bims-ginsta 2026-08-02 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–08–02
forty-one papers selected by
Jinrong Hu, National University of Singapore

Intestinal stem cells count self-renewal divisions to switch multipotency.
Spatiotemporal regulation of DNA repair proteins between Golgi and nucleus maintains genome stability.
Mitochondrial metabolism and epigenetic crosstalk drive SASP.
Golgi organization regulates stem cell function in the small intestine.
METTL3 promotes cell-cycle progression via activation of transcriptional elongation.
A global view of human centromere variation and evolution.
Mechanical forces stimulate Golgi export.
Senotypes define the diverse landscape of senescent cells.
Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.
Nanoscale junctional membrane curvatures recruit BIN1 and SNX9 for endothelial collective migration.
Basement membrane turnover controls cell shape.
Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions.
Dual control of PIP2 drives germline/soma segregation in Drosophila.
TRF2 couples muscle stem cell identity to regenerative repair.
Polo/PLK1 phosphorylation relieves Centrosomin/Cnn autoinhibition to promote centrosome scaffold assembly.
PARP1 hyperactivity stalls translation and triggers stress granule formation following DNA damage.
Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling.
The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
Spatiotemporal control of Atg2 association with the ER during autophagosome formation.
Live-cell co-translational folding tracking reveals bidirectional coupling between translation and folding.
Cellular Retinoic Acid-Binding Protein 2 Promotes Ischemia-Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11-RAD50-NBS1-Mediated DNA Repair.
Cellular stress triggers degradation and global redistribution of RNAPII.
Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.
An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
O-GlcNAc clusters in intrinsically disordered regions regulate transcriptional condensates and gene control.
N-cadherin orientational order decreases with mechanical load at cardiomyocyte adherens junctions.
Multi-omic profiling of cardiomyocyte ageing and functional decline.
Insufficiency of cohesin regulatory protein PDS5B triggers meiotic failure and aneuploidy in oocytes during advanced maternal aging.
Reconstitution of actomyosin networks in cell-sized liposomes dissects distinct mechanisms of membrane blebbing and symmetry breaking.
Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
Regulation of RNA transcript elongation in metazoans and its relevance to disease.
Branched chain amino acid transaminase 1-mediated pathway promotes proline-dependent collagen production in cardiac myofibroblasts.
Targeting chaperone-mediated autophagy by nutritional interventions mitigates age-related cardiac fibrosis and diastolic dysfunction.
Cardiopedia-Ligand: A ligand-receptor perturbation atlas of human cardiac organoid function and transcriptional state.
Planar cell polarity complex internalization is dependent on Celsr1 cis-dimerization.
CellTune: an integrative software for accurate cell classification in spatial proteomics.
TRIM37 interacts with TRIM28 to maintain primordial germ cell identity during migration.
Nuclear size and physical properties of the nucleoplasm are determined by colloid osmotic pressure at the nuclear envelope.
Genomic, epigenomic and transcriptomic regulation of cellular senescence.
A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies.

Nature. 2026 Jul 29.

Intestinal stem cells count self-renewal divisions to switch multipotency.

Dong Tong, Anqi Li, Quanquan Jiang, Qili Yuan, Xiaozhao Liu, Ximiao He, Jiejunyi Liang, Yunyun Han, Zheng Guo.

Multipotent stem cells maintain tissue homeostasis by producing distinct daughter cell types in defined proportions1,2, but how they coordinate type-specific ratios during repeated divisions remains unknown. Drosophila intestinal stem cells (ISCs) switch between producing enteroendocrine cells (EECs) and enterocytes (ECs)3,4, yet maintain a constant EEC:EC ratio despite rapid tissue turnover5-7. Here we show that ISCs intrinsically count self-renewal divisions through an epigenetic mechanism to control multipotency switching. After each asymmetrical division producing an enteroendocrine mother cell (EMC; which divides symmetrically to produce a pair of EECs), ISCs execute precisely eight divisions that generate ECs, before switching back to EMC production at the ninth division. This counting is driven by antagonistic histone modifications: Trithorax group (TrxG)-dependent active marks (H3K4me3 and H3K36me3) progressively decline, whereas Polycomb group (PcG)-dependent repressive marks (H3K27me3) accumulate over successive divisions, triggering fate switching at a threshold. The division count is tunable by modulating TrxG and PcG activities, but withstands acute injury. Crucially, EMC-derived transient Notch signalling establishes active marks in ISCs to initiate the count, designating each EMC production as the cycle's start point. Our work identifies a histone-modification-based division counter that programs developmental fidelity in stem cells, with implications for engineered tissue growth and differentiation disorder therapies.

DOI: https://doi.org/10.1038/s41586-026-10814-y
J Cell Biol. 2026 Sep 07. pii: e202605024. [Epub ahead of print]225(9):

Spatiotemporal regulation of DNA repair proteins between Golgi and nucleus maintains genome stability.

George Galea, Karolina Kuodyte, Muzamil Majid Khan, Peter J Thul, Beate Neumann, Emma Lundberg, Rainer Pepperkok.

The Golgi complex serves as a critical hub for cellular homeostasis, yet its communication with the nucleus remains largely unexplored. By analyzing and siRNA-validating localization data from the Human Protein Atlas, we uncovered substantial proteome interconnectivity between the Golgi and nucleus, including an unexpected enrichment for DNA repair factors. We identify a cluster of DNA damage response (DDR) proteins occupying distinct sub-Golgi compartments that redistribute dynamically between the Golgi and nucleus in response to genotoxic stress, with the type of DNA lesion shaping the direction of redistribution. Focusing on the homologous recombination (HR) regulator RAD51C, we show that DNA damage triggers ataxia telangiectasia mutated (ATM)-dependent release of a giantin-tethered Golgi RAD51C pool, with subsequent importin-β-dependent nuclear import, where repair-associated foci form. Giantin depletion prematurely releases RAD51C, producing aberrant nuclear foci lacking key DDR markers, reducing ATM activation and HR efficiency, elevating genome instability, and accelerating proliferation. The Golgi thus acts as a spatiotemporal coordination node for DDR factors safeguarding genomic stability.

DOI: https://doi.org/10.1083/jcb.202605024
Nature. 2026 Jul 29.

Mitochondrial metabolism and epigenetic crosstalk drive SASP.

Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

DOI: https://doi.org/10.1038/s41586-026-10791-2
Nat Commun. 2026 Jul 29. pii: 7606. [Epub ahead of print]17(1):

Golgi organization regulates stem cell function in the small intestine.

Ilya Belevich, Lucas Porcile, Agustin Sola-Carvajal, David Grommisch, Karl Annusvar, Paul Heinz, Srustidhar Das, Anna T Webb, Simon Andersson, Nalle Pentinmikko, Eduardo J Villablanca, James R Goldenring, Maria Kasper, Eija Jokitalo, Robert J Coffey, Pekka Katajisto, Sandra Scharaw.

Cell-to-cell signaling between niche and stem cells regulates tissue renewal. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. ISCs orient their Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks. Stem cells with multiple lateral Golgi transport stem cell receptors with a higher efficiency than cells with one single Golgi. The lateral Golgi orientation and enhanced receptor transport requires A-kinase anchor protein 9 (Akap9), and is necessary for normal renewal capacity. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal a stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue renewal, which is compromised in the aged epithelium.

DOI: https://doi.org/10.1038/s41467-026-75679-1
Mol Cell. 2026 Jul 31. pii: S1097-2765(26)00497-1. [Epub ahead of print]

METTL3 promotes cell-cycle progression via activation of transcriptional elongation.

