bims-ginsta Biomed News
on Genome instability
Issue of 2026–08–16
twenty-six papers selected by
Jinrong Hu, National University of Singapore
  1. Polyamines buffer labile iron to suppress ferroptosis.
  2. Three-dimensional mapping of intact ovaries reveals the aging dynamics of the ovarian reserve.
  3. Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.
  4. Elongating human heart organoids recapitulate early cardiac morphogenesis and axial organization.
  5. Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
  6. Systematic differences in protein stability underlie species-specific developmental tempo.
  7. The sex and reproductive plasticity of intestinal muscles instruct gut size.
  8. Positional cues, not Notch, direct neuroblast selection during early neurogenesis in the Drosophila embryo.
  9. CDT1 acts with the replisome to remodel replication forks.
  10. Mechanical control of human embryonic mesoderm fate via β-catenin is conserved with other metazoans.
  11. Differential control of both cell cycle-regulated and quantitative histone mRNA expression by Drosophila Mute.
  12. Nucleosomes and IDRs suppress promiscuous GCN4 binding on minichromosomes.
  13. Ovarian Extracellular Matrix Mechanics Regulate Oocyte-Follicle Interactions During Female Reproductive Aging.
  14. Transcriptional and Epigenetic Regulation of Cell Fate by YAP and TAZ.
  15. Human heart valve-like tissues from pluripotent stem cells with enhanced maturation recapitulate inflammatory valve disease.
  16. YAP Promotes Microtubule Growth to Facilitate Sarcomere Disassembly in Adult Cardiomyocytes.
  17. Nuclear compartmentalization at the G1/S transition plays a key role in DNA replication control.
  18. Mechanisms of transcription termination across the coding and noncoding loci of the genome.
  19. Human iPSC-derived heart valve-like assembloids model valve development and disease pathology.
  20. Nodal/Smad2 signaling sustains developmental pausing by repressing Pparg-mediated lipid metabolism.
  21. Torsins organize CLCC1 assembly to safeguard ER bilayer and lipid homeostasis.
  22. Temporal gating dictates stress-induced transcript export from the nucleus.
  23. TNFR1 signaling connects inflammation to impaired fatty acid oxidation to drive intestinal stem cell aging.
  24. Cell surface remodeling caused by the loss of the flippase subunit TMEM30A in immune cells.
  25. Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.
  26. The structural basis for LRRK2's activation and autoinhibition.
  1. Cell. 2026 Aug 14. pii: S0092-8674(26)00872-X. [Epub ahead of print]
    Polyamines buffer labile iron to suppress ferroptosis.
    Pushkal Sharma, Heather R Keys, Ryan P Mansell, Jillian Stark, Louisa Girard, Christalyn Ausler, Rachel Anderson, Sebastian Müller, Shinya Imada, Ivan S Pires, Tenzin Kunchok, Millenia Waite, Bingbing Yuan, Amy Deik, Luke Ferro, Paula T Hammond, Raphaël Rodriguez, Maria-Eirini Pandelia, Whitney S Henry, Ankur Jain.
      Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.
    Keywords:  GPX4; ferroptosis; genetically encoded iron sensor; iron homeostasis; labile iron pool; polyamines; redox-active iron; spermidine; spermine
    DOI:  https://doi.org/10.1016/j.cell.2026.07.040
  2. Nat Aging. 2026 Aug;6(8): 1580-1591
    Three-dimensional mapping of intact ovaries reveals the aging dynamics of the ovarian reserve.
    Arturo D'Angelo, Daniel Franco-Barranco, Marco Musy, Juan Manuel Duran, James Sharpe, Nicholas Stroustrup, Ignacio Arganda Carreras, Elvan Böke.
      Female fertility depends on a finite pool of oocytes that depletes during aging1,2, yet the spatiotemporal dynamics of this depletion remain poorly understood. Traditional methods obscure the three-dimensional architecture of the ovary, limiting quantitative insights. Here we combine light-sheet microscopy, artificial intelligence-driven segmentation and mathematical modeling to map over 85,000 oocytes in whole ovaries across the reproductive lifespan in mouse. We find that newly activated oocytes represent a fixed fraction of the total oocyte pool despite an age-related decline in oocyte numbers. Spatial analysis revealed that oocytes are enriched along the lateral ovarian axis, and local oocyte density positively correlates with activation. We also uncover a bimodal distribution of oocyte sizes, suggesting a bottleneck during oogenesis. Finally, a differential equation-based model captures the kinetics of oocyte activation and loss. Our findings establish a quantitative framework for understanding ovarian aging and suggest that an organ-scale regulatory mechanism coordinates the age-related decline in oocyte numbers.
    DOI:  https://doi.org/10.1038/s43587-026-01178-z
  3. Cell. 2026 Aug 04. pii: S0092-8674(26)00821-4. [Epub ahead of print]
    Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.
    Jessenya Mil, Jose A Soto, Abigail S Krall, Julia Peloggia, Sara Frigui, Olivia S Fong, Laila Sathe, Nedas Matulionis, Francesca Day, Linsey Stiles, Katrina P Montales, Daria J Azizad, Carlos E Gonzalez, Elisa Fazzari, Matthew X Li, Patricia R Nano, Antoni A Martija, Cesar A Perez-Ramirez, Claudia V Nguyen, Brittney Wick, Weihong Ge, Ryan L Kan, Madeline G Andrews, Maximilian Haeussler, Michael F Wells, Heather R Christofk, Aparna Bhaduri.
      Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. We observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.
    Keywords:  cell fate; cortical development; cortical organoids; glycolysis; metabolism; metabolomics; neurodevelopment; pentose phosphate pathway; radial glia
    DOI:  https://doi.org/10.1016/j.cell.2026.07.023
  4. Dev Cell. 2026 Aug 11. pii: S1534-5807(26)00284-4. [Epub ahead of print]
    Elongating human heart organoids recapitulate early cardiac morphogenesis and axial organization.
    Jinwoo Lee, Ahri Kim, Yideul Jeong, Eugene Choi, Tae Young Kim, Mariam Nabukenya, Daesik Kim, Jaecheol Lee, Gyu-Un Bae, Jong-Sun Kang.
      Early heart development involves heart tube elongation, looping, and axial patterning, yet these processes remain difficult to study experimentally. While pluripotent stem cell-derived heart organoids model cardiomyocyte differentiation, they do not recapitulate early morphogenetic events. Here, we generate elongating heart organoids (EHOs) from human induced pluripotent stem cells that undergo coordinated elongation and looping-like curvature, resembling early cardiac morphogenesis. EHOs establish a venous-to-arterial axis with spatially organized sinus venosus-like, atrial, and ventricular cardiomyocytes, and exhibit sequential propagation of contractile activity along this axis. Single-cell transcriptomics and trajectory analyses, together with pulse-labeling, support a model in which progressive incorporation of cardiac cells from proliferative splanchnic mesodermal cells at the venous pole drives elongation of the cardiac structure. Consistent with in vivo phenotypes, TBX5 deletion results in shortened EHOs with reduced looping-like curvature and irregular contractions. Together, EHOs provide a human in vitro system that enables investigation of early cardiac morphogenesis.
    Keywords:  TBX5; cardiac elongation; cardiac looping; cardiac morphogenesis; congenital heart disease; heart organoids; human induced pluripotent stem cells; sinus venosus; venous-arterial axis
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.015
  5. Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2610420123
    Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
    Jordan Matthew Ngo, Justin Krish Williams, Abinayaa Murugupandiyan, Randy Schekman.
      The absence of a cell wall affords animal cells diverse functionality at the cost of acute sensitization to plasma membrane (PM) damage. Thus, animal cells tightly monitor and maintain PM integrity to prevent cell death. Genetic loss of PM repair factors is associated with human diseases such as muscular dystrophy. Despite evidence that annexin and endosomal sorting complex required for transport (ESCRT) proteins are required for PM repair, the extent to which their recruitment is coordinated at sites of membrane damage remains unclear. Here, leveraging quantitative organellar proteomics and genome-wide CRISPR interference screens, we identify sorcin as a PM repair factor that couples annexin A11 (ANXA11)-mediated sensing of PM damage to ESCRT-III assembly. We show that sorcin directly binds ANXA11 and ALIX in the presence of Ca2+ via its penta-EF-hand domain and flexible N terminus, respectively, and is required for ESCRT-III recruitment to PM lesions and membrane resealing. Our data support a model in which ANXA11, recruited to the PM upon damage-induced Ca2+ influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Together, these findings establish a Ca2+-dependent scaffolding mechanism that couples PM damage sensing to ESCRT-III assembly for PM repair.
    Keywords:  annexin; endosomal sorting complex required for transport (ESCRT); membrane repair; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2610420123
  6. Dev Cell. 2026 Aug 13. pii: S1534-5807(26)00281-9. [Epub ahead of print]
    Systematic differences in protein stability underlie species-specific developmental tempo.
    Mitsuhiro Matsuda, Henrik M Hammarén, Jorge Lázaro, Mikhail M Savitski, Miki Ebisuya.
      Human embryonic development proceeds more slowly than in mice. The segmentation clock offers a tractable model for studying species-specific developmental tempo, as its oscillation period in human induced presomitic mesoderm (iPSM) cells is approximately twice that of mouse. While the core clock gene HES7 exhibits slower protein degradation in human cells, it remains unclear whether such cross-species differences in protein stability reflect a general principle. Here, we perform a dynamic stable isotope labeling of amino acids in cell culture (SILAC)-based proteomic analysis of ∼5,000 proteins in human and mouse iPSM, and we uncover a broad trend of slower protein degradation in human cells, regardless of subcellular localization or degradation pathways. Moreover, inhibition of glycolysis in mouse iPSM partially phenocopies the human protein stability profile, and modulation of protein stability alters the tempo of both the segmentation clock and cellular differentiation. Our findings establish protein stability, with systematic differences across species, as a key mediator linking metabolism to developmental tempo.
    Keywords:  SILAC proteomics; allochrony; cross-species comparison; developmental tempo; metabolism; protein stability; segmentation clock
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.012
  7. Cell. 2026 Aug 11. pii: S0092-8674(26)00822-6. [Epub ahead of print]
    The sex and reproductive plasticity of intestinal muscles instruct gut size.
