bims-ginsta Biomed News
on Genome instability
Issue of 2026–06–14
fifty-four papers selected by
Jinrong Hu, National University of Singapore
  1. mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity.
  2. Continuous modeling of primate embryogenesis from totipotency to early organogenesis.
  3. Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages.
  4. Two distinct causes contribute to the low efficiency of human pre-implantation development.
  5. Cell size-dependent mRNA transcription drives proteome remodeling.
  6. Single-nucleus interrogation of primate small intestinal aging reveals NCoR1 decline as a conserved feature that is reversed by metformin.
  7. Long-range mutual activation establishes Rho and Rac polarity during cell migration.
  8. Chromatin architecture sets origin licensing capacity.
  9. Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate.
  10. Contractile perinuclear actomyosin network promotes peripheral and polar chromosome interaction with the mitotic spindle.
  11. Cyclin-dependent kinase CDK1 targets cell-cell junction components and governs epithelial monolayer integrity throughout the cell cycle.
  12. A damage accumulation model identifies distinct aging regimes across species.
  13. IAPEz retrotransposons regulate the first lineage segregation in mouse pre-implantation development.
  14. Loss of STMP1 Perturbs Mitochondrial Cristae and Drives Cellular Inflammation and Heart Failure.
  15. Genome-wide histone humanization in yeast disrupts genome organization, replication, and rDNA stability.
  16. Heterotypic intercellular adhesion tunes efficiency of cell-on-cell migration.
  17. RNA reinforces condensate nucleation on chromatin to amplify oncogenic transcription.
  18. Procollagen 1 assembles into phase-separated condensates in the endoplasmic reticulum.
  19. Prion-based protein self-assembly tunes mutagenesis to enable rapid adaptation.
  20. Nuclear proteome reveals microtubule-associated protein regulating fate and disease.
  21. Cell fusion after wounding requires plasma membrane damage and endocytosis.
  22. Glassy dynamics in active epithelia emerge from an interplay of mechanochemical feedback and crowding.
  23. Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle.
  24. Persistent and transient senescent cells contribute to brain-barrier development.
  25. Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.
  26. DNA repair drives cisplatin-induced neuronal death.
  27. A stretch-responsive fibroblast program promotes epidermal stem cell self-renewal during skin expansion.
  28. Lineage tracing in gastruloids to understand determinants of early fate decisions.
  29. Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
  30. Rpd3L regulates transcription-replication conflict via H3K4 methylation-dependent and -independent chromatin mechanisms.
  31. Laminin α5 and integrins α3 and α6 coordinately regulate collective cell migration in vivo.
  32. VMP1 forms a Ca2+ release channel essential for postnatal heartbeat.
  33. Charting human cellular senescence in aging and disease.
  34. Large-scale, spatially resolved panoramic CRISPR screening in native tissue environments using Perturb-DBiT.
  35. Designing complex organoids through developmental principles.
  36. Somatic cells non-autonomously control germline incomplete cytokinesis through FGF signaling.
  37. Mitochondria directly interact with the nuclear pore complex.
  38. Mitochondria-ER contacts function as an iron supply hub.
  39. Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.
  40. The C. elegans WASH complex supports epithelial polarity by promoting endosomal sorting of E-Cadherin.
  41. Spatially resolved m6A profiling using m6A-ARTR-DBiT.
  42. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  43. CytoSignal detects locations and dynamics of ligand-receptor signaling at cellular resolution from spatial transcriptomic data.
  44. Harnessing the murine inner cell mass mechanical environment enhances derivation of in vitro nascent primitive endoderm precursor cells.
  45. Whole-genome duplication shaped cell-type evolution in the vertebrate brain.
  46. SIRT7 regulates dosage compensation and safeguards the female X chromosome.
  47. The post-reproductive ovary shifts from a reproductive to an immune-like organ.
  48. Opposing roles of serine and charge in IDR condensate miscibility.
  49. DRP1 and MID49 co-diffusion scans mitochondria for fission.
  50. Placental nicotinamide adenine dinucleotide modulates the timing of labor.
  51. Single-cell proteome atlas of aging mouse microglia reveals subpopulation-specific phagoproteome.
  52. HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging.
  53. DDX6 induces immunosuppression in cancer by disrupting structural stability of endogenous double-stranded RNAs.
  54. Rewiring oncogenic signalling to precision ablation of metastatic cancer.
  1. Cell. 2026 Jun 08. pii: S0092-8674(26)00576-3. [Epub ahead of print]
    mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity.
    Yang Luo, Yaofeng Zhong, Sudipto Basu, Ming-Chung Wu, Christine Mayr.
      More than 2,700 human mRNA 3' UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs encode proteins strongly enriched for long intrinsically disordered regions (IDRs) with hydrophobic amino acid clusters. For MYC, UTX, and JMJD3, we show that their mRNA 3' UTRs control protein activity. Rather than affecting protein abundance or localization, we find that the KDM6B 3' UTR co-translationally changes the folding of JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA has IDR chaperone activity that prevents interference between hydrophobic clusters in the IDR with folding of the structured domain. 3' UTRs with chaperone activity are multivalent and mesh-like condensate-enriched, indicating the presence of localized folding environments for IDR-containing proteins. We show here that the protein sequence is insufficient for the biogenesis of fully active IDR-containing transcriptional regulators in cells, suggesting that mRNA 3' UTRs control their activity by preventing co-translational misfolding.
    Keywords:  3′ UTR; RNA multivalency; RNA-based chaperone activity; RNA–IDR interaction; chromatin regulator; co-translational; crosslinking mass spectrometry; hydrophobic clusters; intrinsically disordered regions; mesh-like condensates; protein folding; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2026.05.017
  2. Cell. 2026 Jun 10. pii: S0092-8674(26)00582-9. [Epub ahead of print]
    Continuous modeling of primate embryogenesis from totipotency to early organogenesis.
    Wei Zheng, Bing Peng, Zilin Chen, Kangwei Huang, Yueyao Qi, Huimin Niu, Hui Shen, Jun Wu, Jianwei Jiao, Peng Du.
      Embryo-like structures, or embryoids, are powerful models to investigate early embryonic development. Yet, previous models cover only partial developmental stages, restricting their applications. Here, we successfully generate primate organogenetic embryoids from cynomolgus totipotent blastomere-like stem cells (cTBLCs). cTBLCs, reprogrammed from pluripotent stem cells and stably maintained, can display key totipotent-like molecular and functional features resembling zygotes/2-4-cell blastomeres. cTBLCs spontaneously generate well-organized blastoids that further progress through gastrulation to early organogenesis, thus exhibiting neural-tube-like structures and cardiac-like beating activity. Using single-cell RNA sequencing (scRNA-seq), we visualized stepwise cell-state transitions from cTBLCs to organogenetic lineages and identified an intermediate 8-cell/morula-like state. Interestingly, we uncovered a dynamic cascade of regulatory networks originating from cTBLCs, which represented an intrinsic developmental initiation program occurring independently of classical fertilization-associated events. Together, the cTBLC platform provides a unified in vitro framework to investigate developmental initiation, early lineage specification, and organogenesis.
    Keywords:  beating heart; blastoid; cell-fate determination; embryo-like structures; embryogenesis; gastrulation; organogenesis; primate; stem-cell-derived embryo model; totipotent blastomere-like cells
    DOI:  https://doi.org/10.1016/j.cell.2026.05.023
  3. J Cell Biol. 2026 Aug 03. pii: e202507165. [Epub ahead of print]225(8):
    Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages.
    Isabella M Gaeta, Shuangshuang Du, Clémentine Villeneuve, David G Gonzalez, Catherine Matte-Martone, Smirthy Ganesan, Deandra Simpson, Hilldana Tibebu, Jessica L Moore, Chen Yuan Kam, Sara Gallini, Haoyang Wei, Fabien Bertillot, Dagmar Zeuschner, Lauren E Gonzalez, Ushnish Rana, Kaelyn D Sumigray, Sara A Wickström, Valentina Greco.
      Regenerative organs, like the skin, depend on niche-stem cell interactions that sustain cellular turnover. In culture, skin fibroblasts promote epidermal stem cell proliferation and differentiation. Yet, it remains elusive how fibroblasts regulate epidermal stem cell behaviors and differentiation in vivo in skin. Here, we asked how fibroblast depletion may impact proliferation of the epidermal stem cell compartment. Surprisingly, we find that significant depletion of fibroblast density does not affect epidermal stem cell proliferation during adult or neonatal stages in vivo. These results demonstrate that across different ages, proliferation of epidermal stem cells can persist in the face of a depleted fibroblast population. Interestingly, neonatal fibroblast depletion does not significantly reduce collagen I density but affects basement membrane mechanics and epidermal stem cell delamination. Despite these changes, the skin continues to maintain its protective barrier function. Thus, our work demonstrates the skin regenerative program employs robust compensatory mechanisms in response to fibroblast depletion to maintain functional capacity.
    DOI:  https://doi.org/10.1083/jcb.202507165
  4. Cell. 2026 Jun 11. pii: S0092-8674(26)00637-9. [Epub ahead of print]
    Two distinct causes contribute to the low efficiency of human pre-implantation development.
    Zixuan Li, Lizhi Leng, Jinglei Zhai, Xiaowen Wang, Wuling Yang, Shuhui Wang, Haifeng Wan, Shuoping Zhang, Fei Gong, Xi Liao, Yuhui Li, Qing Zeng, Yansu Chen, Zhenyu Xiang, Feiyao Liu, Fuchu He, Yun Yang, Hongmei Wang, Xiaoming Xu, Ge Lin, Chun So.
      ∼50% of fertilized eggs arrest during human pre-implantation development, representing a major bottleneck for assisted reproductive technology. The underlying causes remain controversial. By imaging ∼150 live human and monkey fertilized eggs for up to 5 days, we uncovered that the second mitotic divisions are the most error-prone, accounting for early embryonic arrest. Stochastic centriole overduplication, which could be effectively suppressed by transient treatment with PLK4 inhibitor centrinone, predisposed 2-cell blastomeres to assembling multipolar spindles and missegregating chromosomes. Missegregated chromosomes in turn resulted in the formation of most micronuclei in human embryos and led to the arrest or death of daughter blastomeres. By contrast, late embryonic arrest was largely independent of chromosome missegregations but involved the activation of endoplasmic reticulum stress response, which could impair the expression of subsets of junctional and cell polarity proteins required for blastocyst formation. Thus, two distinct causes contribute to the low efficiency of human pre-implantation development.