Azime Akçaöz-Alasar, Yanhua Wang, Hang Li, Denis Ostapenko, Carlos A Ramírez Parrado, Daniela Villalobos, Wenxue Li, Prajwal C Boddu, Alexander H Nguyen, Hengyi Li, Marcelo Perez-Pepe, Pénélope Darnat, Bünyamin Akgül, Manoj M Pillai, Yansheng Liu, Lilian Kabeche, Claudio R Alarcón.

  Transcriptional elongation undergoes extensive remodeling at mitotic entry, yet how elongation control is integrated into core cell-cycle kinase networks remains unclear. Here, we identify the m6A methyltransferase METTL3 as a direct substrate of the mitotic kinase CDK1 in mammalian cells. CDK1-dependent phosphorylation of METTL3 at Ser43 is sharply induced at mitotic entry and promotes m6A methylation of the noncoding RNA 7SK, resulting in release of positive transcription elongation factor b (P-TEFb) from the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP) complex. This activation of the m6A/7SK/P-TEFb axis facilitates genome-wide clearance of RNA polymerase II and supports timely mitotic progression. Endogenous mutation of METTL3 Ser43 or disruption of 7SK methylation impairs elongation dynamics, delays mitotic exit, and increases chromosome missegregation. These findings integrate RNA methylation into the CDK1-driven mitotic program and reveal a mechanism by which transcriptional elongation is coordinated with chromosome segregation fidelity.

Keywords:  7SK; CDK1; DNA damage; METTL3; RNA Pol II; RNA modifications; cell cycle; chromosome segregation; m(6)A; transcription

DOI:  https://doi.org/10.1016/j.molcel.2026.07.011
Nature. 2026 Jul 29.

A global view of human centromere variation and evolution.

Human Genome Structural Variation Consortium

Centromeres are essential chromosomal regions that ensure accurate chromosome segregation during cell division, yet their highly repetitive sequence has historically hindered their complete assembly and characterization1. Consequently, the full spectrum of centromere diversity across individuals, populations and evolutionary contexts remains largely unexplored. Here we address this gap in knowledge by assembling and characterizing 2,110 centromeres from diverse individuals representing 5 continental and 28 population groups. Using bioinformatic tools tailored for centromeres, we identify variation, including 226 centromere haplotypes and 1,870 α-satellite higher-order repeat variants. While most centromeres have a single kinetochore site, we find that around 6% have di-kinetochores, and less than 1% have tri-kinetochores, which we confirm using long-read chromatin profiling and multigenerational inheritance. We also show that kinetochore position is closely associated with the underlying sequence and structure of the centromere. To understand the nature of evolutionary change, we compared these centromeres to 5,747 centromeres assembled by the Human Pangenome Reference Consortium. We show that centromeres have a 20-fold variation in mutation rate, and a subset of centromeres has evidence of archaic hominin introgression. We validate these mutation rates in a 4-generation, 28-member family and show that the kinetochore site is the most rapidly mutating region in the centromere. We propose a model that reveals an 'arms race' between centromeric sequence and proteins, with frequent mutations within the kinetochore site that lead to changes in genetic and epigenetic landscapes and, ultimately, rapid evolution of these critically important regions.

DOI: https://doi.org/10.1038/s41586-026-10841-9
J Cell Biol. 2026 Oct 05. pii: e202510026. [Epub ahead of print]225(10):

Mechanical forces stimulate Golgi export.

Chandini Bhaskar Naidu, Javier Vera Lillo, Eugenia Almacellas, Anabel-Lise Le Roux, Sabine Bardin, Nicolas Mateos, Jessica Angulo-Capel, Adam Wolowczyk, Yugo Terashima, Yuichi Wakana, Pere Roca-Cusachs, Maria F Garcia-Parajo, Franck Perez, Bruno Goud, Jean-Baptiste Manneville, Stéphanie Miserey, Felix Campelo.

Cells face diverse mechanical stimuli that vary with cell type, state, and pathological conditions. Mechanobiology investigates how cells sense and respond to these forces. While most work has focused on the cell surface and nucleus as primary mechanosensors, how intracellular organelles adapt to extracellular mechanical forces remains largely unknown. Here, we show that extracellular mechanical signals influence the secretory function of the Golgi apparatus. By subjecting adherent cells to mechanical challenges-cell spreading on different ligands, altered substrate stiffness, or equibiaxial strain-we reveal that extracellular forces modulate Golgi-to-cell surface carrier biogenesis, thereby regulating exocytosis. Together with changes in Golgi membrane tension, we identify molecular determinants of the mechanotransduction pathway, including microtubule acetylation, diacylglycerol production, and protein kinase D activity. In turn, inhibition of Golgi export suppresses this mechanoresponse and causes impaired cell spreading. These findings uncover a bidirectional mechanotransduction axis in which extracellular mechanics tune Golgi secretory output, providing a framework for investigating organelle-based mechanoadaptation in physiology and disease.

DOI: https://doi.org/10.1083/jcb.202510026
Nat Aging. 2026 Jul 29.

Senotypes define the diverse landscape of senescent cells.

Marissa J Schafer, Nathan Basisty, Ann V Hertzel, Alexandra N Rindone, Jennifer H Elisseeff, Vidyani Suryadevara, Constantin Aliferis, Paul D Robbins, Laura J Niedernhofer, Karl N Miller, Peter D Adams, Vilas Menon, Hemali Phatnani, Joao F Passos, Birgit Schilling, Simon Melov, Nicola Neretti, Darren J Baker.

Cellular senescence was initially defined in vitro as a stable cell-cycle arrest that occurs after repeated replication, but it is now recognized as a heterogeneous state shaped by cell type, species, senescence-inducing stress, tissue microenvironment and time. To organize this complexity, we propose the term 'senotype' to classify senescent cells by their inputs, molecular features and functional effects. We outline a practical framework incorporating: (1) cell identity and context; (2) inducing mechanism; (3) temporal stage; (4) multimodal molecular and structural features; and (5) physiological or pathological functions. Experimentally defined senotypes can serve as references for interpreting tissue-derived senotypes, where parameters may be incomplete. Senotypes should be anchored in combinations of core hallmarks (that is, durable cell-cycle arrest, altered secretory profiles, macromolecular or organelle damage, disrupted homeostasis) rather than single markers. Advances in single-cell, spatial, proteomic and computational methods enable rigorous senotype characterization, improving consistency and accelerating development of targeted senotherapeutics.

DOI: https://doi.org/10.1038/s43587-026-01148-5
Sci Adv. 2026 Jul 31. 12(31): eaeh9771

Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.

Xiaoai Zhao, Ryan M Feitzinger, Jeeyoon Na, Xin Yan, Andrew Erickson, Kévin Contrepois, Olivia Y Zhou, Francesco Vallania, Mathew Ellenberger, Chloe M Kashiwagi, Stephanie D Gagnon, Cynthia J Siebrand, Matias Cabruja, Gavin M Traber, Andrew McKay, Daniel Hornburg, Purvesh Khatri, Michael P Snyder, Richard N Zare, Anne Brunet.

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs). While mechanisms that restore old NSC function have started to be identified, the role of lipids-especially complex lipids-in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related changes in complex lipids in quiescent NSCs in vitro and in vivo. Moreover, several polyunsaturated fatty acids increase across lipid classes in quiescent NSCs during aging. Using spatial lipidomics, we find that some of the changes in complex lipids are also observed in situ. Several age-related changes in complex lipids and side chain composition are occurring at the plasma membrane, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we show that aging is accompanied by a decrease in plasma membrane order, a key membrane biophysical property, in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knocking out the phospholipid acyltransferase MBOAT2 exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. Mboat2 overexpression reverses age-related lipidomic changes in old quiescent NSCs and boosts their ability to activate in vitro and in vivo. Moreover, supplementation of plasma membrane lipids from young NSCs improves the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs, which has important implications for countering brain decline during aging.

