pii: S0092-8674(26)00341-7. [Epub ahead of print]

Somatic cancer variants enriched in Alzheimer's disease microglia-like cells drive inflammatory and proliferative states.

August Yue Huang, Zinan Zhou, Maya Talukdar, Liz Enyenihi, Michael B Miller, Brian Chhouk, Ila Rosen, Mengyue Zheng, Minye Zhou, Averill Yang, Edward Stronge, Madel Durens, Minh Nguyen, Jaejoon Choi, Boxun Zhao, Sattar Khoshkhoo, Junho Kim, Rebecca Andersen, Zheming An, Yuchen Cheng, Javier Ganz, Levan Mekerishvili, Kyle J Travaglini, Mariano I Gabitto, Rebecca D Hodge, Eitan S Kaplan, Julia A Belk, Dan Landau, Ed S Lein, Philip L De Jager, David A Bennett, Samuele G Marro, Eirini P Papapetrou, Eunjung Alice Lee, Christopher A Walsh.

  Alzheimer's disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood, suggesting a likely hematopoietic origin. Single-nucleus RNA sequencing data from 62 additional AD and control brains revealed increased somatic copy number variants (sCNVs) associated with CH in AD MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia. These signatures were recapitulated in induced pluripotent stem cell-derived microglia-like cells with TET2, ASXL1, and DNMT3A variants. These findings suggest that clonal somatic driver variants in MLBMs are enriched in AD, potentially promoting neuroinflammation and neurodegeneration.

Keywords:  Alzheimer’s disease; brain macrophage; clonal expansion; microglia; somatic variant

DOI:  https://doi.org/10.1016/j.cell.2026.03.040
Cell. 2026 Apr 17. pii: S0092-8674(26)00340-5. [Epub ahead of print]

B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.

Youxiang Mao, Ziyan Xia, Xu Pan, Wenjun Xia, Peng Jiang.

  B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.

Keywords:  B cells; TGF-β1; exercise capacity; hepatic glutamate metabolism; immune-independent regulation; immunoexercise; skeletal muscle function; transforming growth factor

DOI:  https://doi.org/10.1016/j.cell.2026.03.039
Nature. 2026 Apr 22.

Caspase 5c amplifies Wnt via APC cleavage to promote intestinal homeostasis.

JRI Live Cell Bank

Caspase 5 (CASP5) is a member of the inflammatory caspase family of cysteine proteases that is involved in inflammation and cell death1-3. CASP5 shares the highest homology with inflammatory CASP4, but whereas CASP4 is essential for noncanonical inflammasome activation, CASP5 is dispensable4-6, and its function remains unknown. Here we show that CASP5 is restricted to the human intestinal epithelium and manifests as three isoforms-CASP5A, CASP5B and CASP5C-among which CASP5C uniquely promotes Wnt signalling, which is essential for epithelial development and regeneration7. We identified dishevelled, which bridges Wnt receptors to the β-catenin destruction complex8, as a prominent CASP5 binding partner in colonic epithelial cells. Dishevelled interacts with the CASP5 catalytic domain through its DEP (dishevelled, EGL-10 and pleckstrin) domain. Lacking the inhibitory caspase activation and recruitment domain (CARD) of CASP5A and CASP5B, CASP5C cleaves the central scaffold protein APC at Asp556 in the Armadillo repeat domain, destabilizing the β-catenin destruction complex and thereby enhancing Wnt signalling. CASP5C expression peaks in transit-amplifying cells, the Wnt-reliant progeny of intestinal stem cells7, whereas CASP5A and CASP5B predominate in mature enterocytes. Endogenous and ectopic CASP5C drive growth of colonic and small intestinal organoids, which is known to require proliferation of transit-amplifying cells9. Furthermore, CASP5C is selectively induced upon intestinal epithelial injury, and its expression is increased in inflammatory bowel disease. Thus, CASP5C is an enzymatic amplifier of Wnt signalling that cleaves APC to sustain proliferation of transit-amplifying cells amid a declining Wnt gradient, safeguarding epithelial renewal. These findings broaden the roles of inflammatory caspases beyond innate immunity, uncovering their contribution to tissue homeostasis.

DOI: https://doi.org/10.1038/s41586-026-10343-8
Nucleic Acids Res. 2026 Apr 13. pii: gkag315. [Epub ahead of print]54(7):

ATR and TopBP1 oppose to control dormant origin activity and global replication dynamics, providing a first defense against replication stress.