    Keywords:  aneuploidy; centrosome; chromosome segregation; embryonic arrest; endoplasmic reticulum stress response; human embryo; long-term live-cell imaging; micronuclei; pre-implantation development; spindle
    DOI:  https://doi.org/10.1016/j.cell.2026.05.037
  5. Cell Rep. 2026 Jun 10. pii: S2211-1247(26)00566-8. [Epub ahead of print]45(6): 117488
    Cell size-dependent mRNA transcription drives proteome remodeling.
    Dong Shin You, Christopher H Bohrer, Purva H Rumde, Ioannis Sanidas, Matthew P Swaffer, Daniel R Larson, Josh E Elias, Michael C Lanz, Jan M Skotheim.
      Increasing cell size drives proteomic changes that impact cell physiology. However, the molecular basis of size-dependent proteome remodeling has remained unclear. Here, we develop an inducible Cyclin D1 expression system in human cells to generate proliferating cells spanning over a 2-fold size range. We use this system to make comprehensive genome-wide measurements of mRNA and protein concentrations and stability. We find that protein and mRNA turnover rates are weakly related to cell size but that mRNA concentrations are strongly size-dependent. This establishes that transcriptional regulation is the basis of proteome remodeling. Live-cell imaging of nascent mRNAs using the MS2 system is used to measure how transcriptional dynamics change with cell size. Larger cells prolong transcriptional bursts but maintain similar burst amplitudes to achieve transcriptional scaling. Together, our results show how transcription is modulated by cell size to remodel the proteome and alter cell physiology.
    Keywords:  CP: molecular biology; bursting; cell biology; cell size; homeostasis; lysosome; scaling; single-molecule imaging; transcription; turnover
    DOI:  https://doi.org/10.1016/j.celrep.2026.117488
  6. Nat Aging. 2026 Jun 09.
    Single-nucleus interrogation of primate small intestinal aging reveals NCoR1 decline as a conserved feature that is reversed by metformin.
    Jingyi Li, Xiaoyong Lu, Tianhong Tong, Xin Zhou, Baohu Zhang, Xiaoyan Sun, Bing Zhao, Gang Xu, Jinjiang Yang, Yanling Fan, Jianli Hu, Haoteng Yan, Zhejun Ji, Mingheng Li, Shanshan Che, Yuanhan Yang, Yingjie Ding, Qiaoran Wang, Shuhui Sun, Shuai Ma, Si Wang, Juan Carlos Izpisua Belmonte, Jing Qu, Weiqi Zhang, Guang-Hui Liu.
      How the small intestine ages at the cellular and molecular level has been unclear. Here we profile single nuclei from young and aged primate small intestine and find that aging brings barrier dysfunction, chronic inflammation and a shift in stem cell differentiation away from absorptive cells toward secretory cells. Through integrative multimodal analysis, we identify the transcriptional corepressor NCoR1 as a key player whose decline is conserved in the aging human gut. In human intestinal epithelial cells and organoids, knocking down NCOR1 recapitulates aging phenotypes including senescence, disrupted junctions and lineage imbalance, whereas overexpressing NCoR1 alleviates them. Metformin-a geroprotective drug-restores NCoR1 levels and delays intestinal aging in nonhuman primates. Our work points to NCoR1 as a central regulator of small intestinal aging and suggests a pharmacologically actionable strategy to counter age-related intestinal decline.
    DOI:  https://doi.org/10.1038/s43587-026-01131-0
  7. Nat Cell Biol. 2026 Jun 10.
    Long-range mutual activation establishes Rho and Rac polarity during cell migration.
    Henry De Belly, Andreu F Gallén, Evelyn Strickland, Dorothy C Estrada, David Sanchez Godinez, Eric Neiva, Patrick J Zager, Tamas L Nagy, Janis K Burkhardt, Hervé Turlier, Orion D Weiner.
      In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back. How these GTPases are positioned at opposite poles remains unclear. We leverage optogenetics, mechanical perturbations, and mathematical modelling to reveal a surprising mechanochemical long-range mutual activation between front and back polarity programmes that complements their well-known local mutual inhibition. Rac-based protrusions elevate membrane tension, stimulating an mTORC2-dependent activation of Rho at the opposite side of the cell. Conversely, Rho-mediated contractility induces cortical-flow-based regulation of phosphoinositide signalling that triggers Rac activation distally. We develop a minimal mechanochemical model to explain how long-range facilitation, together with local inhibition, enables robust Rho and Rac partitioning. Our findings demonstrate how the actin cortex and plasma membrane interact as an integrated mechanochemical system for long-range Rac-Rho patterning. This circuit is required for efficient polarity and migration in primary human T cells and is conserved in epithelial cells, highlighting the generality of this mechanism.
    DOI:  https://doi.org/10.1038/s41556-026-01965-1
  8. Res Sq. 2026 Jun 01. pii: rs.3.rs-9854530. [Epub ahead of print]
    Chromatin architecture sets origin licensing capacity.
    Antonio Bedalov, Eric Foss, Ilana Nodelman, Alexa Usenko, Holden Furutani, Ayush Goel, Brandon Lofts, Shawna Miles, Zhiguo Zhang, Gregory Bowman, Toshio Tsukiyama.
      Replication origin licensing enables complete and faithful genome duplication, yet how chromatin regulates this process in vivo remains unclear. Using MCM-ChEC-seq to track helicase loading from metaphase through G1 in budding yeast, we find that licensing occurs in a rapid, synchronous burst at mitotic exit and then reaches an early plateau despite continued permissive cell-cycle conditions and persistent ORC binding at origins. Here we show that this plateau is imposed by chromatin architecture at replication origins, which limits the extent of origin licensing. Histone H3K56 acetylation marks newly replicated chromatin and is removed at S-phase exit by the deacetylases Hst3 and Hst4. Persistent H3K56ac severely impairs MCM loading without affecting ORC occupancy, indicating that chromatin limits licensing at the helicase-loading step. Strikingly, deletion or catalytic inactivation of the chromatin remodeler Isw2 increases licensing by approximately 40% in wild-type cells and fully suppresses the licensing defect in hst3Δ hst4Δ mutants, identifying Isw2 as a physiological inhibitor of origin licensing. Isw2- dependent nucleosome repositioning narrows the origin nucleosome-depleted region and restricts helicase loading. Together, these findings show that chromatin architecture at replication origins sets licensing capacity. Newly replicated chromatin transiently adopts an Isw2-dependent inhibitory configuration that is relieved, but not completely eliminated, by post-replicative chromatin maturation. Genome-wide licensing thus reflects integration of chromatin-imposed licensing capacity with cell cycle-dependent control of licensing timing.
    DOI:  https://doi.org/10.21203/rs.3.rs-9854530/v1
  9. Mol Cell. 2026 Jun 12. pii: S1097-2765(26)00344-8. [Epub ahead of print]
    Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate.
    Bing-Rui Zhou, Edgar Luzete-Monteiro, Jingchao Zhang, Naomi Takenaka, Hsin-Yao Tang, Meilin Fernandez Garcia, Mariel Coradin, Megan Frederick, Greg Donahue, Benjamin Garcia, Yawen Bai, Kenneth S Zaret.
      Understanding how pioneer transcription factors target nucleosomal DNA and initiate chromatin accessibility reveals the earliest events in cell fate changes. We integrated structural, biochemical, and genomic approaches to assess how the pioneer factor Ascl1-E12a heterodimer perturbs nucleosomes in vitro and in vivo to induce a neural cell fate. Two Ascl1-E12a heterodimers shift and unwrap 15 bp of nucleosomal DNA in a stepwise manner while eliciting solvent exchanges within the octamer. Nucleosome binding, but not free DNA binding, by Ascl1-E12a is enhanced by two types of associations with the nucleosome that differentially affect the kinetics of DNA unwrapping and shifting. Nucleosome association mutants of Ascl1 perturb chromatin opening on linker histone-compacted nucleosome arrays-independent of nucleosome remodelers-and targeting of closed chromatin in vivo, with consequent deficiencies in cellular reprogramming. Our findings establish that distinct associations with nucleosomes are essential for the pioneer factor Ascl1 to overcome chromatin barriers to reprogram cell fate.
    Keywords:  cell fate; chromatin; chromatin opening; cross-linking; cryo-EM; neural; neuron; nucleosome; nucleosome arrays; pioneer factor; reprogramming
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.020
  10. Elife. 2026 Jun 11. pii: RP110952. [Epub ahead of print]15
    Contractile perinuclear actomyosin network promotes peripheral and polar chromosome interaction with the mitotic spindle.
    Nooshin Sheidaei, John K Eykelenboom, Zuojun Yue, Graeme Ball, Alexander J R Booth, Tomoyuki U Tanaka.
      Chromosomes must efficiently and properly interact with the mitotic spindle during prometaphase for correct segregation in anaphase. Chromosomes at the nuclear periphery or behind the spindle poles interact less efficiently with the mitotic spindle, increasing the risk of missegregation. The mechanisms that mitigate such risks in unperturbed cells are unknown. An actomyosin network (PANEM) forms around the nucleus during prophase. While the myosin-II-dependent PANEM contraction immediately after nuclear envelope breakdown (NEBD) facilitates chromosome interaction with the mitotic spindle, the mechanism by which it does so remains unclear. Here, using human cell lines, we show that immediately after NEBD, PANEM contraction directly pushes chromosomes at the nuclear periphery or behind spindle poles toward the center of cells. Detailed tracking of kinetochore movements following light-induced activation of a myosin II inhibitor reveals that this inward movement of chromosomes facilitates kinetochores' initial interaction with spindle microtubules. It also promotes the onset of kinetochores' congression toward the spindle mid-plane, but not congression itself once it starts. Thus, PANEM contraction ensures high-fidelity chromosome segregation by relocating chromosomes from unfavorable locations. Since some chromosomally unstable cancer cells fail to establish PANEM during early mitosis, the absence of PANEM may contribute to numerical chromosomal instability in these cells.