DOI: https://doi.org/10.1126/sciadv.aeh9771
J Cell Biol. 2026 Sep 07. pii: e202509207. [Epub ahead of print]225(9):

Nanoscale junctional membrane curvatures recruit BIN1 and SNX9 for endothelial collective migration.

Vera Janssen, Hannah de Kraker, Jesse S Aaron, Annett de Haan, Iris de Heer, Satya Khuon, Jason Da Silva, Amber J M Driessen, Teng-Leong Chew, Josephine M E Tan, Anne K Lagendijk, Ana Angulo-Urarte, Stephan Huveneers.

Collective endothelial migration during vascular development relies on dynamic cell-cell contacts, yet how the junctions between leader and follower cells are organized remains poorly understood. Using Cryo-SIM followed by FIB-SEM, we investigated the nanoscale 3D ultrastructure of asymmetric adherens junctions (AAJs), revealing a wide spectrum of membrane folds at the contact interface between migrating endothelial cells. By performing a junction localization screen, we identified a variety of membrane curvature-sensing BAR domain proteins selectively enriched at AAJs. Among these, BIN1 and SNX9 emerged as novel regulators of front-to-rear polarity in follower cells during endothelial collective migration. The spatiotemporal recruitment of these individual BAR proteins associated with distinct phases of AAJ remodeling. Furthermore, depletion of SNX9 disturbed VE-cadherin dynamics, endothelial cell directionality, and sheet migration in the common cardinal vein of zebrafish. These findings highlight junctional nanoscale membrane curvatures as hubs for the spatiotemporal recruitment of a repertoire of BAR proteins to remodel AAJs and guide collective endothelial migration during vascular development.

DOI: https://doi.org/10.1083/jcb.202509207
Cell. 2026 Jul 30. pii: S0092-8674(26)00808-1. [Epub ahead of print]

Basement membrane turnover controls cell shape.

Ricardo Barrientos, Billie Meadowcroft, Besaiz J Sánchez-Sánchez, Brian M Stramer, Ewa K Paluch, Guillaume Charras, Shiladitya Banerjee, Anđela Šarić, Yanlan Mao.

  The regulation of 3D cell shape is a fundamental problem of life. In multicellular tissues, cell shape emerges through the balance of forces inside and outside the cell. In epithelia, the basement membrane (BM) is the first extracellular barrier that cells sense biochemically and mechanically. Despite this, little is known about how BM mechanical properties are regulated and how they impact cell shape. Through mathematical modeling, we show that the stress relaxation time of the BM can regulate cell shape. Using molecular dynamics simulations, we show that the stress relaxation time of a collagen IV network can be inferred from the lifetime of collagen IV molecules. To measure collagen IV lifetime in vivo, we develop a fluorescent timer reporter for collagen IV and show that perlecan modifies collagen IV lifetime. This cross-disciplinary approach establishes a multiscale framework to probe matrix turnover, and its regulation and function in cell shape control.

Keywords:  basement membrane; cell shape; extracellular matrix remodeling; mechanobiology; morphogenesis; physical modeling; protein turnover

DOI:  https://doi.org/10.1016/j.cell.2026.07.010
Science. 2026 Jul 30. 393(6810): eady0832

Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.

Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

DOI: https://doi.org/10.1126/science.ady0832
Nat Genet. 2026 Jul 30.

Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions.

Jonathan Levinsohn, Samuel Grindel, Bernhard Dumoulin, Amin Abedini, Carolina Conte, Aria Zheyuan Huang, Rena Levin-Klein, Boaz Weisz, Grace Rabinowitz, Andi M Bergeson, Eunji Ha, Konstantin A Klötzer, Nancy Zhang, Paul Titchenell, Mingyao Li, Joo-Seop Park, Juan Pablo Arroyo, Laura S Finn, Kotaro Sasaki, Pazit Beckerman, Oren Pleniceanu, Paola Romagnani, Alex J Hughes, Katalin Susztak.

Evolution has used cell-cell communication as a strategy to coordinate organ development, enabling the reproducible generation of intricate structures. Classically, these interactions have been studied one at a time in model organisms, limiting our understanding of how cellular interplay coordinates human development. We investigated human kidney development using single-cell RNA sequencing and spatial transcriptomics, analyzing over 700,000 cells. By mapping gene expression and differentiation trajectories in space, we define the spatial organization of kidney development. Our analysis revealed unrecognized plasticity, showing that cell fate established during early patterning can be later revised. This plasticity provides a potential mechanism for how cell fate is robustly established in complex patterned tissues. Additionally, through a genome-wide, spatially aware cell-cell interaction analysis, we link localized ligand signals to cell fate decisions. We also define biologically meaningful cellular neighborhoods based on aggregated extracellular cues, providing a blueprint to understand the coordination of human development at scale.

DOI: https://doi.org/10.1038/s41588-026-02665-0
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2604429123

Dual control of PIP2 drives germline/soma segregation in Drosophila.

Marcus D Kilwein, Liu Yang, Robert A Marmion, Char A Wynter, Akira Nakamura, Stanislav Y Shvartsman, Elizabeth R Gavis.

  Embryonic cell fate decisions require precise spatial coordination between competing lineage determinants. In the syncytial Drosophila embryo, primordial germ cells (PGCs) and posterior endoderm are specified at the posterior pole in overlapping domains, creating a conflict between germline and somatic fates. PGC formation depends on germ granules, which locally promote production of the phospholipid PIP2 at the posterior plasma membrane. PIP2 regulates actin dynamics leading to membrane protrusions that generate PGCs. We find that the posterior endoderm determinant, the receptor tyrosine kinase (RTK) Torso, antagonizes germ granule activity by activating phosphoinositide 3-kinase (PI3K) which converts PIP2 to PIP3. PIP3 prevents PGC formation, ensuring endoderm specification. Loss of Torso or PI3K expands the posterior PIP2 domain, increasing both the number and spatial extent of PGCs. Germ granules counteract this activity through production of the E3 ubiquitin ligase Germ cell-less (Gcl), which locally eliminates Torso and prevents PI3K-mediated PIP2 depletion at the posterior pole. In gcl mutants, PIP3 accumulates at the posterior membrane and PGC formation fails, a defect that can be partially rescued by targeted posterior expression of the PIP3 phosphatase Pten. Together, these findings demonstrate that mutual antagonism between germ granules and Torso signaling generates a PIP2/PIP3 boundary in the plasma membrane that governs the earliest germline-soma fate decision. Our work reveals how opposing maternal cues can be integrated at the level of membrane phospholipids to pattern cell fate during the earliest stages of development.

Keywords:  PI3K; PIP3; RTK signaling; endoderm; primordial germ cells

DOI:  https://doi.org/10.1073/pnas.2604429123
Sci Adv. 2026 Jul 31. 12(31): eaei7316

TRF2 couples muscle stem cell identity to regenerative repair.

Ji-Hyung Lee, Kiran Kumar Nakka, Ryan P Calhoun, Sarah Hachmer, Adity Gupta, Eric Arreza, Lynn A Megeney, Patrick Seale, Roger A Greenberg, F Jeffrey Dilworth, Foteini Mourkioti.

Stem cell-mediated regeneration is essential for tissue integrity. In skeletal muscle, tissue repair largely depends on muscle stem cells (MuSCs), which undergo dynamic cell-state transitions through making precise fate decisions during regeneration. However, the molecular regulators of cell-state conversion in MuSCs remain unclear. Here, we identify a previously unrecognized, noncanonical role for TRF2 in MuSC biology. TRF2 is dynamically regulated upon injury and required to preserve stem cell identity, support reparative myogenesis, and sustain self-renewal. MuSC-specific TRF2 disruption exacerbates muscular dystrophy pathology in mice, recapitulating key features of human disease. Mechanistically, TRF2 associates with regulatory regions enriched for DNA G-quadruplex-forming sequences at lineage-specific genes, sustaining their expression. These findings establish TRF2 as a pivotal regulator of adult stem cell function and tissue-specific regenerative responses.