    Alessandro Mineo, Laura Blackie, Alexandra Milona, Emily Strachan, Pedro Gaspar, Nuno Miguel Luis, Alvaro Castano-Medina, Tomotsune Ameku, Bryon Silva, Anadika Prasad, Clara L Essmann, Jake Jacobson, Todd Fallesen, Vanessa Dao, Sanjay Khadayate, George Young, Filipe Cabreiro, Frank Schnorrer, Irene Miguel-Aliaga.
      Adult organs enlarge or regress in response to functional demands: changes commonly attributed to the dynamics of their resident stem cells. A striking example is the intestine, whose length varies with diet and reproductive status. We find that the size of the adult gut is extrinsically controlled by its surrounding muscles. In Drosophila, intestinal muscle differs in size and structure between sexes and grow in females during reproduction. By altering the sex or reproductive status of gut muscle cells, we establish that muscle-intrinsic sex determinants determine baseline sex differences in muscle myofibril width and organ size. Female muscles integrate hormonal and nutritional inputs during reproduction to elongate their sarcomeres; this reduces intestinal transit and further increases organ size. Such remodeling is adaptive and also occurs in mice. Our findings redefine the intestinal muscle as a responder to specific signals that adjust adult organ-level features and sustain reproductive demands.
    Keywords:  Drosophila; Mus musculus; intestinal visceral muscles; intestine; juvenile hormone; organ remodeling; peristalsis; plasticity; reproduction; sex differences
    DOI:  https://doi.org/10.1016/j.cell.2026.07.024
  8. Curr Biol. 2026 Aug 12. pii: S0960-9822(26)00942-5. [Epub ahead of print]
    Positional cues, not Notch, direct neuroblast selection during early neurogenesis in the Drosophila embryo.
    David Green, Khalil Mazouni, Marcel Nos, Francois Schweisguth.
      Notch-mediated lateral inhibition is a conserved patterning process that controls alternative cell fate decisions and produces regular cell fate patterns. Prevailing models posit that lateral inhibition singles out cells from fields of initially equipotent cells by amplifying stochastic fluctuations of Notch or pre-existing fate biases. Here, we revisited the role of Notch in early Drosophila neurogenesis, studying the dynamics of neuroblast specification by live imaging the transcription of two proneural genes, scute and lethal of scute. We found that proneural gene expression is biased spatially along the dorsal-ventral axis prior to germ band extension and that early proneural expression predicts neuroblast fate acquisition. This indicated that neuroblast specification is pre-patterned by positional cues. Additionally, positional cues appeared to instruct individual cells to delaminate in a correct stereotyped pattern in proneural mutant embryos. Finally, contrary to current models, Notch signaling, measured by E(spl)m8 expression, was not detectable within proneural clusters until after neuroblasts had initiated delamination. This indicated that Notch functions to stabilize rather than initiate fate decisions. We therefore propose that positional cues, not Notch, single out neuroblasts during early Drosophila neurogenesis, challenging long-held assumptions about the role of Notch in neuroblast selection.
    Keywords:  Delta; Drosophila; Notch; cell fate; cell-cell signaling; lateral inhibition; proneural
    DOI:  https://doi.org/10.1016/j.cub.2026.07.043
  9. Sci Adv. 2026 Aug 14. 12(33): eaee6914
    CDT1 acts with the replisome to remodel replication forks.
    Caitlin Hathaway, Thanh Le, Yuki Hatoyama, Masato Kanemaki, Huzefa Dungrawala.
      Replication forks encounter problems during genome duplication that trigger replication stress. Fork reversal is a key stress tolerance pathway that helps mitigate replication challenges to facilitate DNA synthesis. Here, we report the function of origin licensing factor CDT1 in fork remodeling by replication fork reversal. Characterization of replication dynamics during early stages of origin reactivation revealed that CDT1 blocks fork progression without inducing DNA breaks. Notably, CDT1 mediates replication fork reversal under conditions of re-replication and genotoxic stress exposure, and this function is dependent on the interaction with the CMG helicase. Although proliferating cell nuclear antigen (PCNA) sequesters CDT1 for proteolytic degradation under unperturbed conditions, ATAD5-mediated PCNA unloading at stressed forks releases CDT1 to interact with the CMG helicase and promote fork remodeling. Thus, contrary to the notion that CDT1 function must be inactivated in the S phase, our findings uncover a regulatory mechanism that facilitates fork remodeling function of CDT1 in response to replication stress.
    DOI:  https://doi.org/10.1126/sciadv.aee6914
  10. Dev Cell. 2026 Aug 12. pii: S1534-5807(26)00279-0. [Epub ahead of print]61(8): 1595-1597
    Mechanical control of human embryonic mesoderm fate via β-catenin is conserved with other metazoans.
    Laurie Exposito, Paula Cambronera-Ghiglione, Maria Elena Fernández-Sánchez, Emmanuel Farge.
      In this issue of Developmental Cell, Ayad et al.1 show that mesoderm specification in human embryonic stem cells (hESCs) can be induced by mechanical strain in a Y654-β-catenin-dependent mechanotransduction purpose. This feature is conserved with mechanical induction of endomesoderm specification by gastrulation in metazoan representatives of other superphyla.