    Keywords:  PANEM; cell biology; chromosome congression; chromosomes; gene expression; human; human cells; kinetochore interaction with spindle microtubules; perinuclear actomyosin network; peripheral chromosomes; polar chromosomes
    DOI:  https://doi.org/10.7554/eLife.110952
  11. Sci Signal. 2026 Jun 09. 19(941): eadz1593
    Cyclin-dependent kinase CDK1 targets cell-cell junction components and governs epithelial monolayer integrity throughout the cell cycle.
    Margarida Dantas, Lisa Donker, Willem-Jan Pannekoek, Marjolein J Vliem, Jan A van der Beek, Robert M van Es, Harmjan R Vos, Judith Klumperman, Martijn Gloerich.
      The cyclin-dependent kinase CDK1 is a master regulator of cell cycle progression and the associated changes in cell shape. The biochemical functions of CDK1 have been primarily studied in cultured cells lacking adhesion to their neighbors. Within epithelial layers, cells are tightly connected, and cell cycle-associated shape changes must occur without compromising epithelial barrier function. Here, we showed that a pool of CDK1 localized to cell-cell contacts in cultured epithelial cells and phosphorylated substrates at cell-cell junctions throughout the cell cycle. CDK1 substrates identified by proteomic analysis included various components of adherens junctions, tight junctions, and desmosomes, as well as proteins that link cell-cell adhesion complexes to the actomyosin cytoskeleton. CDK1 activity maintained the linear organization of cell-cell junctions and was essential for preserving the integrity of the epithelial barrier. These findings expand the role of CDK1 to the regulation of cell-cell adhesion, establishing that the machinery that governs the cell cycle also controls epithelial integrity.
    DOI:  https://doi.org/10.1126/scisignal.adz1593
  12. Nat Aging. 2026 Jun 09.
    A damage accumulation model identifies distinct aging regimes across species.
    Naveh Raz, Yifan Yang, Glen Pridham, Ben Shenhar, Shachaf Frenkel, Tomer Levy, Tsvi Tlusty, Avi Mayo, Uri Alon.
      Different species age in similar ways but their lifespans differ by orders of magnitude. It is not clear how these similarities and differences arise from the accumulation of damage that underlies aging. Does long lifespan arise from reduced damage production, increased removal or enhanced robustness to damage? Here we apply the saturating removal model-a stochastic model of damage accumulation and removal-and fit it to survival data from well-studied species. Several parameters have near-universal values including ratios of removal rate, noise amplitude and death threshold. The model parameter that best predicts lifespan is the damage production rate, which spans seven orders of magnitude. We identify two distinct aging regimes: ballistic aging where damage production outpaces removal, characterizing yeast, nematodes, flies and mice, and quasi-steady-state aging, where damage tracks a moving set point of balanced production and removal, characterizing humans, dogs, guinea pigs and cats. These results provide a mechanistic model-based basis of comparative aging that awaits experimental validation.
    DOI:  https://doi.org/10.1038/s43587-026-01138-7
  13. Nucleic Acids Res. 2026 Jun 08. pii: gkag577. [Epub ahead of print]54(11):
    IAPEz retrotransposons regulate the first lineage segregation in mouse pre-implantation development.
    Rujin Huang, Zhaoya Han, Zhongqi Liufu, Xiongzhi Quan, Danfeng Li, Hongzhi Dong, Guangliang Hong, Ruhai Chen, Man Zhang, Guangdun Peng, Duanqing Pei, Jiekai Chen, Jiangping He.
      Transposable elements (TEs) comprise nearly half of mammalian genomes and drive species-specific regulatory innovation, but their contributions to the first lineage segregation-establishing trophectoderm versus inner cell mass (ICM)-remain largely unexplored. Here, we identify IAPEz, a rodent-specific retrotransposon, as a key regulator of this process in mouse pre-implantation embryos. IAPEz is highly expressed in the extraembryonic lineage but silenced in the ICM via H3K9me3-dependent heterochromatin. Genome-wide interaction analyses reveal that IAPEz physically contacts hundreds of trophectoderm-associated genes, repressing trophoblast programs in the ICM to ensure proper lineage allocation. CRISPR-mediated activation of IAPEz in embryonic stem cells accelerates direct conversion to trophoblast stem cells, while zygotic activation induces defective lineage specification at the morula stage. These findings highlight how repression of lineage-specific TEs orchestrates early embryonic fate decisions, offering insights into genome evolution and species-specific development.
    DOI:  https://doi.org/10.1093/nar/gkag577
  14. Circulation. 2026 Jun 10.
    Loss of STMP1 Perturbs Mitochondrial Cristae and Drives Cellular Inflammation and Heart Failure.
    Francesco Paolo Ruberto, Chang Jie Mick Lee, Matthew Ackers-Johnson, Pooja Sridharan, Vartika Khanchandani, Lik Hang Wu, Ling Xuan Goh, Tuan Danh Anh Luu, Leroy Sivappiragasam Pakkiri, Isabelle Bonne, Thong Beng Lu, Daniel J Buss, Tell Lovelace, Vivek Subramanian, Erielle Villanueva, Yang Hu, Prasanna Vidyasekar, Rijan Gurung, Jie Min Lee, Wai Khang Yong, Zhe Li, Dennis Kappei, Lena Ho, Chester Lee Drum, Roger S Y Foo.
       BACKGROUND: Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP [guanosine monophosphate]-AMP [adenosine monophosphate] synthase)-STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood.
    METHODS: We investigated the function of STMP1 (short transmembrane mitochondrial protein 1), a 47-amino acid nuclear-encoded mitochondrial-localized peptide featuring a distinctive GxxxGxxxG glycine zipper domain. A mouse with cardiomyocyte-specific knockout of Stmp1 (Stmp1-KO) was generated to investigate its role in cardiac function. We profiled the transcriptome, proteome, and metabolome of Stmp1-KO hearts to determine its functional mechanism of action. Electron microscopy was used to assess the impact of STMP1 depletion and functional rescue after adeno-associated virus 9-mediated gene restoration in the Stmp1-KO mouse.
    RESULTS: STMP1 is downregulated specifically in cardiomyocytes, and not other cardiac cell types, in aged mice and humans. Genetic loss of Stmp1 in cardiomyocytes resulted in heart failure in vivo. STMP1 interacts with components of the cristae organizing complexes MICOS (mitochondrial contact site and cristae organizing complex) and SAM (sorting and assembly machinery). Consequent to Stmp1 loss, mitochondrial cristae were destabilized, mitochondrial DNA was mislocalized to the cytosol, and the cGAS-STING pathway was activated, with ensuing cellular inflammation and cardiomyocyte cell death. Restoration of wild-type Stmp1 or STING inhibition significantly rescued cardiac function in vivo.
    CONCLUSION: Our work reveals a mechanism connecting the micropeptide STMP1 to mitochondrial cristae architecture and cardiomyocyte cellular inflammation, both of which are present as potential drivers of heart failure and cardiac aging.
    Keywords:  heart failure; inflammation; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.073677
  15. Cell Rep. 2026 Jun 10. pii: S2211-1247(26)00562-0. [Epub ahead of print]45(6): 117484
    Genome-wide histone humanization in yeast disrupts genome organization, replication, and rDNA stability.
    Luciana Lazar-Stefanita, Max A B Haase, Dana Branzei, Jef D Boeke.
      Eukaryotic DNA wraps around histone octamers forming nucleosomes, which modulate genome function by defining chromatin environments with distinct accessibility. These well-conserved properties allowed "humanization" of the nucleosome core particle (NCP) in Saccharomyces cerevisiae at high fitness costs. Here, we studied histone-humanized yeast genomes to understand how species-specific chromatin affects nuclear organization and function. We found a size increase in human-NCP, linked to shorter free linker DNA, supporting decreased chromatin accessibility. Three-dimensional (3D) humanized genome maps showed increased chromatin compaction and defective centromere clustering, correlated with high chromosomal aneuploidy rate. Site-specific chromatin alterations were associated with lack of initiation of early origins of replication and dysregulation of the ribosomal (rDNA and rRNA) metabolism. This latter led to nucleolar fragmentation and rDNA-array instability, through a non-coding RNA-dependent mechanism, leading to its extraordinary, but entirely reversible, intra-chromosomal expansion. Overall, our results reveal species-specific properties of the NCP that define epigenome function across vast evolutionary distances.
    Keywords:  CP: Molecular biology; chromatin structure; genome instability; nucleolus; nucleosome humanization; replication; ribosomal DNA
    DOI:  https://doi.org/10.1016/j.celrep.2026.117484
  16. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2524496123
    Heterotypic intercellular adhesion tunes efficiency of cell-on-cell migration.
    Chandrashekar Kuyyamudi, Suhrid Ghosh, Cassandra G Extavour.
      Cell migration across epithelial barriers occurs in diverse developmental, immunological, and pathological contexts. Here, we investigate the contribution of heterotypic adhesion between migrating cells and epithelial "substrate" cells to transepithelial migration. Using an in silico model inspired by the migration of primordial germ cells across the midgut epithelium in the Drosophila embryo, we show that heterotypic adhesion modulates migration efficiency in a nonmonotonic manner, revealing the existence of an optimal adhesion regime. Consistent with this prediction, in vivo overexpression of E-cadherin in germ cells accelerated their exit from the midgut relative to controls. Beyond providing experimentally testable predictions, our model integrates and explains previous observations on the role of heterotypic adhesion in cell-on-cell migration, offering a framework for understanding transepithelial migration across biological contexts.
    Keywords:  Cellular Potts model; CompuCell3D; E-cadherin; germ cell migration; intercellular adhesion
    DOI:  https://doi.org/10.1073/pnas.2524496123
  17. Mol Cell. 2026 Jun 12. pii: S1097-2765(26)00348-5. [Epub ahead of print]
    RNA reinforces condensate nucleation on chromatin to amplify oncogenic transcription.
    Krista A Budinich, Xinyi Yao, Chujie Gong, Lele Song, Xiaoting Wang, Michelle C Lee, Kaeli M Mathias, Qinglan Li, Sylvia Tang, Yiman Liu, Son C Nguyen, Eric F Joyce, Yuanyuan Li, Haitao Li, Liling Wan.