DOI: https://doi.org/10.1126/sciadv.aei7316
EMBO J. 2026 Jul 30.

Polo/PLK1 phosphorylation relieves Centrosomin/Cnn autoinhibition to promote centrosome scaffold assembly.

Nada Mohamad, Siu-Shing Wong, Anupa Majumdar, Alan Wainman, Ingelise Holland-Kaye, Lars Hubatsch, Zsofia Novak, Andrey Pozniakovsky, Martine Ruer-Gruss, Andreas F M Haensele, Anna Caballe, Steven Johnson, Susan M Lea, Anthony A Hyman, Jordan W Raff.

Mitotic centrosome maturation requires Polo/PLK1-dependent expansion of the pericentriolar material (PCM). In Drosophila, Centrosomin (Cnn) assembles a scaffold around mitotic centrioles through interactions between its PReM and CM2 domains. Here, we show that PReM adopts an autoinhibited helical hairpin conformation that prevents CM2 binding. Polo/PLK1 phosphorylation relieves this autoinhibition, enabling scaffold assembly, whereas phospho-blocking mutations disrupt PReM-CM2 binding in vitro and Cnn scaffold assembly in vivo. Potential functionally analogous domains have been identified in the human and C. elegans Cnn homologues CDK5RAP2 and SPD-5. We find that the human protein appears to share a structurally similar mechanism for scaffold assembly, but the worm protein does not. Consistent with this, deletion of these domains alters the dynamics of Cnn condensates in vitro, but has little effect on SPD-5 condensate dynamics. We conclude that Polo/PLK1 promotes mitotic centrosome assembly, at least in part, by relieving autoinhibitory intramolecular interactions.

DOI: https://doi.org/10.1038/s44318-026-00878-x
J Cell Biol. 2026 Aug 03. pii: e202409149. [Epub ahead of print]225(8):

PARP1 hyperactivity stalls translation and triggers stress granule formation following DNA damage.

Maria Tereshchenko, Rebecca Earnshaw, Christopher Chin Sang, Minjung Won, Jeanine L Van Nostrand, Ryan C Russell, Hyun O Lee.

Cells respond to various stressors by inhibiting global translation and forming stress granules (SGs), cytoplasmic organelles enriched in certain RNA-binding proteins, and RNA. Genotoxic stress also induces SG assembly, but it is unclear how nuclear stress signals are transmitted to trigger cytoplasmic responses. We show that DNA-damaging agents that activate a nuclear poly(ADP-ribose) polymerase (PARP), PARP1, stall translation and induce SGs. We find that PARP1 activation depletes NAD+, which depletes cellular ATP, activating ATP-sensor AMPK and inhibiting mTORC1 via Raptor phosphorylation. Subsequent hypophosphorylation of 4EBP1 inhibits translation. These effects are suppressed by PAR-metabolism regulators, XRCC1, PARG, and Nudix5, and reversed by NAD+ precursor supplementation. Cells lacking SG scaffolds, G3BP1 and G3BP2, show reduced viability after genotoxic stress, which is rescued by G3BP1 overexpression. These findings link PARP1 activity to translational control and SG formation, which may protect against cell death following DNA damage. These mechanisms provide insight into PARP1- and stress granule-associated diseases, including cancer and neurodegeneration.

DOI: https://doi.org/10.1083/jcb.202409149
Nat Cell Biol. 2026 Jul 28.

Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling.

Nathaniel F Henneman, Genki Kawamura, Ying Luo, Catia Oliveira Dias, Jiaqi Su, Arianna Segaloni, Ivan Nemazanyy, Samuel le Cam, Calvin Rodrigues, Nicolas Kuperwasser, Nicolas Cagnard, Karim Hnia, Raphaël Margueron, Dominik Lutter, Takeaki Ozawa, Ganna Panasyuk.

Transcriptional remodelling during fasting ensures metabolic adaptation and provides health benefits across species. Although several regulators of fasting-induced transcription and chromatin are known, how nutrient levels directly influence RNA polymerase II (RNAPII) and epigenetic writers remains unclear. Here we show that lipid kinase class 3 phosphatidylinositol 3-kinase (PI3K-3), a master regulator of autophagy, also functions on chromatin as a co-activator of epigenetic writers to promote RNAPII transcription. PI3K-3 overlaps with transcriptionally engaged RNAPII phosphorylated at Ser5 and with Setd1a/COMPASS, the complex that deposits the activating H3K4me3 mark. Nuclear PI3K-3 interacts with RNAPII and Setd1a/COMPASS and promotes their chromatin binding. PI3K-3 loss reduces RNAPII-S5p and H3K4me3 at selected genes, whereas PI3K-3 overexpression co-activates p300/CBP and chromatin-targeted PI3K-3 increases H3K4me3. During starvation, PI3K-3 induces autophagy genes and drives fasted liver towards ketogenesis and lipid degradation. These findings link nutrient stress to chromatin-mediated transcriptional activation.

DOI: https://doi.org/10.1038/s41556-026-02030-7
Nat Aging. 2026 Jul 30.

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.

Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.

DOI: https://doi.org/10.1038/s43587-026-01172-5
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2606606123

Spatiotemporal control of Atg2 association with the ER during autophagosome formation.

Tetsuya Kotani, Haruki Tanabe, Shinri Kitta, Momoko Higashi, Tatsuya Niwa, Tatsuya Kaminishi, Chika Kakuta, Junko Shimasaki, Hidetaka Kosako, Tamotsu Yoshimori, Akiko Kuma, Hitoshi Nakatogawa.

  Autophagy degrades various intracellular components by sequestering them within membrane vesicles called autophagosomes and delivering them to lysosomes or vacuoles. Previous studies have revealed that the conserved, bridge-like lipid transfer protein Atg2 tethers autophagosome precursors to the endoplasmic reticulum (ER) and mediates lipid supply from the ER to drive their expansion into autophagosomes. However, how Atg2 docks onto the ER has remained unclear. Here, we show in Saccharomyces cerevisiae that Atg2 interacts with the ER-resident VAP family protein Scs2. This interaction is mediated by a phospho-FFAT motif in Atg2 and the major sperm protein domain of Scs2 and enhanced by phosphorylation of the motif by the autophagy-initiating kinase Atg1, which is activated at the autophagosome formation site upon autophagy induction. This interaction cooperates with the N-terminal region of Atg2, which contains a weakly amphipathic helix, to mediate Atg2 association with the ER. Thus, the Atg2-Scs2 interaction functions as a spatiotemporal switch that controls Atg2-ER association. We also show that mammalian ATG2 interacts with the VAP-like proteins MOSPD1 and MOSPD3 to promote autophagosome formation. Collectively, this study reveals a conserved mechanism that initiates lipid transfer during autophagosome formation.

Keywords:  Atg2; VAP protein; autophagy; lipid transfer protein; phospho-FFAT motif

DOI:  https://doi.org/10.1073/pnas.2606606123
bioRxiv. 2026 Jul 14. pii: 2026.07.12.738044. [Epub ahead of print]

Live-cell co-translational folding tracking reveals bidirectional coupling between translation and folding.

Rhiannon M Sears, Luis U Aguilera, Tristan M Bunting, Ning Zhao.