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.010
  11. Genes Dev. 2026 Aug 12.
    Differential control of both cell cycle-regulated and quantitative histone mRNA expression by Drosophila Mute.
    Mark S Geisler, James P Kemp, Christina A Hill, William F Marzluff, Robert J Duronio.
      Coupling histone gene expression to S phase of the cell cycle is essential for genome duplication and stability. Activation of Cyclin E/Cdk2 at the G1-S transition stimulates high-level expression of histone genes during S phase, but how histone genes are turned off at the end of S phase is not understood. Here we demonstrate that the essential Drosophila gene mute functions to repress inappropriate histone mRNA accumulation outside of S phase by counteracting Cyclin E/Cdk2-dependent phosphorylation of Mxc, which activates histone gene expression. Additionally, Mute plays contrasting roles in histone gene expression during S phase by promoting high levels of H1, H2a, and H2b expression but not H3 and H4 Although Mute is present only at replication-dependent histone genes, its loss leads to 801 differentially expressed genes, primarily those involved in muscle related processes in late-stage embryos. Thus, disruptions of histone gene expression control alter the transcriptome resulting in developmental defects.
    Keywords:  Drosophila; biomolecular condensates; cell cycle; histones; transcription
    DOI:  https://doi.org/10.1101/gad.353837.126
  12. Nat Struct Mol Biol. 2026 Aug 13.
    Nucleosomes and IDRs suppress promiscuous GCN4 binding on minichromosomes.
    Zelin Wei, Oluwakemi E Abiodun, Yick Hin Ling, Fijare Plous, Maryam Yamadi, Katherine Chen, Songgao Shan, Annie Huang, Carl Wu.
      Eukaryotic sequence-specific transcription factors (TFs) must find their cognate DNA targets hidden in genomic chromatin amid an excess of nonspecific sequences and degenerate motifs. Although static TF interactions with nucleosomal targets have been elucidated, how TFs efficiently search for cognate sites within native gene-sized chromatin domains has been unclear. Here we used purified Saccharomyces cerevisiae HIS3 minichromosomes and single-molecule imaging to compare association and dissociation kinetics of transcription activator GCN4 on chromatin and naked genomic DNA. GCN4 displays widespread and stable off-target binding on bare DNA because of entrapment by degenerate sites and interactions with nonspecific DNA of increasing length, indicative of one-dimensional (1D) diffusion. Nucleosome organization on the minichromosome reduces promiscuous GCN4 residence times by obstructing TF association and restricting 1D target search within nucleosome-free regions. Furthermore, the intrinsically disordered GCN4 activation domain independently enhances targeting efficiency and specificity by accelerating association-dissociation kinetics in vitro and in living cells. Altogether, both nucleosome organization and activation domains independently suppress promiscuous GCN4 binding, which, if unchecked, may cause aberrant cryptic transcription known to occur upon chromatin disruptions.
    DOI:  https://doi.org/10.1038/s41594-026-01864-x
  13. Aging Cell. 2026 Aug;25(8): e70668
    Ovarian Extracellular Matrix Mechanics Regulate Oocyte-Follicle Interactions During Female Reproductive Aging.
    Xingyu Shen, Haiyang Wang, Gefei Cao, Yaelim Lee, Jin Zhu, Loo Chien Wang, Tianyun Zhao, Siok Ghee Ler, Radoslaw M Sobota, Rong Li, Jennifer L Young.
      Female reproductive aging is associated with ovarian functional decline, leading to infertility. During aging, biochemical and biophysical changes in the ovarian extracellular matrix (ECM) occur, yet how these properties affect follicle growth and oocyte quality remains poorly understood. Here we describe spatiotemporal changes in the ovarian ECM with age using mass spectrometry, immunohistochemistry, and nanoindentation. While follicle stiffness remains unchanged, stromal matrix remodeling is associated with a ~2.5-fold increase in stiffness. To understand how this increase in stromal stiffness affects age-related follicular dysfunction, isolated young follicles were cultured in soft and stiff hydrogels mimicking young and aged ovarian stromal stiffness, respectively. Higher stiffness lead to a decrease in granulosa cell (GC) proliferation, oocyte quality, and GC-oocyte interactions mediated via transzonal projections (TZPs). RNA-seq revealed TGF-β signaling as a major pathway affected by stiffness, and activation of TGF-β signaling through Smad7 silencing rescued TZP formation and oocyte quality in stiff matrix. These findings provide mechanistic insight into how changes in ECM mechanics contribute to ovarian aging functional decline and reveal potential therapeutic targets to counter fertility loss associated with tissue aging and fibrosis.
    Keywords:  TGF‐β; infertility; ovarian stroma; stiffness; transzonal projections
    DOI:  https://doi.org/10.1111/acel.70668
  14. Cold Spring Harb Perspect Biol. 2026 Aug 10. pii: a041914. [Epub ahead of print]
    Transcriptional and Epigenetic Regulation of Cell Fate by YAP and TAZ.
    Ju-Gyeong Kang, Taejun Seol, Younghoon Kim, Dae-Sik Lim.
      Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (YAP/TAZ) are key transcriptional coregulators that govern mammalian cell fate through complex epigenetic mechanisms. As core effectors of the Hippo signaling pathway, they integrate diverse cellular signals-including those mechanical, metabolic, or biochemical in nature-to control lineage specification, organ development, and tissue homeostasis. Although they have been traditionally known for their roles in the control of organ size and tumorigenesis, more recent evidence has revealed their function as important epigenetic modulators that reshape chromatin landscapes to direct cell fate transitions across multiple tissue contexts. Through interactions with chromatin-modifying complexes, the transcriptional machinery, and lineage-specific factors, YAP/TAZ coordinate enhancer activation, superenhancer formation, and chromatin looping to establish transcriptional programs essential for cellular identity. This work reviews the current understanding of YAP/TAZ-mediated epigenetic regulation and examines their tissue-specific roles. We propose a unified mechanistic framework by which the level of YAP/TAZ activity determines enhancer landscapes that favor either differentiated or progenitor-like cellular states, providing a potential basis for applications to regenerative medicine and therapeutic interventions.
    DOI:  https://doi.org/10.1101/cshperspect.a041914
  15. Cell Stem Cell. 2026 Aug 11. pii: S1934-5909(26)00270-5. [Epub ahead of print]
    Human heart valve-like tissues from pluripotent stem cells with enhanced maturation recapitulate inflammatory valve disease.
    Holly K Voges, Jessica Durrant-Whyte, Michael See, Valerii Iaprintsev, Serene Yeow, Benjamin L Parker, Kaitlyn Bibby, Ellen Keen, Ingrid King, Adam T Piers, Anita C Thomas, Daniel G Donner, Akriti Varshney, Sara Alaei, David Yoannidis, Timothy Semple, Natalie Charitakis, Jerico Revote, Adriano Morandini, Purva Kumbhar, Rebecca Sutton, Francesca Butera, Edouard G Stanley, Janice D Reid, James E Hudson, Amr H Allam, Sara Ellis, Lina H H Le, James P Burgess, Sean J Humphrey, Salvatore Pepe, Hazem Alkazemi, Daniel E Heath, Mirana Ramialison, Fernando J Rossello, Christian P Brizard, David A Elliott, Alejandro Hidalgo, Enzo R Porrello.
      Therapeutic management of heart valve disease is currently hampered by a lack of mechanistic understanding of human valve development and pathobiology. Here, we develop a protocol to generate three-dimensional human heart valve-like tissues from pluripotent stem cells with enhanced maturational properties that partially recapitulate key molecular features of native valves. This includes an abundance of valve interstitial cells, resident macrophage cells, and the transcriptional profile of native heart valves. Importantly, we define a heart valve maturation signature from proteomic analysis and show that maturation of stem cell-derived valve cells is enhanced under 3D culture. We demonstrate that bioengineered valve-like microtissues can be used for modeling valve disease. Namely, treatment with inflammatory cytokines augmented tissue passive tension and induced molecular hallmarks of valve calcification, consistent with the pathological signature of clinical samples from diseased valves. Thus, bioengineered human heart valve-like tissues provide a platform to understand human heart valve development, maturation, and disease pathogenesis.
    Keywords:  bioengineering; disease modeling; heart valves; inflammatory valve disease; maturation; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.stem.2026.07.010
  16. Circulation. 2026 Aug 11.
    YAP Promotes Microtubule Growth to Facilitate Sarcomere Disassembly in Adult Cardiomyocytes.
    Feng Zhang, Jenna K Cusick, Jie Liang, Fangfei Wang, Andrew T Fernandes, Jacob T Gafranek, Joshua S Waxman, Zhiyuan Chen, Katherine E Yutzey, Shijie Liu.
       BACKGROUND: Mature mammalian cardiomyocytes (CMs) develop compact sarcomeric structures that inhibit proliferation. Consequently, CMs must dedifferentiate to a fetus-like state, which is accompanied by sarcomere disassembly, to enable successful cytokinesis. However, the regulation and coordination of CM dedifferentiation, cell cycle progression, and sarcomere reorganization remain unclear.
    METHODS: We generated adenovirus and adeno-associated virus (MyoAAV) vectors expressing YAP5SA and YAP5SA-S94A under Xon control for LMI070-inducible protein expression. We also developed MyoAAV-cTnT-Tuba1b-shRNA-miR30 for cardiomyocyte-specific knockdown of Tuba1b. These tools were used to investigate CM dedifferentiation and proliferation and sarcomere disassembly. We also performed Cleavage Under Targets and Release Using Nuclease to map the genome-wide binding sites of YAP5SA and YAP5SA-S94A in combination with RNA sequencing to identify YAP target genes. In addition, time-course live-imaging analysis was used to evaluate microtubule and sarcomere dynamics in adult CMs.
    RESULTS: We show that microtubule expression and network density decline with cardiac maturation. Overexpression of YAP5SA, a constitutively active YAP mutant, promotes microtubule growth by stabilizing microtubule dynamics, leading to CM dedifferentiation, cell cycle re-entry, and sarcomere disassembly. In contrast, colchicine blocks these processes and significantly attenuates YAP-induced cardiac regeneration. Live imaging reveals a distinct mode of sarcomere disassembly driven by enhanced microtubule polymerization, wherein microtubule plus-ends directly interact with α-actinin and displace α-actinin fragments, thereby facilitating sarcomere breakdown. Furthermore, the YAP5SA-S94A mutation, which disrupts the YAP and TEA domain interaction, significantly reduces YAP5SA-induced microtubule growth, sarcomere disassembly, and cell cycle activity. Mechanistically, cleavage under targets and release using nuclease combined with RNA sequencing identified direct YAP targets, including Ajuba and Tuba1b, which are critical for microtubule growth. CM-specific knockdown of Tuba1b attenuates YAP-driven sarcomere disassembly.