Stéphane Koundrioukoff, Nathan Alary, Su-Jung Kim, Thibault Collin, Antoine Toffano, Rodrigo Melendez-Garcia, Xia Wu, Yaqun Liu, Stefano Gnan, Sami El-Hilali, Olivier Brison, Filippo Rosselli, Chun-Long Chen, Michelle Debatisse.

Replication stress and resulting genome instability, a major driver of cancer progression, stem from perturbations of replication fork progression. The first defense against this stress is activation of "dormant" replication origins, which supports replication completion. To determine whether ATR, in itself, contributes to this compensation process, we submitted human cells to a range of low stresses sufficient to activate ATR, not CHK1. Using molecular combing, we developed a dose-response assay that quantifies compensation efficiencies, enabling accurate comparison of cells with different genotypes. Combined with Repli-seq and OK-seq, this assay revealed that ATR activation is key to compensation triggering. We next asked how TopBP1, the main ATR activator, impacts compensation. In stark contradiction to what would be expected from its checkpoint function, we found that TopBP1 represses compensation and acts downstream of ATR. Instead, the function of TopBP1 in replisome assembly, which remains unclear in mammalian cells where the protein is not essential, well-accounts for our results positing that TopBP1 locks dormant origins at the pre-initiation stage, an intermediate in the assembly process, and that ATR activation allows assembly to resume. TopBP1 engagement in the pre-initiation complex would thus serve as a switch linking replisome assembly to the stress response.

DOI: https://doi.org/10.1093/nar/gkag315
Nat Commun. 2026 Apr 21. pii: 3659. [Epub ahead of print]17(1):

The vault associates with membranes in situ.

Katharina Geißler, Jan Philipp Kreysing, Yuning Wang, Desislava Glushkova, Agnieszka Obarska-Kosinska, Patrick C Hoffmann, Stefanie Böhm, Alexander Schmidt, Jakob Meier-Credo, Julian D Langer, Gerhard Hummer, Martin Beck.

The eukaryotic vault particle is a giant ribonucleoprotein complex that assembles into an iconic barrel-like cage. Its cellular function has remained elusive despite extensive characterization. Using cryo-electron tomography of Dictyostelium discoideum cells, we define the distribution, structural states, and interaction landscape of vault particles in situ. Surprisingly, we detect a subpopulation of vault particles associated with the endoplasmic reticulum (ER) and nuclear envelope membranes. This association occurs at a defined barrel height of the vault particle. Membrane-associated particles appear to localize to patches of reduced membrane bilayer thickness and altered curvature. We further find that a fraction of vaults encloses 80S ribosomes in highly ordered orientations. These structural findings are further corroborated by proximity labeling experiments, which identify ER-resident proteins and numerous ribosomal components as vault particle interactors. The membrane-bound and ribosome-encapsulating vault populations that we uncover will direct future studies towards revealing vault function.

DOI: https://doi.org/10.1038/s41467-026-71837-7
Nucleic Acids Res. 2026 Apr 13. pii: gkag354. [Epub ahead of print]54(7):

rRNA expansion segments mediate ribosome dimerization as a conserved stress response.

Wenhong Jiang, Chen Chen, Xing Wang, Wei Huang, Dawid Krokowski, Ziyao Chen, Jiahao Xie, Zhaoming Su, Maria Hatzoglou, Derek J Taylor, Qiang Guo.

Inhibition of messenger RNA translation is a common feature in proteostatic stress cellular responses. Puromycin, a widely used compound for studying translation, disrupts protein synthesis by mimicking the 3' end of aminoacyl-transfer RNAs. Despite its extensive use as a research tool to probe the connection between translation activity and various physiological and pathological states, the cellular response associated with puromycin-induced translation stress remains incompletely understood. Here, we used electron tomography and topology analysis to define the effects of puromycin on the translation machinery in situ. We show that puromycin-treated neuronal cells exhibit an accumulation of eIF5A-bound ribosomes in a translationally inactive "idle" state, and thereby defining a broader role of eIF5A in ribosome homeostasis. Additionally, the idle ribosomes formed dimeric complexes mediated by ribosomal RNA expansion segments, suggesting an evolved mechanism involving these regions in translational hibernating and protecting idle ribosomes. We further show that the hibernating disome formation is not unique to puromycin administration but represents a conserved mechanism as a response to different cellular stressors including endoplasmic reticulum stress and amino acid depletion. Collectively, our findings illuminate distinct states of mammalian ribosome hibernation and dimerization, providing new insights into the relationship of cellular stress and the dynamic regulation of ribosomal activity.