Translation elongation and protein folding have long been proposed to coordinate during co-translational folding, yet the lack of technologies capable of simultaneously tracking both processes in live cells has hindered mechanistic understanding of this relationship. Here, we developed co-translational folding tracking (coTFT), a live-cell imaging platform that directly and simultaneously tracks translation and folding from individual mRNAs. Using reporters with distinct folding kinetics, we found that differences in folding kinetics were accompanied by corresponding changes in translation elongation rates. Conversely, altering translation elongation markedly affected protein folding outcomes. Combining coTFT with mathematical modeling enabled estimation of reporter folding times on translating ribosomes in live cells, confirming their distinct folding kinetics. Together, our results reveal that translation elongation and folding are bidirectionally coupled during co-translational folding.

DOI: https://doi.org/10.64898/2026.07.12.738044
J Am Heart Assoc. 2026 Jul 31. e049049

Cellular Retinoic Acid-Binding Protein 2 Promotes Ischemia-Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11-RAD50-NBS1-Mediated DNA Repair.

Zhenyang Su, Hui Shen, Jinyu Sun, Xiangqing Kong, Wei Sun.

   BACKGROUND: Cardiac fibrosis is a hallmark of ischemic heart failure and is driven by activated myofibroblasts. DNA damage and defective repair promote fibroblast activation, yet the upstream regulators that couple DNA damage responses to profibrotic remodeling remain unclear.
METHODS: Single-cell RNA sequencing data sets from human ischemic cardiomyopathy were analyzed to identify fibroblast-enriched candidate genes. In vivo, Postn promoter-driven adeno-associated viruses were used to knock down or overexpress CRABP2 (cellular retinoic acid-binding protein 2) in an isoproterenol-induced mouse model, followed by assessment of ventricular function and fibrosis. In vitro, neonatal cardiac fibroblasts were subjected to CRABP2 gain or loss of function and TGF-β (transforming growth factor-β) stimulation. Mechanistic studies combined RNA sequencing, immunoprecipitation-mass spectrometry, structural modeling, γ-H2AX staining, comet assays, and MRE11/MRE11-RAD50-NBS1 (MRN) perturbation.
RESULTS: Single-cell analyses identify CRABP2 as a fibroblast-enriched gene upregulated in profibrotic fibroblast subsets in human ischemic hearts. In vivo, CRABP2 knockdown in Postn+ myofibroblasts preserves left ventricular function and attenuates interstitial fibrosis, whereas CRABP2 overexpression exacerbates dysfunction and fibrosis in isoproterenol-treated mice. In vitro, CRABP2 promotes TGF-β-induced fibroblast migration, proliferation, activation, and collagen production. Mechanistically, CRABP2 binds MRE11, suppresses MRN-ATM-CHK2 signaling, and enhances DNA damage accumulation. Inhibiting or silencing MRE11 abrogates the antifibrotic and cardioprotective effects of CRABP2.
CONCLUSIONS: CRABP2 drives profibrotic cardiac fibroblast activation by inhibiting MRE11/MRN-mediated DNA repair. The CRABP2-MRE11-MRN axis represents a potential therapeutic target for limiting fibrotic remodeling in ischemic heart failure.

Keywords:  CRABP2; DNA repair; MRE11/MRN complex; cardiac fibroblasts; ischemic heart failure

DOI:  https://doi.org/10.1161/JAHA.126.049049
Sci Adv. 2026 Jul 31. 12(31): eaec6649

Cellular stress triggers degradation and global redistribution of RNAPII.

Hansong Qi, Kangning Chen, Ningyawen Liu, Mengqiu Yin, Yongfang Chen, Xiaoli Ren, Ke Yang, Guijun Chen, Fan Lai, Xinglou Yang, Jumin Zhou.

Transcription is essential for cellular stress response. However, how RNAPII respond to and are regulated during stress are poorly understood. We show that RNAPII is degraded during many types of cellular stresses. In osmotic stressed cells, the TNFα-p38 pathway was activated and promoted the neddylation of the CUL1 E3 ligase complex, which interacted with RPB1 through FBXO11 to ubiquitylate and degrade RNAPII. This caused genome wide RNAPII binding reduction, but prevented RNAPII binding loss from genes with low promoter GC content. This redistribution protected the RNAPII loss from stress response genes in the cell adhesion, MAPK and GPCR pathways. RNAPII redistribution is vital for cell survival, as degradation blockage resulted in the loss of RNAPII from low GC promoters and compromised stress response from disrupted cell adhesion to increased apoptosis. Thus, rapid RNAPII degradation and RNAPII redistribution are components of the cellular stress response to benefit cell survival.

DOI: https://doi.org/10.1126/sciadv.aec6649
Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00845-4. [Epub ahead of print]45(8): 117767

Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.

Arijita Ghosh, David Weaver, Chi Li, Gyӧrgy Hajnóczky.

  Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP3 receptor Ca2+ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca2+ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca2+ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca2+ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy of ER-mitochondrial Ca2+ transfer without changing ER Ca2+ release, despite attenuating mitochondrial Ca2+ uptake. We find interaction between Bcl-xL and each IP3R isoform occurring at the mitochondria and a complex formed by OMM-localized Bcl-xL and IP3Rs. OMM Bcl-xL interacts with IP3Rs in trans at ER-mitochondrial contacts to optimize local Ca2+ signal propagation into the mitochondria.

Keywords:  Bcl-xL; CP: cell biology; CP: metabolism; ERMC; IP3R; calcium signaling; endoplasmic reticulum; local Ca(2+) transfer; mitochondria; organellar crosstalk

DOI:  https://doi.org/10.1016/j.celrep.2026.117767
Science. 2026 Jul 30. 393(6810): eads5397

An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.

Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Dean R Campagna, Mark D Fleming, Sarah Ducamp, Julia R Kardon.

Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.

DOI: https://doi.org/10.1126/science.ads5397
Protein Cell. 2026 Jul 30. pii: pwag053. [Epub ahead of print]

O-GlcNAc clusters in intrinsically disordered regions regulate transcriptional condensates and gene control.

Guojian Shao, Qidong Deng, Tianyu Wang, Yunfan Xiang, Cuihua Li, Na Wang, Jun Liu, Yun Ge.

  Post-translational modifications (PTMs) dynamically regulate the liquid-liquid phase separation (LLPS) that organizes biomolecular condensates, yet for the monosaccharide O-linked β-N-acetylglucosamine (O-GlcNAc) modification, the general rules and their links to protein function remain undefined. Here we identify O-GlcNAc as a widespread LLPS modulator by revealing clustered O-GlcNAc sites enriched in intrinsically disordered regions (IDRs) of transcription-related proteins, with Bromodomain-containing protein 4 (BRD4) exhibiting this pattern most prominently. Twelve clustered O-GlcNAc sites are identified in BRD4 C-terminal IDR, where modifications decrease condensate size while increasing fluidity in vitro and in cells. Removing O-GlcNAc strengthened BRD4 binding at active enhancers and promoted LLPS-mediated recruitment of transcriptional cofactors, including YTHDC1, leading to elevated expression linked to the cell cycle and DNA repair. Our findings define O-GlcNAc clusters as regulators of condensate material properties and transcriptional outcomes, supporting a general paradigm in which PTMs fine-tune the molecular grammar of biomolecular condensates.

Keywords:  BRD4; LLPS; O-GlcNAcylation; intrinsically disordered regions; transcriptional regulation

DOI:  https://doi.org/10.1093/procel/pwag053
bioRxiv. 2026 Jul 20. pii: 2026.07.17.739172. [Epub ahead of print]

N-cadherin orientational order decreases with mechanical load at cardiomyocyte adherens junctions.

Yen T B Tran, William F Dean, Yerin Han, Korina I Karpov, Collin M Ainslie, Alexa L Mattheyses, Adam V Kwiatkowski.