      Aberrant chromatin-associated condensates have emerged as drivers of transcriptional dysregulation in cancer, yet how extrinsic factors modulate their assembly and function remains poorly understood. Gain-of-function mutations in the chromatin reader ENL ("Eleven-nineteen-leukemia") drive oncogenesis by inducing condensate formation at select target loci. Here, we demonstrate that locally produced transcripts reinforce the nucleation, chromatin engagement, and oncogenic activity of mutant ENL condensates. Mutant ENL binds to RNA in part through a basic patch within its YEATS domain, and this interaction enhances condensate formation in vitro and in cells. Using a chemically inducible condensate displacement and renucleation system, we show that blocking ENL-RNA interactions or transcription impairs condensate reformation at endogenous targets. RNA binding preferentially enhances mutant ENL occupancy and transcriptional bursting at condensate-permissive loci. In mouse models, disrupting RNA binding suppresses mutant ENL-driven oncogenic transcription and leukemogenesis. These findings reveal how chromatin-associated oncogenic proteins hijack local transcripts to reinforce condensate nucleation and drive tumorigenesis.
    Keywords:  ENL; RNA-mediated condensate nucleation; YEATS domain; acute myeloid leukemia; biomolecular condensates; cancer epigenetics; chromatin reader; oncogenic transcription; transcriptional bursting
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.024
  18. J Cell Biol. 2026 Aug 03. pii: e202603129. [Epub ahead of print]225(8):
    Procollagen 1 assembles into phase-separated condensates in the endoplasmic reticulum.
    Soumya Bhattacharyya, Jose Wojnacki, Nathalie Brouwers, Vivek Malhotra.
      Procollagen I (PC1) is assembled into a trimer within the lumen of the endoplasmic reticulum (ER). In vitro, collagen trimers form rigid molecules reaching lengths of up to 400 nm, and this conformation is presumed to represent their assembled state in vivo. Here, we demonstrate that endogenous PC1 assembles into biomolecular condensates in the ER of activated human hepatic stellate cells. PC1 condensates form in response to increased collagen synthesis and are part of a multicomponent system enriched in the chaperones Hsp47 and calreticulin, as well as the disulfide isomerases PDIA1 and PDIA6, but notably lacking the unfolded protein sensor BiP. PC1 condensates localize to ER exit sites, a process mediated by TANGO1, and dissipate upon ER stress. We propose that this organization enables the accommodation of large quantities of PC1 in the ER lumen without triggering degradation. Furthermore, we suggest that PC1 within condensates is exported in a manner resembling liquid extrusion rather than as a rigid trimer.
    DOI:  https://doi.org/10.1083/jcb.202603129
  19. Cell. 2026 Jun 09. pii: S0092-8674(26)00577-5. [Epub ahead of print]
    Prion-based protein self-assembly tunes mutagenesis to enable rapid adaptation.
    Alexandria Van Elgort, Christopher M Jakobson, Yiwen R Chen, James S Byers, Raymond A Futia, Thomas M Lozanoski, Zachary H Harvey, Jinglin L Xie, David M Garcia, Daniel F Jarosz.
      Mutations supply the raw material for evolution, yet because most are neutral or deleterious, elevated mutation rates are typically transient. Nonetheless, modeling predicts that a mechanism for heritable but reversible "mutagenesis switches" would be advantageous in some selective contexts. Here, we report that frequent prion-based switching of DNA repair and recombination proteins alters mutagenesis in Saccharomyces cerevisiae populations from diverse ecological niches, including the laboratory and clinic, providing adaptive benefits in short-term evolution under strong selective pressure. Self-templating protein assembly alters the activities and interactions of multiple DNA-fidelity factors, reshaping adaptive outcomes while maintaining resilience to genotoxic stress. In the WHO priority pathogen Candida albicans, which diverged from S. cerevisiae ∼300 million years ago, a key regulator of prion inheritance accelerates the rapid emergence of fluconazole resistance. These findings suggest that protein self-assembly can generate epigenetic memory that tunes genome diversification over multiple generations, enabling rapid adaptation in challenging environments.
    Keywords:  C. albicans; DNA damage; FANCM; adaptability; chemotherapeutic; drug resistance; evolution; genome stability; mutagenesis; prions
    DOI:  https://doi.org/10.1016/j.cell.2026.05.018
  20. Cell. 2026 Jun 11. pii: S0092-8674(26)00578-7. [Epub ahead of print]
    Nuclear proteome reveals microtubule-associated protein regulating fate and disease.
    Florencia Merino, Lucas Miranda, Aparajita Kumar, Yiling Li, Deepak Kumar Sundaramoorthy, Juliane Merl-Pham, Eva-Maria Schentarra, Clemens Steinek, Veronica Pravata, Claire Kittock, Martina Bürkle, Bob A Hersbach, Javier Ferri Beneito, Florian Giesert, Ralf Jungmann, Louis-Jan Pilaz, Stefanie M Hauck, Silvia Cappello, Magdalena Götz.
      Cellular differentiation and morphogenesis require the coordination between cytoskeletal remodeling and transcriptional programs, raising the question of how cytoskeletal information is conveyed to the nucleus. Here, we profile the nuclear and cytosolic proteome of human and murine neural stem cells (NSCs) and uncover abundant cytoskeletal proteins in the nucleus, including the microtubule-associated protein 1B (MAP1B), implicated in disease. We find that MAP1B shuttles to the nucleus where it interacts with the BRG1-containing chromatin remodeling complex. MAP1B's nuclear enrichment promotes NSC fate, as opposed to its cytosolic function promoting neuronal differentiation. In vivo, increasing the nuclear/cytosol ratio disrupts neuronal positioning, reminiscent of patients with MAP1B mutations. Mutant human brain organoids show aberrant MAP1B nuclear enrichment, enhanced BRG1 chromatin binding, and neuronal ectopia formation. Our study uncovers a nuclear pool of cytoskeleton-associated proteins, revealing their role in fate regulation during brain development and reshaping our understanding of neurodevelopmental disease etiology.
    Keywords:  MAP1B; brain development; cell fate; cortical malformations; migration; moonlighting proteins; neural stem cells; neurogenesis; organoids; periventricular heterotopia
    DOI:  https://doi.org/10.1016/j.cell.2026.05.019
  21. bioRxiv. 2026 Jun 02. pii: 2026.05.31.728998. [Epub ahead of print]
    Cell fusion after wounding requires plasma membrane damage and endocytosis.
    Junmin Hua, Evan S Krystofiak, Andrew D Pumford, Andrea Page-McCaw, M Shane Hutson.
      Tissue wounds comprise both dead and damaged cells. In epithelial wounds, repair is accomplished by cells at the wound edges, which are themselves often damaged. In the Drosophila pupal notum, wound-adjacent epithelial cells with plasma membrane damage often fuse to form syncytia; when plasma membrane damage is prevented, syncytia do not form. Damaged cells share cytoplasm as soon as milliseconds after wounding, and fusion pores connecting cell membranes form minutes later. A genetic screen reveals that wound-induced fusion requires endocytosis machinery, and dynamin localization indicates that endocytosis preferentially targets plasma membrane removed during fusion. Endocytosis promotes cell fusion by specifically promoting fusion pore expansion, indicated by quantitative analysis of cytoplasmic sharing between cells over time. Without endocytosis-mediated cell fusion, wound healing is slowed. Together, our results support a model of damage-induced cell fusion in which plasma membrane damage initiates fusion pores and endocytosis expands fusion pores, resulting in cellular fusion as an integration of single cell damage with tissue repair.
    DOI:  https://doi.org/10.64898/2026.05.31.728998
  22. Nat Commun. 2026 Jun 10.
    Glassy dynamics in active epithelia emerge from an interplay of mechanochemical feedback and crowding.
    Sindhu Muthukrishnan, Phanindra Dewan, Tanishq Tejaswi, Michelle B Sebastian, Tanya Chhabra, Soumyadeep Mondal, Soumitra Kolya, Sumantra Sarkar, Medhavi Vishwakarma.
      Glassy dynamics in epithelial tissues remain a subject of debate, as theory predicts its emergence only at unrealistically low cellular activity, yet experimental studies have shown glassy dynamics at physiologically active conditions. In this study, we address this paradox by integrating experimental observations in epithelial monolayers with an active vertex model. We demonstrate that while crowding is essential, it is not sufficient for glassy dynamics to emerge. A mechanochemical feedback loop (MCFL-I), mediated by cell shape changes through the contractile actomyosin network is required to drive glass transition in dense epithelial tissues. Such mechanochemical feedback is captured experimentally via a crosstalk between actin-based cell clustering and dynamic heterogeneity, as well as via force induced actin reorganisation in epithelial cells. Incorporating MCFL into the vertex model reveals contrasting results from those previously predicted by theories- we show that the MCFL can counteract cell division-induced fluidisation and enable glassy dynamics to emerge through active cell-to-cell communication. Furthermore, our analysis reveals the existence of collective mechanochemical oscillations that arise from the crosstalk of MCFL-I with oscillatory MCFL-II, capturing ERK mediated cell shape changes. Together, we demonstrate that an interplay between crowding and active mechanochemical feedback enables the emergence of glass-like traits and collective biochemical oscillations in epithelial tissues with active cell-to-cell contacts.
    DOI:  https://doi.org/10.1038/s41467-026-74163-0
  23. Science. 2026 Jun 11. eadv8291
    Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle.
    Eve Kandyba, Arnaud Jabouille, Ferriol Calvet, Yun Rose Li, Andrea Curtabbi, Diana Cristea, Joyce Shin, Reyno Delrosario, Jonathan Anzules, Di Wu, David Quigley, Mark Taylor, Camila Zanette, Fang Yin Lo, Jacob Higgins, Jesse Salk, Nuria Lopez-Bigas, Allan Balmain.
      The identification of the cancer cell of origin is a fundamental question in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single cell transcriptomics, and Duplex sequencing, to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and / or Lrig1+ stem cells of the upper hair follicle, but only very rarely from the Lgr5+ and Krt19+ hair follicle bulge. Lgr6+ stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded, but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between Hras and Kras pathways that influences clonal selection.