    CONCLUSIONS: These findings identify microtubule networks as an essential regulator modulating CM dedifferentiation and sarcomere reorganization, which is critical for CM cytokinesis and cardiac regenerative repair.
    Keywords:  Tuba1b protein, mouse; YAP-signaling proteins; microtubules; myocytes, cardiac; sarcomeres
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080761
  17. Nat Commun. 2026 08 10. pii: 6961. [Epub ahead of print]17(1):
    Nuclear compartmentalization at the G1/S transition plays a key role in DNA replication control.
    Asami Oji, Kosuke Yusa, Izumi Noda, Takako Ichinose, Yoshiko Kondo, Ichiro Hiratani.
      Upon entry into the G1 phase following mitosis, mammalian chromosomal DNA becomes spatially segregated into A and B compartments, which correspond closely to classic euchromatin and heterochromatin, respectively. The functional significance of this spatial segregation, however, has remained unexplored due to the lack of means to manipulate this level of chromosomal organization. Through a genome-wide loss-of-function CRISPR screen, we identify GINS4, a component of the replicative DNA helicase complex, as a factor essential for segregation of A and B compartments during the G1-to-S phase transition. Using GINS4 depletion experiments, we show that proper A/B compartment organization at the time of S-phase entry plays a key role in efficient DNA synthesis. Furthermore, DNA synthesis with attenuated A/B compartments is associated with defects in replication timing regulation. Our findings uncover a previously unrecognized role for GINS4 in regulating nuclear architecture and underscore the biological significance of nuclear compartmentalization in DNA replication control.
    DOI:  https://doi.org/10.1038/s41467-026-75264-6
  18. Nat Rev Mol Cell Biol. 2026 Aug 10.
    Mechanisms of transcription termination across the coding and noncoding loci of the genome.
    Aixia Song, Minhui Hu, Fei Xavier Chen.
      Transcription termination by RNA polymerase II (Pol II) defines transcriptional boundaries of protein-coding and noncoding transcription units throughout the genome. Rather than being a passive endpoint of elongation, termination is a tightly regulated and context-dependent process that shapes gene expression, RNA surveillance pathways and chromatin environments. This Review summarizes mechanistic and conceptual aspects of Pol II termination, focusing primarily on studies in metazoans and incorporating insights from yeast where relevant. We discuss the major termination pathways operating across different genomic contexts, including canonical cleavage and polyadenylation-dependent termination at 3' ends of genes, promoter-proximal termination mediated by the Integrator-PP2A complex (INTAC), Pol II turnover via the E3 ligase CRL3ARMC5 and cap-dependent RNA surveillance. We further examine how termination restrains pervasive transcription and how its dysregulation compromises genome stability, particularly through the accumulation of R-loops. Finally, we discuss how termination interfaces with RNA processing, export and nuclear decay pathways to guide RNA fate decisions.
    DOI:  https://doi.org/10.1038/s41580-026-01005-8
  19. Cell Stem Cell. 2026 Aug 11. pii: S1934-5909(26)00271-7. [Epub ahead of print]
    Human iPSC-derived heart valve-like assembloids model valve development and disease pathology.
    Yuanhang He, Abbas Jalili, Carter B Jones, Haoting He, Lameck Beni, Daniel Lamont, Junqi Hu, Macy Yost, Lance A Davidson, Si-Yang Zheng, Guang Li.
      Heart valves maintain unidirectional blood flow, yet most understanding of their development and disease comes from animal models that do not fully capture human valve behavior. We present a human induced pluripotent stem cell (iPSC)-derived valve-like assembloid platform that models key aspects of in vivo valve features at the cellular and molecular levels. We found that mechanical forces, endothelial culture conditions, and fluidic shear stress respectively promote valve induction, maintenance, and extracellular matrix stratification. We further used this system to model human valve defects, including genetic mutations, injury, and hyperglycemia-related abnormalities. This assembloid platform enables the in vitro study of human valve development and disease mechanisms.
    Keywords:  congenital valve deficiency; endothelial cell; endothelial-to-mesenchymal transition; hyperglycemia; mechanical force; organoid; valve; valve injury
    DOI:  https://doi.org/10.1016/j.stem.2026.07.011
  20. Dev Cell. 2026 Aug 04. pii: S1534-5807(26)00275-3. [Epub ahead of print]
    Nodal/Smad2 signaling sustains developmental pausing by repressing Pparg-mediated lipid metabolism.
    Giacomo Furlan, S Bryn Martin, Brandon Cho, Ying Yu Ng, Sarah A McClymont, Abdul Rahman, Elizabeth J Robertson, Evelyne Collignon, Miguel Ramalho-Santos.