Adherens junctions physically connect neighboring cells and are built around classical cadherins, homophilic transmembrane proteins that link to the actin cytoskeleton. Classical cadherins can organize into ordered arrays in vitro, but whether they do so in cells remains to be established. Here, we use fluorescence polarization microscopy to show that the classical cadherin N-cadherin is orientationally ordered at cardiomyocyte cell-cell junctions. Whereas the desmosomal cadherin desmoglein 2 was similarly ordered across junction types, N-cadherin order was spatially heterogeneous. Order was lowest where organized myofibrils terminate at high-load, vinculin-enriched axial junctions and highest at low-load, vinculin-poor lateral junctions. This inverse relationship between order and mechanical load suggests that robust cadherin-mediated adhesion does not require ectodomain order. Our findings provide evidence that a classical cadherin is orientationally ordered in cells and show that mechanically active adhesions adopt distinct organizational strategies according to local mechanical demands.
Summary Statement: At cardiomyocyte junctions, N-cadherin is ordered where mechanical load is low but disordered where load is high, suggesting that cadherin organization adapts to local force conditions.

DOI: https://doi.org/10.64898/2026.07.17.739172
Cardiovasc Res. 2026 Jul 31. pii: cvag165. [Epub ahead of print]

Multi-omic profiling of cardiomyocyte ageing and functional decline.

Dogacan Yucel, Michael A Trembley, Qingen Ke, Zexuan Wu, Durgesh Bonde, Peter Kang, William T Pu.

   AIMS: Ageing is the strongest risk factor for heart failure, yet the molecular mechanisms underlying cardiomyocyte (CM) ageing remain unclear. We aimed to map the transcriptomic and epigenomic landscape of CM ageing and to test whether DNA hypermethylation is a causal driver of diastolic dysfunction.
METHODS AND RESULTS: We performed single-nucleus multiomics (concurrent snRNA-seq and snATAC-seq) on 4- and 28-month-old ventricular myocardium of C57BL/6J mice. Aged CMs showed widespread chromatin remodelling, with 28,324 regions having greater accessibility compared to only 2 with reduced accessibility. 1963 genes were differentially expressed in aged ventricular CMs, with 78.5% neighbouring differentially accessible regions. Promoter accessibility positively associated with expression. Reduced-representation bisulphite sequencing of ventricular CM nuclei identified 1422 regions associated with genes that were hypermethylated in aged CMs, compared to only 167 that were hypomethylated. CpG hypermethylation inversely correlated with differential gene expression. Multi-omic integration revealed ageing signatures shared across cell types, and identified the long non-coding RNA Gm12381 as a CM-selective ageing marker. To test whether DNA hypermethylation is associated with ageing phenotypes, we used cardiotropic MyoAAV to overexpress Dnmt3a in adult hearts. Dnmt3a overexpression induced CM hypermethylation, causing cardiac hypertrophy and diastolic dysfunction, key ageing phenotypes, and altering the transcriptome profile toward that of aged CMs.
CONCLUSIONS: Gain of chromatin accessibility and CpG hypermethylation associated with transcriptomic reprogramming characterize CM ageing. Experimental elevation of DNA methylation is sufficient to induce diastolic dysfunction and hypertrophy, supporting DNMT3A-mediated hypermethylation as a mechanistic driver. Further work should test whether attenuating methylation prevents or reverses age-related cardiac dysfunction.

Keywords:  Aging; Cardiomyocyte; DNA methylation; DNMT3A; Diastolic function

DOI:  https://doi.org/10.1093/cvr/cvag165
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2605947123

Insufficiency of cohesin regulatory protein PDS5B triggers meiotic failure and aneuploidy in oocytes during advanced maternal aging.

Yu Zhang, Jie Bai, Na Li, Bo Xiong.

  Oocytes rely on a cohort of proteins whose sustained expression ensures normal meiotic progression and reproductive competence throughout an animal's reproductive life. Age-related declines in these proteins are a major cause of reduced oocyte quality and female fertility during reproductive aging. Here, we report that the cohesin regulatory protein PDS5B, a dynamically maintained factor in oocytes, declines with age and plays a noncanonical role in the spindle pole formation independent of its cohesion function during oocyte meiotic maturation. Specifically, we found that PDS5B was expressed throughout the oocyte meiosis and localized at the spindle poles at metaphase stages, while its protein abundance was reduced in aged oocytes, concomitant with decreased messenger ribonucleic acid (mRNA) levels and translational efficiency. Knockdown or heterozygous knockout of PDS5B caused spindle assembly defects, meiotic arrest, and aneuploidy in oocytes, ultimately leading to female subfertility. Mechanistically, immunoprecipitation/mass spectrometry analyses revealed that PDS5B recruited deubiquitinating enzyme USP9X to spindle poles to stabilize nuclear mitotic apparatus and promote proper spindle assembly. Moreover, expression of exogenous PDS5B in aged oocytes partially alleviated meiotic defects associated with advanced maternal age. Altogether, our findings uncover a unique spindle pole-specific function of PDS5B in oocytes and suggest that maintaining PDS5B levels may be a potential strategy to improve the quality of aged oocytes.

Keywords:  NuMA; PDS5B; USP9X; reproductive aging; spindle pole

DOI:  https://doi.org/10.1073/pnas.2605947123
Sci Adv. 2026 Jul 31. 12(31): eaed8818

Reconstitution of actomyosin networks in cell-sized liposomes dissects distinct mechanisms of membrane blebbing and symmetry breaking.

Makito Miyazaki, Fahmida Sultana Laboni, Taeyoon Kim.

The actin cortex, a thin layer of actomyosin network beneath the plasma membrane, regulates various cell functions by generating active forces and inducing membrane deformations, including blebs. Although upstream signaling is involved in regulating cell shape, the extent to which downstream actomyosin molecules can control the shape remains elusive. Here, using a minimal reconstituted system combined with an agent-based computational model, we show that actin-membrane coupling strength determines the magnitude of membrane deformation, while its balance with actin network connectivity governs the bleb initiation mechanism, either by detachment of the cortex from the membrane or by rupture of the cortex. This balance also modulates single versus multiple bleb formation, thereby regulating symmetry breaking. Furthermore, our results suggest that not only the dense cortical network but also the sparse volume-spanning network actively contributes to the regulation of bleb number. These findings provide mechanistic insights into how cells tune actin network organization to control their shape and polarity.

DOI: https://doi.org/10.1126/sciadv.aed8818
Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140
Nat Rev Mol Cell Biol. 2026 Jul 30.

Regulation of RNA transcript elongation in metazoans and its relevance to disease.

Claudia A Mimoso, Isaac Fianu, Karen Adelman.

Our understanding of transcript elongation by metazoan RNA polymerase II (Pol II) has grown notably in recent years. Advances in structural biology have defined the interactions that underlie promoter-proximal pausing of Pol II and the transition from pausing to productive elongation. Improved targeted protein degradation together with sensitive, time-resolved assays of RNA synthesis has transformed our view of transcript elongation control in living cells. In this Review, we discuss the highly orchestrated interactions between elongating Pol II and co-transcriptional RNA-processing factors, revealing that the splicing factor U1 small nuclear ribonucleoprotein (U1 snRNP) directly stimulates productive elongation. Biochemical and cell-based techniques have shed new light on how Pol II overcomes obstacles to elongation such as nucleosomes. Emerging studies have demonstrated the importance of quality control during early transcript elongation by factors such as Integrator and Restrictor. These surveillance machineries ensure the integrity of mRNA synthesis and suppress spurious RNAs arising from transposable elements or regulatory regions such as enhancers. Finally, we discuss how defects in Pol II elongation contribute to diseases ranging from developmental disorders to cancer and inflammation, emphasizing the importance of a fuller understanding of Pol II elongation to human health.