    DOI:  https://doi.org/10.1126/science.adv8291
  24. Cell. 2026 Jun 10. pii: S0092-8674(26)00581-7. [Epub ahead of print]
    Persistent and transient senescent cells contribute to brain-barrier development.
    L Ashley Watson, Zoe Adelsheim, Mackenzie J Carter, Grace T Carter, Karen L Jimenez-Reyes, Huijie Du, Ziqing Zhu, David B Berry, Mia C Paredez, Rania H Palaniappan, John M Augustine, Hiruy S Meharena.
      Establishment of the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier requires precise coordination between diverse cell types to protect and nourish the brain. Here, we identify developmentally programmed p21+ senescent cells that exhibit divergent senescence-associated features across these two brain interfaces in mice. In the choroid plexus (ChP), epithelial cells adopt a lifelong, non-inflammatory senescent state associated with CSF production and blood-CSF barrier integrity. In contrast, vascular endothelial cells and brain-resident macrophages transiently exhibit pro-inflammatory senescence profiles during brain vascularization, with reciprocal signaling linked to angiogenic patterning and extracellular matrix assembly. The ablation of p21+ cells during mid-gestation disrupts brain vascular patterning and ChP integrity, which results in hemorrhage, impaired CSF production, and ventricular collapse. These findings indicate that embryonic senescent cells adopt divergent transient and long-lived states that support brain-barrier formation and homeostasis, thus reframing the prevailing view of persistent senescence beyond solely a pathological state.
    Keywords:  blood-brain barrier; blood-cerebrospinal fluid barrier; brain development; brain-resident macrophages; choroid plexus; senescence; vascular endothelial cells
    DOI:  https://doi.org/10.1016/j.cell.2026.05.022
  25. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00585-1. [Epub ahead of print]45(6): 117507
    Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.
    Kaja Plucińska, Charlotte R Wayne, Henry Sanford, Boby Mathew, Nathalie Ropek, Stephanie M Adaniya, Corey Model, Nicolás Gómez-Banoy, Ksenia Morozova, Xiongwen Cao, Jeffrey M Friedman, Ken H Loh, Paul Cohen, Ekaterina V Vinogradova.
      Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we develop a method enabling temporally controlled, cell-type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. The expression of TurboID in hepatocytes, adipocytes, and B lymphocytes enabled the characterization of cell type-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue- and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy balance and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.
    Keywords:  CP: metabolism; ER proteomics; TurboID; inflammation; obesity; plasma proteomics; proximity labeling
    DOI:  https://doi.org/10.1016/j.celrep.2026.117507
  26. Cell. 2026 Jun 10. pii: S0092-8674(26)00584-2. [Epub ahead of print]
    DNA repair drives cisplatin-induced neuronal death.
    William J Nathan, Chuanyuan Chen, Rosy Sakr, Bruno Siqueira Mietto, Vincent van Batenburg, Jeroen van den Berg, Josette J Wlaschin, Ferenc Livak, Elsa Callen, Nancy Wong, Eliza Y H Lloyd, Hanna Silberberg, Sushma Sharma, Raj Chari, Tzipporah Freeman, Baek Kim, Alexander van Oudenaarden, Alexander T Chesler, Michael E Ward, Lisa D Boxer, Peter J McHugh, Andrei Chabes, Claire E Le Pichon, André Nussenzweig.
      Platinum agents are cornerstone therapies for many cancers but often cause neurotoxicity in post-mitotic tissues, for which effective interventions are lacking. This limitation reflects an incomplete understanding of neuronal responses to DNA damage. We show that nucleotide excision repair (NER) mediates cisplatin lesion removal in neurons; however, unlike its protective role in dividing cells, NER promotes neuronal death in response to cisplatin. This vulnerability arises because neurons possess low deoxynucleoside triphosphate (dNTP) pools. dNTPs are initially consumed during transcription-coupled NER to resolve transcription-blocking lesions. As dNTP levels become depleted, repair fails to complete, leading to accumulation of double-strand breaks, particularly during global-genome NER. Supplementation with deoxynucleosides or genetic upregulation of dNTP synthesis restores nucleotide pools, protects neurons from cell death, and reduces cisplatin-induced neuropathic pain. These findings identify limited dNTP availability as a key vulnerability in post-mitotic cells and suggest nucleoside supplementation as a potential strategy to mitigate chemotherapy-induced neurotoxicity.
    Keywords:  DNA repair; chemotherapy; cisplatin; deoxynucleotides; neuron; neuropathy; neurotoxicity; nucleotide excision repair
    DOI:  https://doi.org/10.1016/j.cell.2026.05.025
  27. Nat Commun. 2026 Jun 12.
    A stretch-responsive fibroblast program promotes epidermal stem cell self-renewal during skin expansion.
    Caroline Aguilera Stewart, Ceyhun Alar, Gaia Andrea Gozza, Leslie Bargsted, Ioanna Kaklamanou, Maria Pia Polito, Giulia Bergamini, Lorenzo Tagliazucchi, Andrea Alessandrini, Maria Paola Costi, Elena Enzo, Alejandro Sifrim, Mariaceleste Aragona.
      Stretch-mediated tissue expansion is commonly used to grow extra skin for reconstructive surgeries. To ensure harmonious growth, the two main skin compartments, the epidermis and the dermis, must both expand in a coordinated manner. How fibroblasts respond to stretch-mediated tissue expansion in supporting keratinocyte proliferation remains unclear. Here we map the fibroblast transcriptional response to stretching in vivo and demonstrate that stretching forces fibroblasts to exit their quiescent state and restart proliferation. Concurrently, fibroblasts reduce collagen production and upregulate extracellular matrix remodelling factors, adopting a more embryonic-like program. Because embryonic fibroblasts are widely used as feeder layers to support the expansion of epidermal stem cells for clinical application, we leveraged this model to show that a low collagen state enhances epidermal stem cell self-renewal, thereby coordinating epidermal and dermal responses during skin expansion. These findings provide valuable insights to guide the design of in vivo stretch-mediated tissue expansion protocols and the production of in vitro skin grafts for clinical application.
    DOI:  https://doi.org/10.1038/s41467-026-73979-0
  28. Curr Opin Genet Dev. 2026 Jun 06. pii: S0959-437X(26)00065-1. [Epub ahead of print]99 102498
    Lineage tracing in gastruloids to understand determinants of early fate decisions.
    Sung-Eun Park, Junhong Choi.
      A central goal in developmental biology is to understand how cell fates are specified during development. Advances in stem cell-derived embryoid models, such as gastruloids, have enabled the use of powerful single-cell lineage tracing approaches that are difficult to apply in whole organisms due to the complexities of genetic engineering. Here, we highlight four recent studies that use these techniques to examine fate decisions and spatial organization in gastruloids, uncovering the interplay between cell lineage and signaling in cell fate decisions.
    DOI:  https://doi.org/10.1016/j.gde.2026.102498
  29. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00404-3. [Epub ahead of print]45(6): 117326
    Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
    Giovanni J Mastromarco, Rebecca Earnshaw, Gaelen Moore, X Y Sherwin Xu, Nour H Sadek, Fiona Cui, Natalie Lo, Hyun O Lee.
      Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.
    Keywords:  ALS; CP: molecular biology; CP: neuroscience; FUS; HSP70; J-domain proteins/HSP40; biomolecular condensates; cellular stress response; molecular chaperones; neurodegeneration; protein aggregation; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2026.117326
  30. Sci Adv. 2026 Jun 12. 12(24): eadz7842
    Rpd3L regulates transcription-replication conflict via H3K4 methylation-dependent and -independent chromatin mechanisms.
    Shin Yen Chong, Ya-Ling Chen, Yueh-Tzu Hsu, Chia-Ling Hsu, Tsai-Ming Lu, Yi-Chen Lo, Cheng-Fu Kao.
      Faithful genome duplication requires coordination between transcription and replication. Disruption of this coordination causes transcription-replication conflicts (TRCs), leading to replication stress and genome instability. How chromatin regulators modulate these processes remains unclear. Here, we show that the Rpd3L histone deacetylase complex dynamically modulates chromatin state to control replication fork progression and buffer TRCs in Saccharomyces cerevisiae. Rpd3L is targeted through both histone H3 lysine 4 methylation-dependent recruitment and methylation-independent mechanisms engaged under replication stress. Loss of H3K4 methylation or Rpd3L function promotes histone acetylation, accelerates fork progression through transcribed regions, and increases transcription-associated genome instability. Balanced acetylation at multiple histone lysines is required to stabilize replication forks under stress. While histone deacetylase complexes have been implicated in repairing damaged forks, our findings reveal that Rpd3L acts preemptively to modulate chromatin state and replication dynamics during TRCs, defining a chromatin-based mechanism that safeguards genome stability.
    DOI:  https://doi.org/10.1126/sciadv.adz7842
  31. Development. 2026 Aug 15. pii: dev205312. [Epub ahead of print]153(16):
    Laminin α5 and integrins α3 and α6 coordinately regulate collective cell migration in vivo.
    Anna Mertens, Nicola Moratscheck, Petra A Klemmt, Chaitanya Dingare, Melanie Heyde, Marion Basoglu, Stefan Eimer, Virginie Lecaudey.
      Collective cell migration is essential for development and tissue homeostasis, yet how integrin-extracellular matrix adhesion coordinates migratory force generation in vivo remains poorly understood. Here, we have used the zebrafish posterior lateral line primordium (pLLP) as a model for epithelial collective cell migration. We show that integrins α3 and α6b are expressed in different, yet overlapping, domains of the pLLP and function redundantly to support migration. The systematic combination of itga6b, itga3b and itga3a mutants disrupts integrin β1 localization, increases protrusive activity and impairs migration, revealing a spatially organized, partially redundant adhesion system. We further identify laminin α5 (Lama5) as a key component of the basement membrane (BM) underlying the migrating pLLP. While loss of Lama5 alone compromises BM integrity and pLLP morphology without impairing migration, simultaneous depletion of lama5 and itga6b leads to severe migration defects, with the formation of invadopodia-like structures and ultimately the stalling of migration. Together, these findings reveal a robust, redundant adhesion machinery that ensures persistent collective migration in vivo, and they establish fundamental principles of integrin-mediated adhesion that are relevant to development and disease.