DOI: https://doi.org/10.1093/nar/gkag354
Nature. 2026 Apr 22.

Ubiquitination of glycogen and metabolites in cells and tissues.

Marco Jochem, Simon A Cobbold, Craig A Goodman, Catharina Kueng, Anthony Cerra, Laura F Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S Wang, Simon R Scutts, Michael Pandos, Lin Tang, Thomas Hermanns, Shane M Devine, Martin Brzozowski, Yuri Shibata, Niall D Geoghegan, Catriona A McLean, Bernhard C Lechtenberg, Kay Hofmann, Paul Gregorevic, David Komander.

Ubiquitin signalling covers a vast realm of protein modifications, yet may still be underestimated due to non-proteinaceous substrates, such as sugars, lipids, and nucleotides1 . The breadth of ubiquitinated non-protein substrates, their abundance, and cellular roles are currently unclear, since current ubiquitinomic and proteomic techniques are blind to non-proteinaceous modifications. We report Non-Protein Ub-clipping (NoPro-clipping) as a mass-spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a vast new canvas of ubiquitin modifications in mammalian cells, and in mouse and human tissues. We find ubiquitinated glycogen in any glycogen-containing tissue in mice, with highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes, and leads to reduced glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and regulated by the Met1-polyubiquitin machinery. Strikingly, glycogen depletion in the liver during fasting coincides with elevated glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping hence unveils unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.

DOI: https://doi.org/10.1038/s41586-026-10548-x
Physiol Rev. 2026 Apr 21.

Transitional Cell States at the Crossroad of Development, Disease, and Repair-Regeneration.

Xiangyi Ke, Wellington V Cardoso.

  Cells undergoing transitional states have been broadly referred to as plastic intermediates emerging between stable identities in multiple biological contexts. Once regarded as indistinct midpoints on lineage trajectories, these states are now recognized as discrete, biologically meaningful epigenetically permissive states, exquisitely responsive to environmental and stress signals at critical junctures of biological events that confer competence to proceed along their trajectories. These high-plasticity nodes have emerged as central regulators of developmental progression and determinants of disease outcomes, serving as functional bottlenecks in which resolution or persistence dictates normal or maladaptive pathological responses. Recent single-cell and multiomiocs technologies enabled their detection with unprecedented resolution, revealing conserved regulatory themes, including stress-response activation and striking context-dependence shaped by niche cues and tissue architecture. Yet challenges remain in capturing their rapid heterogeneous dynamic in the multiple contexts, and defining their function, in vivo. Here we summarize current concepts on the identification, diversity, role and regulation of these cell states in events from early development to adult homeostasis, repair and diseases. The increasing recognition that transitional states can be productive conduits or pathological traps underscores their relevance in these processes and potential for the identification of therapeutic targets for intervention in disease, cancer and regenerative medicine.

Keywords:  cancer; cell fate; development; epithelial progenitors; morphogenesis; repair-regeneration; stem cell; transdifferentiation; transitional cell state

DOI:  https://doi.org/10.1152/physrev.00041.2025
Science. 2026 Apr 23. eadz7118

Severe obesity in human HFpEF alters contractile protein function and organization.

Vivek P Jani, Marcus Rhodehamel, Axel J Fenwick, Weikang Ma, Eli Fisher, Maria T Giannakopoulos, Sun Moon, Romi L Castillo, Leslie M Kennedy, Thomas C Irving, Jil C Tardiff, Elizabeth Murphy, Raghothama Chaerkady, Qing Wang, Meaghan E Barry, Virginia S Hahn, Kavita Sharma, Kenneth B Margulies, Kenneth C Bedi, Anthony Cammarato, David A Kass.

Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality and has few effective therapies. Its phenotype has changed over time, with morbid obesity and metabolic defects supplanting hypertension and cardiac hypertrophy. We reveal that cardiomyocytes from patients with severe obesity and HFpEF have very depressed contractile reserve, including reduced calcium- and length-stimulated tension, power, and myosin activation compared to less-obese HFpEF and non-failing (NF) controls ±obesity, but similar to advanced HF with reduced EF. Myocyte defects correlate with body mass index and exercise hemodynamics in patients with HFpEF but not NF and appear reversible upon weight loss. Increased troponin-I phosphorylation at Thr181 occurs only in HF+obesity contributing to sarcomere dysfunction. Weight reduction and sarcomere enhancers may offer benefits in HFpEF with obesity.