DOI: https://doi.org/10.1038/s41580-026-01003-w
J Clin Invest. 2026 Jul 16. pii: e182216. [Epub ahead of print]

Branched chain amino acid transaminase 1-mediated pathway promotes proline-dependent collagen production in cardiac myofibroblasts.

Noburo Takizawa, Takanori Hironaka, Hayato Watanabe, Haruna Suetsugu, Keisuke Yoshioka, Yuma Horii, Yuri Nagata, Hiroaki Matoba, Hidetaka Kosako, Kenji Hamase, Go Hirai, Michio Nakaya.

  Myofibroblasts are the cells responsible for collagen production, leading to tissue fibrosis. Because 20.5% of the total amino acids in collagen are proline, myofibroblasts must acquire a well-developed proline-producing mechanism during their differentiation. However, the detailed mechanism for myofibroblasts to acquire and keep the developed proline biosynthesis machinery remains obscure. Here, we show branched-chain amino acid transaminase 1 (Bcat1) is up-regulated in a substantial subset of Postn-expressing proto-myofibroblast-like fibroblasts, transitional cells en route to fully differentiated myofibroblasts, as well as in myofibroblasts in the fibrotic heart and liver of mice and humans and promotes the proline production. The branched-chain amino acid (BCAA) production by BCAT1 promotes SMAD3 phosphorylation via HDAC5 phosphorylation at Ser488, thereby enhancing SMAD3-dependent transcription of proline biosynthesis-related genes, Aldh18a1, Pycr1, and Eprs, in proto-myofibroblast-like fibroblasts and myofibroblasts. In BCAT1-deficient mice, expression of proline biosynthesis-related genes is significantly attenuated in their hearts after myocardial infarction, resulting in decreased cardiac fibrosis. Moreover, BCAT1 inhibitor treatment of mice with myocardial infarction reduces cardiac fibrosis. Our results identified a BCAT1-mediated pathway that promotes collagen production via proline biosynthesis regulation in proto-myofibroblast-like fibroblasts and myofibroblasts, which may provide a therapeutic target for cardiac fibrosis.

Keywords:  Amino acid metabolism; Cardiology; Cardiovascular disease; Fibrosis; Metabolism; Therapeutics

DOI:  https://doi.org/10.1172/JCI182216
Autophagy. 2026 Jul 30.

Targeting chaperone-mediated autophagy by nutritional interventions mitigates age-related cardiac fibrosis and diastolic dysfunction.

Ziwen Wang, Ziyuan Zhang, Zheng Ping, Xin Zheng, Ting Wang, Zhongyong Jiang, Ge Yang, Xiaoli Zhang, Zhaochuan Liu, Bo Wu, Haimei Sun, Shu Yang, Deshan Zhou, Tingyi Sun, Xuebin Cao.

  Cardiac fibrosis, a major pathological hallmark of aging that leads to heart failure, is characterized by excessive collagen deposition. Our knowledge of what sustains collagen synthesis in the aging heart is still very preliminary. Here, we uncover a central role for chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, in this process. We demonstrate that CMA is suppressed in the aging heart, which promotes collagen overproduction in fibroblasts, whereas enhancing CMA activity ameliorates fibrosis and diastolic dysfunction. Mechanistically, we identify SHMT2 (serine hydroxymethyltransferase 2) as a CMA substrate whose accumulation with aging drives collagen synthesis by increasing glycine availability. Integrative omics revealed a systemic downregulation of the ketone body β-hydroxybutyrate (BHB) in aged mice. BHB supplementation - via a cyclic ketogenic diet - restored CMA, attenuated fibrosis, and improved cardiac function. This recovery was mediated through BHB-induced activation of the HCAR2 receptor and subsequent phosphorylation of HSPA8/HSC70, which systemically reactivates the CMA machinery. Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging.

Keywords:  Aging; SHMT2; chaperone-mediated autophagy; collagen synthesis; fibrosis; nutritional interventions; β-hydroxybutyrate

DOI:  https://doi.org/10.1080/15548627.2026.2711595
Cell Stem Cell. 2026 Jul 28. pii: S1934-5909(26)00264-X. [Epub ahead of print]

Cardiopedia-Ligand: A ligand-receptor perturbation atlas of human cardiac organoid function and transcriptional state.

Janice D Reid, Simon R Foster, Mary Lor, Alexander S Hauser, Brendan Griffen, Rebecca L Fitzsimmons, James E Hudson.

  Large-scale perturbation atlases have transformed systems biology, yet no equivalent resource exists for the human heart, where contractile function and transcriptomic state must be measured together. Here, we establish Cardiopedia-Ligand, a comprehensive perturbation-function-transcriptome atlas generated by stimulating human cardiac organoids (hCOs) with 87 ligands targeting 98 cell-membrane receptors expressed in the human heart. We developed an automated high-throughput pipeline enabling individualized contractility measurements and single-organoid mRNA sequencing. We use this pipeline to define both recognized and previously unrecognized functional and transcriptional clusters, including inotropes, endothelin peptides, extracellular matrix regulators, and multiple inflammatory clusters. Clustering analysis, machine learning, and the "fingerprinting" of human heart failure biopsies revealed previously underappreciated similarities between ligands and an interferon-γ signaling signature driving heart failure with preserved ejection fraction (HFpEF). Together, this comprehensive Cardiopedia-Ligand dataset provides a valuable and accessible resource for interrogating cardiac biology and human disease.

Keywords:  cardiac organoids; cell signaling; contraction; heart failure; inflammation; interferons; organoid screening; pharmacology; systems biology; transcriptional regulation

DOI:  https://doi.org/10.1016/j.stem.2026.07.004
iScience. 2026 Aug 21. 29(8): 116761

Planar cell polarity complex internalization is dependent on Celsr1 cis-dimerization.

Sarah G Latario, Thomas Saba, Brandon Trejo, William Giang, Stephanie E Zimmer, Danelle Devenport, Sara N Stahley.

  Planar cell polarity (PCP) coordinates collective cell polarity along a tissue plane through the asymmetric localization of junctional complexes comprised of core transmembrane proteins: Celsr1, Fz6, and Vangl2. Basal cells of embryonic mouse epidermis undergo numerous cell divisions to support the developing tissue while also maintaining tissue-level polarity. To achieve this, junctional PCP complexes are selectively co-internalized by the dividing cell, facilitating the restoration of tissue polarity upon mitotic exit. In Celsr1 Crsh/Crsh epidermis, we identify aberrant mitotic internalization of Celsr1 and Fz6, and a failure to co-internalize Vangl2. Mixed-cell in vitro assays reveal Crsh is deficient in mediating trans-endocytosis of Celsr1 and Vangl2. These defects are rescued through forced dimerization of Crsh, supporting the hypothesis that Celsr1 adhesive interactions stabilized by cis-dimers are required for both PCP establishment and maintenance via trans-endocytosis of PCP complexes. Overall, these findings establish a Celsr1 dimerization-dependent mechanism for control of tissue polarity during cell division.

Keywords:  cell adhesion; dimerization; junctional trafficking; mitosis; planar cell polarity; trans-endocytosis

DOI:  https://doi.org/10.1016/j.isci.2026.116761
Nat Methods. 2026 Jul 31.

CellTune: an integrative software for accurate cell classification in spatial proteomics.

Yuval Bussi, Dana Shainshein, Eli Ovits, Sarah Posner, Nofar Azulay, Noa Maimon, Tal Keidar Haran, Raz Ben-Uri, Caitlin Brown, Noam Schuldiner, Eylon Yaniv, David Van Valen, Idan Milo, Ofer Elhanani, Robert Schiemann, Leeat Keren.