    Keywords:  Adhesion; BM; Basement membrane; Collective cell migration; ECM; Extracellular matrix; Integrin; Itga3; Itga6; Lama5; Laminin; Lateral line primordium; Zebrafish; pLLP
    DOI:  https://doi.org/10.1242/dev.205312
  32. Sci Adv. 2026 Jun 12. 12(24): eadz0706
    VMP1 forms a Ca2+ release channel essential for postnatal heartbeat.
    Yuying Ma, Qiguang Li, Yuting Jia, Bo Hao, Jiahe Li, Ziyi Zhang, Na Yin, Sui Fang, Yao Wang, Zhifang Wu, Zhaobing Gao, Bingqing Xia, Min Peng.
      Normal heart contraction requires synchronized calcium ion (Ca2+) release from the sarcoplasmic reticulum (SR), traditionally attributed to ryanodine receptor 2 (RyR2). Here, we identify vacuole membrane protein 1 (VMP1) as a previously unrecognized SR Ca2+ release channel essential for postnatal cardiac function. VMP1 expression is up-regulated in cardiomyocytes after birth, and its genetic deletion causes severe arrhythmias, dilated cardiomyopathy, and sudden cardiac death. Mechanistically, VMP1 loss results in increased SR Ca2+ content and aberrant cardiac action potentials. Single-channel electrophysiology reveals that VMP1 forms a Ca2+-regulated Ca2+ channel, which senses luminal Ca2+ via aspartic acid 272. Notably, VMP1 expression is elevated in human heart failure, suggesting a pathophysiological role. These findings establish VMP1 as a critical component of the cardiac Ca2+ release machinery and uncover its involvement in heart failure.
    DOI:  https://doi.org/10.1126/sciadv.adz0706
  33. Cell. 2026 Jun 11. pii: S0092-8674(26)00587-8. [Epub ahead of print]189(12): 3501-3505
    Charting human cellular senescence in aging and disease.
    NIH SenNet consortium
      Cellular senescence comprises diverse cell states emerging across human tissues during aging and disease. Integrating single-cell and spatial multi-omics with AI-driven analyses enables systematic mapping of senescent cell heterogeneity ("senotypes"), revealing tissue-specific programs and microenvironmental interactions. These advances provide frameworks for biomarker discovery and development of targeted senotherapeutic strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.028
  34. Nat Biotechnol. 2026 Jun 11.
    Large-scale, spatially resolved panoramic CRISPR screening in native tissue environments using Perturb-DBiT.
    Alev Baysoy, Xiaolong Tian, Paul Renauer, Feifei Zhang, Zhiliang Bai, Hao Shi, Mingyu Yang, Dingyao Zhang, Miao Liu, Haikuo Li, Bo Tao, Archibald Enninful, Yao Lu, Fu Gao, Guangchuan Wang, Wanqiu Zhang, Thao Tran, Nathan Heath Patterson, Jie Sheng, Shuozhen Bao, Chuanpeng Dong, Shan Xin, Binfan Chen, Mei Zhong, Sherri Rankin, Cliff Guy, Yan Wang, Jon P Connelly, Shondra M Pruett-Miller, Daifeng Wang, Mina Xu, Mark B Gerstein, Hongbo Chi, Sidi Chen, Rong Fan.
      Spatially resolved CRISPR screening in vivo has been limited to small perturbation panels and subsets of protein-coding RNAs. We present Perturb-DBiT, a method for co-sequencing of spatial total RNA whole transcriptomes and single guide RNAs (sgRNAs) on the same tissue section in situ. In a human cancer metastatic colonization model, we applied large (80,000+) sgRNA panels across tumor colonies in multiple consecutive tissue sections alongside their corresponding total RNA transcriptomes. We linked perturbations affecting long noncoding RNA covariation, microRNA-mRNA interactions and distinct amino acid-specific tRNA alterations to tumor migration and growth. By integrating transcriptional pseudotime trajectories, we further observed the impact of perturbations on clonal dynamics and cooperation. In an immune-competent syngeneic mouse model, investigation of the tumor immune microenvironment indicated distinct, synergistic effects on immune infiltration and suppression. Perturb-DBiT provides a spatially resolved comprehensive view of perturbation responses in complex tissues, including small and large RNA regulation, tumor proliferation, migration, metastasis and immune interactions.
    DOI:  https://doi.org/10.1038/s41587-026-03127-y
  35. Cell Stem Cell. 2026 Jun 08. pii: S1934-5909(26)00196-7. [Epub ahead of print]
    Designing complex organoids through developmental principles.
    Jonathan A Brassard, James M Wells.
      Principles of developmental biology have inspired efforts for directed differentiation of human pluripotent stem cells (hPSCs), leading to the first generation of organoids that are now well established as models of human development and disease. However, first-generation organoid models were missing many cell types that would be needed to study normal and pathological processes. Here, we discuss how designing next-generation organoids with increased cellular complexity has been possible by better reproducing developmental processes in play during organogenesis in vivo. We focus on recent conceptual and technical advances in reconstructing appropriate cellular diversity in organoids, dissecting the importance of tissue-tissue interactions and specialized cell addition, and how engineering technologies can further enhance our ability to control how cells are brought together to mimic human development in vitro.
    Keywords:  assembloid; developmental biology; engineering organoid; organogenesis; organoid; self-organization
    DOI:  https://doi.org/10.1016/j.stem.2026.05.004
  36. bioRxiv. 2026 Jun 06. pii: 2026.06.04.729929. [Epub ahead of print]
    Somatic cells non-autonomously control germline incomplete cytokinesis through FGF signaling.
    Beth Kern, Zachary Y Berkley, Samuel Price, Kari F Lenhart.
      Across species, germ cells divide and differentiate as interconnected units, termed cysts. These cysts are generated through reiterative rounds of mitosis followed by incomplete cytokinesis to generate stable ring canals (RCs). Despite the ubiquity of germ cell incomplete cytokinesis, it is still unclear how this program is mechanistically regulated across multiple cell cycles to retain integrity of the cyst. Here, by leveraging longitudinal live imaging of the Drosophila testis we have identified a critical, non-autonomous role for somatic support cells in maintenance of germline RC stability. We find that F-actin at RCs is stable throughout interphase but is dynamically disassembled and reassembled at each reiterative mitotic entrance and exit. Importantly, we find that somatic cells regulate the stability of interphase RC F-actin through the secreted growth factor, FGF. Genetic or pharmacological inhibition of FGF signaling induces disassembly of RC F-actin during interphase. Persistent clearance of F-actin from the RC leads to failure of incomplete cytokinesis and cyst abscission, suggesting that stable F-actin at RCs is required for the robust maintenance of incomplete cytokinesis through multiple rounds of germ cell divisions. Finally, we mechanistically link FGF signaling to germline activity of the non-receptor tyrosine kinase, Src64, which is known to regulate RC F-actin through Arp2/3. Taken together, we find a previously unappreciated role for somatic support cells in controlling an essential aspect of germ cell biology in the mitotically dividing spermatogonial pool.
    Summary Statement: Somatic cells of the gonad secrete FGF ligand, Pyramus, which is required for maintenance of F-actin at germline ring canals and integrity of germline incomplete cytokinesis.
    DOI:  https://doi.org/10.64898/2026.06.04.729929
  37. Nature. 2026 Jun 10.
    Mitochondria directly interact with the nuclear pore complex.
    Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.
      Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
    DOI:  https://doi.org/10.1038/s41586-026-10588-3
  38. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  39. Nature. 2026 Jun 10.
    Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.
    Xiaocui Lu, Xiuyun Wang, Zheng Yang, Xusheng Wang, Lin Wang, Chunhui Xu, I-Chung Lo, Chenlu Geng, Lin Wang, Yisheng Pu, Keyu Zhang, Ziqiang Zhu, Lanxin Ye, Jiayuan Huang, Xiaofan Wei, Fang Bai, Yanan Zhu, Xiaobing Qian, Hao Dou, Hexiu Su, Yong Cang.
      BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1-3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC.
    DOI:  https://doi.org/10.1038/s41586-026-10613-5
  40. Mol Biol Cell. 2026 Jun 11. mbcE25120612
    The C. elegans WASH complex supports epithelial polarity by promoting endosomal sorting of E-Cadherin.
    Patricia Irizarry-Barreto, Jennifer Smolyn, Victoria Brown, Bhagavathi Ramamurthy, Martha C Soto.
      Epithelial polarity requires polarized distribution of the apical adhesion complex that connects cells through the E-Cadherin transmembrane protein. E-Cadherin is intimately linked to the actin cytoskeleton through alpha catenin, which directly binds F-actin to set up the apical actin belt. Branched actin is formed when the Arp2/3 complex is activated by Nucleation Promoting Factors. C. elegans has three Nucleation Promoting Factors, WASP, WAVE and WASH. Our studies showed that WAVE-dependent branched actin promotes apical transport of E-Cadherin, including apically-directed transport of RAB-11-enriched endosomes. However, the contribution of other Nucleation Promoting Factors to E-Cadherin polarity has not been examined. The C. elegans WASH complex is not well described. Here we characterize components of the WASH complex, and provide evidence that CO5G5.2, despite being highly divergent, is the functional WSHC-2/FAM21 component in C. elegans. We show that the WASH complex is enriched at early and recycling endosomes in the adult intestine, where it supports retrograde E-Cadherin transport. Our findings demonstrate that individual branched actin regulators promote specific transport steps and identify WASH function at RME-1/EHD-enriched endosomes as an important contributor to E-Cadherin polarity and cargo sorting in a mature epithelium.
    DOI:  https://doi.org/10.1091/mbc.E25-12-0612
  41. Nat Methods. 2026 Jun 09.
    Spatially resolved m6A profiling using m6A-ARTR-DBiT.
    Yu Xiao, Zhiliang Bai, Zhuoning Zou, Chang Ye, Bo Tao, Zhong Zheng, Yan-Ming Chen, Zhongyu Zou, Liudan Jiang, Lijie Zhao, Yuhang Fan, Yun Gao, Rong Fan, Chuan He.