      Mammalian embryonic diapause is a reversible state of pre-implantation dormancy characterized by metabolic rewiring toward lipid usage as energy source. Whether active signaling sustains this dormant state remained unclear. Here, we show that the transforming growth factor- β (TGF-β) pathway, previously thought to only be required post-implantation, is essential for diapause. Nodal signaling is activated and its downstream effector SMAD family member 2 (Smad2) is required during diapause in vivo. Using ex vivo blastocyst and embryonic stem cells models of diapause, we show that Smad2 represses peroxisome proliferator-activated receptor gamma (Pparg), a master regulator of lipid storage. Loss of Smad2-mediated Pparg repression leads to lipid accumulation and is incompatible with pausing. Our findings establish a Nodal-Smad2-Pparg axis that is pivotal for sustaining the transcriptional and metabolic programs of embryonic diapause. This axis may be redeployed in other contexts, including cancer dormancy and metabolic disorders.
    Keywords:  Nodal; Pparg; Smad2; diapause; lipid metabolism; pre-implantation development
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.006
  21. Mol Cell. 2026 Aug 04. pii: S1097-2765(26)00503-4. [Epub ahead of print]
    Torsins organize CLCC1 assembly to safeguard ER bilayer and lipid homeostasis.
    Yonglun Wang, Renqian Wang, Yuanhang Yao, Rongxian Hou, Lu Yan, Yiechang Lin, Yating Hu, Youlei Li, Lingzhi Wu, Yuangang Zhu, Ning Gao, Chen Song, Xiao Wang, Zhejian Ji, Xiao-Wei Chen.
      The TMEM41B scramblase and its regulatory partner CLCC1 initiate lipid flux by equilibrating newly synthesized phospholipids across the endoplasmic reticulum (ER) bilayer, a fundamental process required for diverse events ranging from membrane biogenesis to bulk lipid supply. Loss of CLCC1/TMEM41B causes ER bilayer imbalance, which induces giant ER-enclosed lipid droplets (geLDs) and drives rapid progression into severe metabolic-dysfunction-associated steatohepatitis (MASH). Combining both human cell lines and mouse models, we herein reveal CLCC1 to be the long-missing client of the luminal torsin ATPases, which selectively engage oligomerized CLCC1 at sites of ER bilayer imbalance. Mice hepatic torsinA inactivation triggers geLD formation amid disrupted lipoprotein biogenesis and severe MASH, closely phenocopying CLCC1/TMEM41B deficiency. Mechanistically, torsins act as assembly-promoting ATPases that drive CLCC1 oligomerization for its recruitment to imbalanced bilayers. Remarkably, ectopic CLCC1 expression reverses cellular and systemic lipid disorders arising from hepatic torsinA deficiency. Hence, torsin ATPases emerge as fundamental regulators that organize CLCC1 and the downstream TMEM41B scramblase to govern lipid partitioning and membrane homeostasis.
    Keywords:  AAA+ ATPase; ER membrane homeostasis; lipid metabolism; torsins
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.017
  22. Genes Dev. 2026 Aug 11.
    Temporal gating dictates stress-induced transcript export from the nucleus.
    Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Prior studies have largely focused on transcriptional and translational control during stress, but how regulated nuclear mRNA export contributes to the stress response remains unresolved. We show that nuclear mRNA export is progressively inhibited during arsenite and heat stress in human cells. In contrast to previous work largely in yeast that suggests nuclear export of stress-induced transcripts is prioritized through sequence-specific mechanisms, we found that mRNA export is governed by temporal gating, in which the timing of mRNA biogenesis determines the nucleocytoplasmic distribution of mRNAs during stress. Using single-molecule mRNA imaging and transcriptome-wide analyses, we observe the majority of stress-induced mRNAs, including heat shock protein transcripts, accumulate in the nucleus during stress. However, a subset of stress-induced mRNAs, notably HMOX1, JUN, and FOS, escape nuclear retention. mRNAs transcribed early during stress, including those encoding immediate early genes, redox mediators, and protein chaperones, are exported from the nucleus prior to the global inhibition of mRNA export. In contrast, mRNAs transcribed later are retained in the nucleus until stress is resolved. Reporter RNA assays confirm that transcriptional timing determines mRNA export competence. This work reveals that the timing of mRNA production, rather than transcript-specific sequence features, is the major determinant of nuclear export efficiency of stress-induced transcripts in human cells.
    Keywords:  heat shock proteins; heat shock response; integrated stress response; nuclear export; stress-induced genes
    DOI:  https://doi.org/10.1101/gad.353896.126
  23. Nat Aging. 2026 Aug;6(8): 1631-1646
    TNFR1 signaling connects inflammation to impaired fatty acid oxidation to drive intestinal stem cell aging.
    Ruixuan Wang, Tahmineh Tabrizian, Donghai Wang, Jeb English, Anita Ayer, Maya Gal, Weng-Lang Yang, Zhiping Wu, Kai Mao, Ardijana Novaj, Xusheng Zhang, Indranil Basu, Nils P Brodin, Wade Koba, Deepak Saxena, Jiahn Choi, Leonard H Augenlicht, Aaron Ericsson, Evripidis Gavathiotis, Chandan Guha, Derek M Huffman.