Spatial proteomics measures multiple proteins in situ, capturing tissue complexity. However, cell classification in densely packed tissues remains challenging because of the lack of efficient classification algorithms, annotation tools and high-quality labeled datasets to benchmark computational methods. We introduce CellTune, an integrated software for analysis of large spatial proteomics datasets, which streamlines precise cell classification through an optimized human-in-the-loop active learning workflow. It advances core capabilities for analysis of large datasets with an intuitive and code-free interface. To evaluate CellTune, we created CellTuneDepot, a resource of 40,000 manually annotated cells and 3.5 million high-quality labeled cells across 60 cell types. CellTune outperforms alternative methods, achieving accuracy comparable to human performance while enabling increased classification resolution and discovery of novel cell types. Together, CellTune and CellTuneDepot provide researchers with a tool for state-of-the-art classification accuracy and resolution at scale to drive biological insights.

DOI: https://doi.org/10.1038/s41592-026-03162-2
Cell Res. 2026 Jul 30.

TRIM37 interacts with TRIM28 to maintain primordial germ cell identity during migration.

Qing Li, Xidi Yin, Chuanyin Li, Li Guo, Yingyi Wang, Yanbo Cheng, Nan Liu, Qi Yin, Yifu Ding, Meng Yan, Zihan Liu, Junyu Chen, Jin Zhang, Shuo Huang, Wangpeng Gu, Anjing Guo, Huanhuan Deng, Yuanyuan Li, Di Chen, Ian Chambers, Hui Zheng, Ronggui Hu, Man Zhang, Jinsong Li.

During primordial germ cell (PGC) specification, repression of somatic programs is essential for the establishment of germline identity. However, mechanisms that safeguard PGC fate thereafter remain unknown. Here, we identify the E3 ubiquitin ligase TRIM37 as a critical safeguard of PGC fate during migration. Trim37 deficiency causes severe PGC defects beginning at embryonic day 9.5 (E9.5) with complete PGC depletion by E12.5, and leads to an aberrant transition toward somatic cell states. Mechanistically, TRIM37 binds TRIM28 through its MATH domain and ubiquitinates TRIM28 via its RING domain, enhancing the TRIM37-TRIM28 interaction and promoting the nuclear retention of TRIM37. Forced nuclear export of TRIM37 results in PGC loss. Moreover, disruption of TRIM37 ligase activity or mutation of TRIM28 ubiquitination sites compromises PGC maintenance. We further show that the TRIM37-TRIM28 complex, likely acting in cooperation with AP2γ, restricts chromatin accessibility and H3K27ac levels at somatic gene loci, thereby repressing somatic transcriptional programs in PGCs. Together, our findings uncover a TRIM37-TRIM28-AP2γ regulatory complex that safeguards germ cell fate by preventing the activation of somatic transcriptional programs during PGC migration.

DOI: https://doi.org/10.1038/s41422-026-01272-2
bioRxiv. 2026 Jul 23. pii: 2026.07.21.739918. [Epub ahead of print]

Nuclear size and physical properties of the nucleoplasm are determined by colloid osmotic pressure at the nuclear envelope.

Joël Lemière, Zhidong Tan, Fred Chang.

The size of the nucleus scales with cell size, suggesting a universal scaling rule. Yet the biophysical determinants of nuclear size and the significance and consequences of altered nuclear-to-cell (N/C) ratios, which are observed across diverse pathological states and cell-fate transitions, remain poorly understood. Recent theoretical models propose that nuclear size arises from a balance of colloid osmotic pressures generated by macromolecules in the nucleoplasm and cytoplasm. Here we demonstrate that altering this osmotic balance through massive overexpression of an exogenous protein targeted to either the nucleoplasm or cytoplasm produces predictable changes in the N/C ratio in S. pombe . These quantitative perturbations show that nuclear size is set primarily by the number of proteins in the nucleus and cytoplasm, providing strong support for a pure osmotic pressure mechanism. Furthermore, cells with altered N/C ratios display tunable changes in nucleoplasmic crowding, nuclear condensate formation, nucleolar scaling and heterochromatin organization, establishing a causal link between nuclear size and gene regulatory processes. These findings reveal how cells exploit osmotic forces to set organelle dimensions, with broad implications for understanding how nuclear size shapes gene expression and cell identity in health and disease.

DOI: https://doi.org/10.64898/2026.07.21.739918
Nat Rev Genet. 2026 Jul 29.

Genomic, epigenomic and transcriptomic regulation of cellular senescence.

Rahagir Salekeen, Tra L Kieu, Paul D Robbins, Laura J Niedernhofer, Linshan Laux.

Cellular senescence is a complex, highly regulated cell state induced by cellular damage and stress. Senescence is central to many areas of biology, with roles in tumour suppression, tissue regeneration, antiviral defence and diverse age-related pathologies. Senescence is characterized by stable cell cycle arrest, metabolic alterations, chromatin remodelling and the secretion of pro-inflammatory and tissue-modifying factors that are collectively termed the senescence-associated secretory phenotype. Recent technological advances, including new genetic models, single-cell and spatial multi-omics platforms and machine-learning approaches, promise to enable the phenotyping, tracing and manipulation of senescent cells with unprecedented precision and resolution. This Review defines our current understanding of the genetic pathways that regulate senescence induction, maintenance, propagation and heterogeneity, including the DNA damage response, non-genotoxic stress pathways, epigenetic changes and cell-cell communication. We also emphasize key challenges in distinguishing senescence from other cell fates and the need for next-generation biomarkers to capture the varied phenotypes and functions of senescent cells.

DOI: https://doi.org/10.1038/s41576-026-00982-y
bioRxiv. 2026 Jul 13. pii: 2026.07.10.737576. [Epub ahead of print]

A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies.

Magdalena Riedl Khursigara, Alissa C Goss, Maria Kost-Alimova, Keith Keller, Christine Danielle De Mata, Ranjithmenon Muraleedharan, Edward Ryan Collantes, Matthew Brown, Elizabeth Grinkevich, Felichi Mae Arines, John Lin, Patrick Byrne, Silvana Bazua Valenti, Elizabeth Morici, Julie Roignot, Jason Zavras, Brianna R Silverman, John Carlos Ignacio, Yoochan Myung, Seulki Kwon, Andrew Nelson, Hyery Yoo, Michelle Melanson, Matthew Racette, Valeria Padovano, Seth L Alper, Dominique Carey, Namrata D Udeshi, Steven A Carr, Moran Dvela-Levitt, Toshio Narimatsu, Gustavo Sakuno, Victor San Martin Carvalho Correa, Nikolaos E Efstathiou, Dimitrios P Ntentakis, Tian Cao, Zhiqian Dong, Kim Thien Nguyen, Carolline Rodrigues Menezes, Ravi Kurumbail, Steven Kazmirski, Le Xiao, Hao Wu, David Liu, Sumaiya Iqbal, Eric S Lander, Demetrios G Vavvas, Krzysztof Palczewski, Juan Lorenzo B Pablo, Anna Greka.

Severe proteinopathies-such as retinitis pigmentosa, a form of inherited blindness-are driven by genetic mutations that overwhelm the quality control of the post-endoplasmic reticulum (post-ER) secretory pathway, causing toxic protein accumulation. Here, we identify a therapeutic node defined by a hetero-oligomeric cargo receptor complex consisting of TMED7, 2, 9, and 10. This "entrapment complex" anchors structurally and functionally diverse mutant clients within the early secretory pathway via TMED7 binding to the integral Golgi protein GRASP55. Disruption of the entrapment complex results in the clearance of accumulated protein cargoes. In vivo ablation of the entrapment node via inducible genetic deletion or via the small molecule BRD7635 reverses histopathological hallmarks and rescues functional deficits in clinically distinct proteinopathies of the kidney and the eye, including mitigating vision loss in a mouse model of retinitis pigmentosa.

DOI: https://doi.org/10.64898/2026.07.10.737576