      N6-methyladenosine (m6A) on RNA plays diverse regulatory roles, yet its spatial distribution within tissues remains largely unexplored. Here we introduce m6A-ARTR-DBiT, a spatial m6A profiling assay that leverages reverse-transcription-based detection and deterministic barcoding in tissue to map transcriptome-wide m6A distribution while preserving native tissue context. Applying m6A-ARTR-DBiT to mouse embryonic tissues and adult brains generates spatially resolved m6A landscapes and reveals region-associated m6A features across different functional domains. Pairwise comparison of spatial m6A profiles with spatial transcriptomes uncovers positive correlations between m6A levels and the expression of its methyltransferases and binding proteins, which also enables systematic identification of tissue-region-specific epitranscriptomic regulation. In the mouse hippocampus, m6A-ARTR-DBiT allows for high-resolution mapping of m6A organization within fine-scale tissue structures. Together, m6A-ARTR-DBiT provides a platform for interrogating RNA modification distribution within intact tissue sections, offering insights into the link between spatially patterned m6A deposition and gene regulation.
    DOI:  https://doi.org/10.1038/s41592-026-03123-9
  42. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  43. Nat Genet. 2026 Jun;58(6): 1396-1408
    CytoSignal detects locations and dynamics of ligand-receptor signaling at cellular resolution from spatial transcriptomic data.
    Jialin Liu, Hiroaki Manabe, Weizhou Qian, Shion Orikasa, Javid Ghaemmaghami, Yichen Wang, Yichen Gu, Angel Ka Yan Chu, Gaurav Gadhvi, Yuxuan Song, Patrick McClinden, Vibha N Lama, Noriaki Ono, Joshua D Welch.
      Cells communicate through ligand-receptor (LR) signaling interactions, but identifying when and where these interactions are active remains challenging. We developed CytoSignal to infer the locations and dynamics of cell-cell communication at cellular resolution from spatial transcriptomic data. Here we show that our cellular resolution, spatially resolved signaling scores enable several important analyses-identifying spatial gradients in signaling strength, quantifying the locations of contact-dependent and diffusible interactions, detecting signaling-associated genes and identifying differential signaling across multisample data. Additionally, we can predict the temporal dynamics of a signaling interaction at each spatial location. We experimentally validate our results in situ by proximity ligation assay, confirming that CytoSignal predicts the locations of LR interactions more accurately than previous approaches. This study addresses the field's current need for a robust and scalable tool to detect cell-cell signaling interactions and their dynamics at cellular resolution from spatial transcriptomic data.
    DOI:  https://doi.org/10.1038/s41588-026-02624-9
  44. Development. 2026 Aug 15. pii: dev205226. [Epub ahead of print]153(16):
    Harnessing the murine inner cell mass mechanical environment enhances derivation of in vitro nascent primitive endoderm precursor cells.
    Elena Corujo-Simon, Siiri I Salomaa, Lawrence E Bates, Ayaka Yanagida, William Mansfield, Hannes Becher, Jennifer Nichols, Kevin J Chalut.
      Stem cell-based models resembling murine blastocysts represent a useful system to investigate subsequent developmental processes. While existing cell lines derived from epiblast and trophectoderm can be aggregated to form 'blastoids', some previously tested in vitro cultured extra-embryonic endoderm cells tended to progress to later stages of development, so integrated inefficiently into blastoids. We attempted to capture the precursor population for extra-embryonic endoderm in vitro by reproducing the mechanical environment of the in vivo peri-implantation embryo as closely as possible. We investigated expression of candidate cell adhesion receptor integrins in the blastocyst inner cell mass, and from this information we assembled an extracellular matrix intended to support primitive endoderm growth by promoting signalling pathways responsible for specification of this lineage. In addition, inner cell mass cells from blastocysts were plated on soft or stiff substrates to investigate whether an appropriate mechano-environment could enhance their self-renewal as primitive endoderm in culture. We could expand nascent primitive endoderm cell lines over several passages, which provided a reproducible, albeit short-term, system sufficient to identify some essential requirements for early primitive endoderm expansion and function.
    Keywords:  Extracellular matrix; FGF signalling; Fibronectin; Hydrogels; Integrins; Mechanical properties; Mouse; Primitive endoderm
    DOI:  https://doi.org/10.1242/dev.205226
  45. Nature. 2026 Jun 10.
    Whole-genome duplication shaped cell-type evolution in the vertebrate brain.
    Yuanzhen Zhu, Shuai Zhang, Jiankai Wei, Diego Dolgetta-Garcia, Katia Jindrich, Huimin Liu, Chenggang Shi, Rongrong Pan, Yuwei Chen, Yan Xu, Qiye Li, Günter P Wagner, Peter W H Holland, Guang Li, Sebastian M Shimeld.
      The complex brains of vertebrates have more cell types than those of their closest relatives. Whole-genome duplications (WGDs) occurred during early vertebrate evolution1, but it is unclear whether the duplicated genes (ohnologues) facilitated cell-type evolution. Here using brain single-cell transcriptomes from five chordates-human2, mouse3, lizard4, lamprey5 and amphioxus-we report that many cell-type families with conserved core transcription factors in vertebrates do not show one-to-one homology with amphioxus. Moreover, ohnologues, particularly those from the first WGD, were more important than small-scale duplication paralogues for vertebrate cell-type evolution. To explore whether ohnologues are mechanistically important for this process, we predicted ancestral cell-type states and compared them to amphioxus and experimentally investigated macroglia. The findings indicate that ohnologues had a role in early vertebrate cell-type diversification. Moreover, by examining paralogue expression across cell types and species, we show that expression changes were mainly driven by dosage selection and subfunctionalization. We also link ohnologues to cellular diversity at different anatomical and cell-type scales. Our findings demonstrate the importance of WGDs for the evolution of early vertebrate brain complexity and highlight that the resultant ohnologues continued to capacitate cell-type evolution long after they were formed.
    DOI:  https://doi.org/10.1038/s41586-026-10629-x
  46. Nature. 2026 Jun 10.
    SIRT7 regulates dosage compensation and safeguards the female X chromosome.
    Nicolas G Simonet, Joshua K Thackray, Barry Kesner, Anna Guitart-Solanes, François Serra, Maria Espinosa-Alcantud, Anna Lappala, Laia Marín-Gual, Cristina Marín-García, Uri Weissbein, Josema Castelló-García, Moritz Bauer, Danni Wang, Llorenç Rovirosa, Jay Tischfield, Lourdes Serrano, Bernhard Payer, Aurora Ruiz-Herrera, Berta N Vazquez, Biola M Javierre, Alejandro Vaquero, Jeannie T Lee.
      Sirtuins are deacetylases implicated in stress responses and longevity in mammals1,2. Although their differential impact on disease for the two sexes has been noted3-7, the underlying reasons are unclear. Here, using Sirt7 as a model in mice, we examine the mechanisms leading to sex differences and find that Sirt7-/- female mice have decreased fitness throughout their lifespan. Notably, SIRT7 preferentially localizes to the sex chromosomes. In female individuals, SIRT7 loss affects X-chromosome inactivation, the first arm of dosage compensation that equalizes X-linked gene expression between males and females8-10. Xist is overexpressed and gene silencing becomes more efficient. However, SIRT7 loss has greatest impact on the active X (Xa) chromosome. The Xa chromosome becomes hyperacetylated at Lys36 of histone H3, structurally disorganized, prone to DNA damage and overexpressed. Increased Xa-chromosome expression leads to genome imbalance and augmented X-chromosome upregulation-the second arm of dosage compensation that balances X-chromosome versus autosomal gene expression. These data reveal an essential crosstalk between sirtuins and the sex chromosomes, with SIRT7 safeguarding X-chromosome integrity and dosage balance with autosomes. We propose that the sex bias in SIRT7 biology can be explained in part by unequal effects on the sex chromosomes.
    DOI:  https://doi.org/10.1038/s41586-026-10645-x
  47. Mol Hum Reprod. 2026 Jun 10. pii: gaag038. [Epub ahead of print]
    The post-reproductive ovary shifts from a reproductive to an immune-like organ.
    Aubrey Converse, Shweta S Dipali, Ian P Schowe, Emmett B Kelly, Shivani S Jambunathan, Sarah R Ocañas, Michael B Stout, Michele T Pritchard, Francesca E Duncan.
      Reproductive aging in females is characterized by the irreversible depletion of ovarian follicles, yet the structure and function of the post-reproductive ovary remain poorly defined. Using paired histological and bulk transcriptomic analyses of ovaries from reproductively young (2 m), reproductively old (18 m), and post-reproductive (24 m) mice, we mapped how ovarian identity evolves beyond follicle exhaustion. As expected, follicle loss, stromal remodeling, and increased collagen deposition were observed in the reproductively old and post-reproductive cohorts. Transcriptomic analyses revealed a shift from reproductive functionality to an immune-dominant signature with age. Correspondingly, post-reproductive ovaries exhibited increased infiltration of T cells, macrophages, and multinucleated giant cells. Although old and post-reproductive ovaries diverged substantially from young ovaries, they also showed discrete transcriptomic differences, indicating that the ovary continues to undergo molecular changes after reproductive senescence. Lastly, age-dependent changes in ovarian factors that are predicted to be secreted suggest that the post-reproductive ovary could be a source of pro-inflammatory signaling mediators with the potential to modulate extra-ovarian tissues. These findings challenge the assumption that the post-reproductive ovary is inert, instead indicating that it acquires an immune identity with potential endocrine and paracrine influence on whole-body aging.
    Keywords:  Menopause; fibrosis; inflammation; oopause; ovarian aging; ovary; post-reproductive; stroma
    DOI:  https://doi.org/10.1093/molehr/gaag038
  48. Nat Chem Biol. 2026 Jun 08.
    Opposing roles of serine and charge in IDR condensate miscibility.
    Gaofeng Pei, Xinxin Wang, Xuebo Quan, Danqian Geng, Zhuo Chen, Weifan Xu, Kai Huang, Tingting Li, Pilong Li.