      Aging is characterized by a decline in function of intestinal stem cells (ISCs), but the extent to which this is shaped by systemic factors is unclear. Here we show that the ISC aging phenotype can be propagated from old to young mice utilizing heterochronic parabiosis, and implicate a role for inflammation in these effects, as anti-inflammatory drugs, including TNF antibodies, restored function. Parabiotic rescue experiments demonstrate that TNFR1 knockout protected young ISCs from the old environment. In young organoids, TNF downregulated crypt budding, while impairing mitochondrial pathways and fatty acid oxidation (FAO). However, aged ISC function was enhanced by boosting mitochondrial fusion, whereas FAO in aged crypts was improved by countering inflammation with salicylate treatment. Thus, these data identify the old environment through the progeronic factor TNF, as a driver of ISC aging phenotypes through intestinal epithelial cell TNF receptor 1 signaling to downregulate FAO, proliferation and regenerative capacity in these cells.
    DOI:  https://doi.org/10.1038/s43587-026-01170-7
  24. J Cell Sci. 2026 Nov 01. pii: jcs264813. [Epub ahead of print]139(21):
    Cell surface remodeling caused by the loss of the flippase subunit TMEM30A in immune cells.
    Cenk O Gurdap, Franziska Ragaller, Marion Muller, Ellen Sjule, Taras Sych, Linnea Blomén, Fredrik B Thorén, Ilya Levental, Kandice R Levental, Quentin J Sattentau, Erdinc Sezgin.
      Plasma membrane lipid asymmetry is tightly regulated and fundamental to mammalian cell physiology. TMEM30A is the β-subunit of P4-ATPases, flippase enzymes that maintain strict phosphatidylserine (PS) asymmetry by pumping it from the outer to the cytosolic leaflet. Loss of TMEM30A function causes constitutive PS externalization and has been implicated in diseases such as diffuse large B-cell lymphoma and tumor immune evasion. Here, we systematically define the biophysical and molecular consequences of TMEM30A deletion in immune cells. Using a live-cell lipid reporter, membrane order probe, and surface proteome mapping, we show that TMEM30A-knockout cells display robust PS externalization accompanied by faster lateral diffusion of membrane constituents and decreased plasma membrane order. Surface proteome reorganization includes increased abundance of tetraspanins and CD47. Furthermore, TMEM30A loss triggers glycocalyx remodeling via ADAM10-dependent shedding, which removes major transmembrane mucins, including CD43 and CD162 (also known as SPN and SELPLG, respectively). Together, these data reveal a coordinated reorganization of lipids, glycans and proteins upon TMEM30A loss, suggesting mechanistic links between flippase dysfunction and increased plasma membrane dynamics and potential sensitization to immune therapy. Furthermore, our study provides an integrated surfaceome framework that might shed light on the relationship between TMEM30A expression and clinical outcomes in cancer.
    Keywords:  ADAM10; CD162; CD43; CD47; CDC50A; Immune evasion; Lipid asymmetry; Membrane order; Mucin shedding; Phosphatidylserine
    DOI:  https://doi.org/10.1242/jcs.264813
  25. Cell. 2026 Aug 14. pii: S0092-8674(26)00875-5. [Epub ahead of print]
    Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.
    Simone Brioschi, Julia A Belk, Steffen E Storck, Yue Wu, Zhuoying Wang, Ziang Feng, Lynn van Olst, Josie L Emery, Raki Sudan, Junjie Wu, Siling Du, Marco Genua, Federica La Terza, Alex J Edwards, Khai M Nguyen, Jessie Sanford, Daniel D Lee, Mattia Bugatti, Arnold J Federico, Yun Chen, Zuoxu Wang, Silvia Penati, Patrick Fernandes Rodrigues, Alina Ulezko Antonova, Hui Qi Loo, Igor Smirnov, Susan Gilfillan, Carmen M Halabi, Jennifer Ponce, Jun Yan, Howard Y Chang, Gwendalyn J Randolph, William Vermi, Marina Cella, Michael Meers, Renato Ostuni, David Gate, Aivi T Nguyen, Carlos Cruchaga, Song Hu, Jonathan Kipnis, Marco Colonna.
      Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.
    Keywords:  APOE4; Alzheimer's disease; IGF1; arteries; cMAF; cerebral blood flow; cerebrospinal fluid; immune-vascular axis; microglia; perivascular macrophages
    DOI:  https://doi.org/10.1016/j.cell.2026.07.043
  26. Cell. 2026 Aug 10. pii: S0092-8674(26)00825-1. [Epub ahead of print]
    The structural basis for LRRK2's activation and autoinhibition.
    Amalia Villagran Suarez, Kathryn S Hatch, Tatyana Bodrug, Wei Gai, Katherine J Surridge, Elizabeth Moussikhina, Kendrick H V Nguyen, Marta Sanz-Murillo, Robert Callahan, Erica Xiong, Delisa Ramos, Lawrence Zhu, Verena Dederer, Sebastian Mathea, Janet Iwasa, Stefan Knapp, Kevan M Shokat, Samara L Reck-Peterson, Andres E Leschziner.
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the guanosine diphosphate (GDP)-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.
    Keywords:  G2019S; GTPase; LRRK2; Parkinson’s disease; R1441C; R1441H; activation; autoinhibition; cryo-EM; kinase
    DOI:  https://doi.org/10.1016/j.cell.2026.07.027
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