DOI: https://doi.org/10.1126/science.adz7118
Sci Adv. 2026 Apr 24. 12(17): eadw4136

Directional guidance to orient Schwann cell alignment in nerve regeneration requires Plexin-B1.

Jiaxi Li, Haofei Ni, Dalia Halawani, Molly Estill, Aarthi Ramakrishnan, Chrystian Junqueira Alves, Li Shen, Xijing He, Roland H Friedel, Hongyan Zou.

Directional cues are essential for orienting cells during tissue morphogenesis and repair. In peripheral nerve regeneration, Schwann cells (SCs) align longitudinally in the nerve bridge to guide axonal pathfinding, but the mechanisms are not fully understood. We show here that after nerve injury, activated SCs up-regulate the guidance receptor Plexin-B1, enabling membrane plasticity required for SC polarization and longitudinal alignment along the axons. Aligned axon-SC provides positional cues to orient macrophages and extracellular matrix. Loss of Plexin-B1 disrupts SC morphological transformation, contact inhibition of locomotion between SCs, and axon-SC alignment, leading to SC misorientation, excessive inflammation, and delayed axon regeneration and functional recovery. These findings identify Plexin-B1 as a key orchestrator to orient SCs by regulating both SC-SC and axon-SC interactions during nerve repair. Elucidating the mechanisms of spatial guidance in nerve repair after injury has potential implications for therapeutic strategies to enhance neural regeneration.

DOI: https://doi.org/10.1126/sciadv.adw4136
Curr Biol. 2026 Apr 21. pii: S0960-9822(26)00384-2. [Epub ahead of print]

Microtubule organization and molecular architecture of ciliary basal bodies in multiciliated airway cells.

Emma J van Grinsven, Eugene A Katrukha, Karen B van den Anker, Fangrui Chen, Jeffrey M Beekman, Lukas C Kapitein, Anna Akhmanova.

  Microtubule organization depends on cell type and function. Microtubule networks of many differentiated cell types, such as epithelial cells, are poorly understood due to their complexity and high density. Here, we used expansion microscopy to visualize and quantitatively map the three-dimensional organization of the microtubule network in human airway multiciliated cells. In these cells, most apical and apicobasal microtubules nucleate and anchor at the basal foot, a part of the ciliary basal body. A small subset of stable microtubules is detached from basal bodies and forms an apical crescent. By combining expansion microscopy with a newly developed averaging tool for multichannel volumetric data, we generated a high-resolution 3D map of the basal body. We delineated the position of structural components and proteins involved in microtubule nucleation and anchoring, uncovering some interesting differences with centrioles of dividing cells. γ-TuRC, its binding partners NEDD1 and augmin/HAUS, and centriolar appendage proteins ninein and AKNA localize to the basal foot. Functional analyses demonstrated that NEDD1 is essential for basal foot-dependent microtubule organization. Our data reveal the distinct architecture of microtubule-organizing centers responsible for the formation of dense microtubule arrays in multiciliated cells.

Keywords:  NEDD1; airway epithelium; basal body; centriole; cilia; expansion microscopy; microtubule; γ-tubulin

DOI:  https://doi.org/10.1016/j.cub.2026.03.064
Mol Cell. 2026 Apr 21. pii: S1097-2765(26)00210-8. [Epub ahead of print]

Deciphering the dual effects of transcription on DNA replication elongation by replication-associated Micro-C.

Zhengrong Zhangding, Xuhao Liu, Haoxin Liang, Yaxu Fan, Yu Peng, Wanqin Rao, Wanlin Chen, Jiazhi Hu.

  The encounters between transcription and DNA replication may remodel replication dynamics, yet the coordination of these two essential processes remains elusive. Here, we developed a replication-associated Micro-C (Repli-MiC) method to map replication fountains, which are dynamic chromatin-interaction structures induced by coupled replication forks, at nucleosome resolution in mammalian cells. We implemented a reinforcement-learning-based computational framework to enable unbiased and quantitative characterization of replication fountains, thereby allowing precise assessment of how transcription influences sister-fork elongation. With this integrated platform, we found that co-directional transcription induces a bias in the speed of sister replication forks toward the transcriptional orientation without compromising fork coupling, which is further enhanced upon depletion of DNA topoisomerase I (TOP1). Conversely, head-on transcription potentially impairs fork elongation to weaken replication fountains. This study provides a comprehensive assay for profiling the entire DNA-replication elongation process and sheds light on the dual roles of transcription in modulating fork elongation.