      Numerous biomolecular condensates coexist within cells, yet the factors governing their miscibility remain poorly understood. Here, by examining 28 intrinsically disordered regions in 378 pairwise combinations, we identify key sequence determinants of condensate miscibility: serine and aromatic residues promote miscibility, while charged amino acids drive immiscibility. Mutagenesis experiments establish these as causal relationships. Protein-protein interaction network analyses and molecular simulations reveal that serine and aromatic residues favor heterotypic interactions, whereas high charge content reinforces homotypic association. Serine phosphorylation acts as a regulatory switch that shifts this balance, altering condensate miscibility. We further show that miscibility between transcription factor (TF) and RNA polymerase II (Pol II) condensates directly influences transactivation, TFs with high overall charge content display reduced Pol II miscibility and impaired transcriptional output, and modulating charged residue content in TFs correspondingly tunes transcription. These findings establish a residue-level grammar for predicting and engineering condensate miscibility.
    DOI:  https://doi.org/10.1038/s41589-026-02251-9
  49. Nat Cell Biol. 2026 Jun 11.
    DRP1 and MID49 co-diffusion scans mitochondria for fission.
    Cristiana Zollo, David Gomez Suarez, Elmira Parvindokht Bararpour, Andreas Jenner, Pratima Verma, Jan Koch, Sabine Wilhelm, Christian Jüngst, Lukas Faber, Faye White, Ana J García-Sáez.
      DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
    DOI:  https://doi.org/10.1038/s41556-026-01986-w
  50. Science. 2026 Jun 11. 392(6803): 1194-1199
    Placental nicotinamide adenine dinucleotide modulates the timing of labor.
    Erin J Ciampa, Luana M Machado, Kathy J Lee, Amanda J Clark, Kyle Q Vu, Nawal A Khan, Sarah Kispert, Samantha Armstrong, Yunping Li, Ginger L Milne, Ashley Solmonson, S Ananth Karumanchi, Samir M Parikh.
      Labor is mediated proximately by prostaglandin signaling within gestational tissues and must be tightly regulated for birth to occur after appropriate fetal development. Metabolic changes accompanying gestational aging have been postulated as a determinant of birth timing, but specific nutrients, sensors, and messengers remain obscure. We report that placental nicotinamide adenine dinucleotide (NAD+) dynamically tunes gestational length. Depletion of placental NAD+ in mice provoked labor onset, mediated by the role of NAD+ as a cofactor for 15-hydroxy prostaglandin dehydrogenase, an enzyme responsible for suppressing prostaglandin accumulation. Augmentation of placental NAD+ prolonged gestation at baseline and in a model of preterm labor. These findings suggest a central role for metabolic exhaustion in provoking labor and reveal potential therapeutic avenues for preterm labor and the optimization of labor induction.
    DOI:  https://doi.org/10.1126/science.adz1624
  51. Neuron. 2026 Jun 11. pii: S0896-6273(26)00385-5. [Epub ahead of print]
    Single-cell proteome atlas of aging mouse microglia reveals subpopulation-specific phagoproteome.
    Haoran Zhang, Zhen Liu, Bijia Chen, Guangxin Zhang, Longteng Wang, Changsheng Wei, Xiaohui Zhang, Yuxiang Luo, Ting Peng, Qing Fang, Lei Gu, Ruicheng Ge, Jiangning Zhu, Ruiying Yang, Weiguo Shen, Zhujun Jiang, Yufang Sun, Weixun Duan, Jincheng Liu, Tingting Li, Jing Wang, Zhihua Gao, Xiang Yu, Hebing Chen, Zilu Ye, Xiaomeng Shi, Cheng Li.
      Microglia are brain-resident immune cells with complex physiological functions. Exploring their proteomic heterogeneity at the single-cell level has remained technically challenging. Here, we optimized a label-free single-cell proteomics (SCP) workflow using Orbitrap Astral mass spectrometry (MS) and applied it to fluorescence-activated cell sorting (FACS)-sorted microglia from the hippocampus and prefrontal cortex of young, middle-aged, and aged mice. This yielded one of the largest SCP datasets to date, comprising 3,085 single cells, with an average of 1,153 protein groups identified per cell. Compared with single-cell transcriptomic data, the SCP dataset showed higher expression completeness and moderate cross-modality correlation. This dataset revealed spatiotemporal proteomic heterogeneity of microglia during aging. Notably, we defined the microglial "phagoproteome," uncovering state-specific phagocytic preferences, and verified these results by imaging. This study underscores the potential of SCP to reveal subpopulation-specific proteomic dynamics and provides a new resource for studying microglial state transitions during aging.
    Keywords:  brain aging; mass spectrometry; microglia heterogeneity; single-cell proteomics
    DOI:  https://doi.org/10.1016/j.neuron.2026.05.014
  52. Res Sq. 2026 Jun 01. pii: rs.3.rs-9261217. [Epub ahead of print]
    HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during liver aging.
    Peter Adams, Rouven Arnold, Marcos Teneche, Xue Lei, Armin Gandhi, Christina Shi, Jessica Proulx, Adarsh Rajesh, Aaron Havas, Shiqi Su, Annanya Sethiya, Shanshan Yin, Hiroshi Tanaka, Zong Chua, Andrew Davis, Laurence Haddadin, Michael Alcaraz, Irene Huang, Angela Liou, Anaïs Equey, Nirmalya Dasgupta, Karl Miller, Margaret Tulessin, Buddy Charbono, Adriana Charbono, Siva Varanasi, K Evensen, April Williams Wehner, Rebecca Porritt, Guillermina Garcia, Sakshi Chauhan, Brian Egan, Michael Choob, Carolin Mogler, Kevin Y Yip, Keiko Ozato, Susan Kaech, Yu Xin Wang.
      Age-associated functional decline is partly driven by progressive chromatin degeneration. Maintenance of chromatin integrity preserves cell identity and promotes healthy aging, but through different mechanisms in proliferating and non-proliferating cells. However, specific mechanisms of chromatin maintenance and their compensatory capacity in proliferating and non-proliferating cells are undefined. The histone chaperone HIRA deposits the histone variant H3.3 in a DNA replication-independent manner, leading to its accumulation in aging, non-proliferating cells. Here, we show that hepatocyte-specific loss of HIRA causes loss of cell identity, metabolic dysfunction, and accelerated fibrotic pathology with age. Transcriptomic and epigenomic analyses indicate that HIRA-H3.3 preserves chromatin integrity and sustains transcription of highly expressed genes, including cell identity genes. Partial hepatectomy, associated with induced proliferation, restores identity of HIRA knockout livers with compensatory deposition of canonical histones H3.1/2. Together, these results demonstrate that HIRA-mediated H3.3 deposition is essential for safeguarding cell identity and tissue function during aging of non-proliferating cells, but this function can be rescued by tissue regeneration and associated cell proliferation.
    DOI:  https://doi.org/10.21203/rs.3.rs-9261217/v1
  53. Sci Immunol. 2026 Jun 12. 11(120): eaea6909
    DDX6 induces immunosuppression in cancer by disrupting structural stability of endogenous double-stranded RNAs.
    Larry Ng, Vincent Tano, Priyankaa Pitcheshwar, Wei Liang Gan, Jinghe Xie, Jesslyn Zhou, Kelvin Han Chung Chong, Danielle Huey Ren Chin, Xi Ren, Omer An, Sze Jing Tang, Vanessa Hui En Ng, Jian Han, Haoqing Shen, Yangyang Song, Daryl Jin Tai Tay, Bryan Y L Ng, Bin Wu, Dahai Luo, Leilei Chen.
      Cellular double-stranded RNA (dsRNA) can activate immune pathways similar to viral RNA. Adenosine deaminases acting on RNA 1 (ADAR1)-mediated adenosine-to-inosine (A-to-I) RNA editing has long been believed to destabilize endogenous dsRNA, thus preventing immune activation. We identified DEAD-box RNA helicase 6 (DDX6) as a potent editing repressor and an immune protector under normal conditions but as an immunosuppressor in cancer contexts. Through its interaction with ADAR1, DDX6 binds preferentially to cytoplasmic dsRNA, repressing editing of adenosines in A:C mismatches across the transcriptome, disrupting dsRNA structural stability, and suppressing interferon signaling and immune responses. Depleting DDX6 in tumor cells triggers dsRNA accumulation and activates both intrinsic and extrinsic immunity to hinder tumor growth. Our findings broaden our understanding of the paradigm that RNA editing not only destabilizes cellular dsRNAs but also can stabilize them through I-C pairing, a process preferentially suppressed by DDX6, to limit cytosolic dsRNA sensor recognition. Targeting DDX6 and harnessing RNA-associated tumor cell-intrinsic innate immune activation holds promise for cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciimmunol.aea6909
  54. Nat Biomed Eng. 2026 Jun 12.
    Rewiring oncogenic signalling to precision ablation of metastatic cancer.
    Xinzhi Zou, Elizabeth Palafox, Cynthia Zhao, Kevin T Beier, Chil-Yong Kang, Michael Z Lin.
      Despite recent advances, long-term survival in metastatic carcinomas such as ovarian cancer remains limited by off-tumour toxicities of targeted therapies and low response rates to immunotherapy. Synthetic proteins have been engineered for selective recognition of oncogenic signalling states, but how they can be used to treat metastatic disease in vivo remains unclear. Addressing cancers driven by ErbB-family receptor tyrosine kinases such as EGFR and HER2, we used engineered proteins to restrict replication of a clinically approved viral backbone to kill cells with aberrant ErbB signalling. The resulting ErbB oncogene-selective virus (ErbB-OSV) showed superior safety to a benchmark oncolytic virus of the same family and superior efficacy against ErbB2/HER2-positive ovarian cancer xenografts. In a syngeneic model of advanced ovarian cancer, combining ErbB-OSV with chemotherapy and enabling repeated dosing by B cell depletion conferred a 180% larger survival benefit compared to chemotherapy alone, while single-agent ErbB-OSV cured most early cases. Thus, rationally restricting viral replication to ErbB-hyperactive cells with synthetic signalling proteins yields a highly specific therapeutic agent that ablates metastatic tumours in vivo more effectively than existing treatments.
    DOI:  https://doi.org/10.1038/s41551-026-01704-9
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