Keywords:  Micro-C; replication elongation; topoisomerase I

DOI:  https://doi.org/10.1016/j.molcel.2026.03.034
Cell. 2026 Apr 22. pii: S0092-8674(26)00453-8. [Epub ahead of print]

Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation.

Yibo Zuo, Qin Wang, Wanying Tian, Xinhe Wang, Zhijin Zheng, Wei He, Renxia Zhang, Qian Zhao, Ying Miao, Yukang Yuan, Tingting Zhang, Qun Cui, Yuerong Zhang, Chunyan Liu, Haiyan Zhou, Hui Zheng.

DOI: https://doi.org/10.1016/j.cell.2026.04.018
Nat Cancer. 2026 Apr 21.

TMEM87A suppresses ferroptosis and increases cancer immunotherapy resistance by maintaining the Golgi apparatus pH homeostasis.

Jing Li, Yuhan Zhou, Xiong Li, Songlin Yin, Yuan Gao, Haotian Shang, Yongfeng Lai, Liguo Yang, Ying Xue, Xiaoxiao Li, Yan Li, Zhenzhen Chang, Jing Chen, Xiang Cheng, Xiaoyan Zhang, Qian Chu, Fujia Lu, Weimin Wang.

Most membrane-bound organelles have been linked to the initiation and execution of ferroptosis. However, the role of the Golgi apparatus and its resident proteins in ferroptosis remain elusive. Here we show that ferroptosis inducer triggers rapid oxidation of Golgi membrane lipids in the early phase of ferroptosis, resulting in disruption of Golgi pH. The Golgi-localized transmembrane protein TMEM87A is identified to mediate ferroptosis resistance through buffering Golgi pH. Depletion of TMEM87A leads to Golgi overacidification, which impairs FSP1-mediated reduction of coenzyme Q. In vivo, TMEM87A ablation suppresses the progression of multiple murine tumors including melanoma, colorectal cancer and liver cancer. TMEM87A ablation also enhances antitumor T cell responses and potentiates PD1 blockade therapy. Clinically, tumoral TMEM87A expression negatively correlates with immunotherapy response and treatment outcome. Our study reveals that TMEM87A functions as a suppressor of tumoral ferroptosis by maintaining Golgi pH homeostasis and targeting TMEM87A is potent to augment cancer immunotherapy.

DOI: https://doi.org/10.1038/s43018-026-01156-9
Am J Physiol Heart Circ Physiol. 2026 Apr 23.

From Bump to Pump: Extracellular Matrix Remodeling, Dynamics, and Biomechanics in the Maternal Heart.

Avery N Kendall, Iona M A Palmer, Helen E Collins.

  Although a large percentage of pregnancy-related morbidity and mortality is the result of cardiovascular diseases, little is known about the underlying mechanisms that contribute to the development of adverse cardiac changes during pregnancy. It is clear that during pregnancy, the heart adapts to increased ventricular preload through the development of a reversible, pregnancy-induced cardiac hypertrophy. Cardiomyocyte growth must be supported by changes in the cardiac extracellular matrix (ECM), an extremely diverse and dynamic set of components, whose composition and regulation affect cardiac biomechanics. The ECM undergoes extensive remodeling during periods of cardiac stress, such as those experienced during pregnancy and the postpartum period; however, the full extent of ECM changes and their contributions to biomechanical changes and maternal heart plasticity remain vastly understudied. Recent studies suggest alterations in the expression of several fibrillar collagens, such as collagens I and III, and regulatory proteins, such as matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases, occur during a healthy pregnancy. On the contrary, in the setting of pregnancy-associated cardiovascular diseases, such as preeclampsia and peripartum cardiomyopathy, adverse changes in ECM remodeling have been reported. This review aims to summarize the current state of the field highlighting changes in the cardiac ECM and its components during healthy pregnancies, how perturbations in ECM remodeling can lead to the development of pregnancy-related cardiovascular pathologies, and discuss the notable gaps in knowledge that need to be addressed if we are to fully understand ventricular remodeling in the context of pregnancy and reduce maternal cardiovascular disease burden.

Keywords:  cardiac remodeling; cardiovascular disease; hypertrophy; postpartum; pregnancy

DOI:  https://doi.org/10.1152/ajpheart.00917.2025