bims-ginsta Biomed News
on Genome instability
Issue of 2026–03–29
48 papers selected by
Jinrong Hu, National University of Singapore
  1. Hyperinnervation inhibits organ-level regeneration in mammalian skin.
  2. Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
  3. Epigenetic memory of colitis promotes tumour growth.
  4. Nucleolar migration regulates meiotic sex chromosome inactivation via phase separation during mammalian spermatogenesis.
  5. Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions.
  6. Restoring the FOXO1 geroprotective pathway via seno-resistant mesenchymal progenitor cells alleviates primate epididymal aging.
  7. Mechanical regulation of cuboidal-to-squamous epithelial transition in the Drosophila developing wing.
  8. Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
  9. Midgestation metabolic constraint in purine metabolism drives distinct strategies for placenta and fetal growth.
  10. Microtubules guide Aurora B substrate geometries for accurate chromosome segregation.
  11. Macrophages regulate meiotic initiation and germ cell clearance in the developing ovary.
  12. The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
  13. Transcription elongation can be sufficient, but is not necessary, to advance replication timing.
  14. NAC promotes co-translational protein folding at the ribosomal tunnel exit.
  15. Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
  16. Drift of positional identity drives reproductive aging in a long-lived regenerative animal.
  17. Cellular and molecular landscapes of human tendons across the lifespan revealed by spatial and single-cell transcriptomics.
  18. Actin-membrane interface stress regulates Arp2/3-branched actin density during lamellipodial protrusion.
  19. STING signaling modulation by COPII cargo recognition.
  20. RF-SIRF reveals a replication stress-specific epigenetic code by spatio-temporal mapping of reversed forks.
  21. Cellular Repair and Removal of Protein-Damage Modifications.
  22. Mechanosensitive feedback organizes cell shape and motion during hindbrain neuropore morphogenesis.
  23. Ribosome Molecular Aging Shapes Translation Dynamics.
  24. Nonsense-mediated mRNA decay safeguards telomeres in pluripotent stem cells.
  25. Deciphering mechanical determinants of morphological evolution.
  26. CDK1-dependent N-terminal NuMA phosphorylation promotes dynein-dynactin-NuMA assembly for accurate chromosome segregation.
  27. Biomolecular condensates mediate C-N bond formation.
  28. Asymmetric histone inheritance regulates olfactory stem cell fates during regeneration.
  29. RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
  30. The coordinated action of UFMylation and the RQC pathways clears arrested polypeptides at the ER.
  31. ER tethering and active transport govern condensate diffusion during hyperosmotic stress.
  32. At the tip of regeneration.
  33. Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center.
  34. Ki-67 shapes the nucleolus by anchoring chromatin via its amphiphilic properties.
  35. Active size control of condensates by a kinase-based mechanism.
  36. A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR.
  37. A cytomegalovirus-encoded lncRNA blocks cell-cycle progression.
  38. Dynamic remodeling of epithelial junctions in trophoblast cells of the mammalian blastocyst.
  39. Tuft cells shape airway remodeling by eliciting OXGR1- and SOX9-dependent stem cell programs.
  40. Systems-level organization of extracellular proteostasis.
  41. Export or explode: Export defects cause micronucleus membrane rupture.
  42. Decoding the spatiotemporal development of the blood-brain barrier in human cortex.
  43. SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis.
  44. Mitochondrial lactate venting limits oxidative stress.
  45. Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures.
  46. Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
  47. DNA-triggered AIM2 condensation orchestrates immune activation and regulation.
  48. YAP1 and QSER1 are key modulators of embryonic signaling pathways in the mammalian epiblast.
  1. Cell. 2026 Mar 20. pii: S0092-8674(26)00234-5. [Epub ahead of print]
    Hyperinnervation inhibits organ-level regeneration in mammalian skin.
    Hannah T Tam, Jingyu Peng, Rebecca Freeman, Yulia Shwartz, Shlomi Brielle, Sakshi Garg, Siti Rahmayanti, Stephen J Crocker, Devin Coon, Ya-Chieh Hsu.
      Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration-restoring diverse cell types across lineages-remains rare. Here, we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper connectivity. However, this ability is lost soon after birth, resulting in failure to restore most cell types and hyperinnervation within the wound bed. Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered that three PWF-enriched genes-Timp1, Cxcl12, and Ccl7-inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation in postnatal wounds through the depletion of Cxcl12 in fibroblasts or nerve ablation enables regeneration of diverse lineages after injury. Our study identifies mechanisms that transition an organ from regenerative to non-regenerative, discovers fibroblast-driven hyperinnervation as a key barrier, and demonstrates that removing this barrier unlocks organ-level regeneration.
    Keywords:  Cxcl12; hyperinnervation; injury repair; nerve-tissue interactions; organ-level regeneration; regeneration; wound healing
    DOI:  https://doi.org/10.1016/j.cell.2026.02.027
  2. Science. 2026 Mar 26. 391(6792): eadz6830
    Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
    Christopher J Cowley, Sairaj M Sajjath, Luis F Soto-Ugaldi, Mara Steiger, Samantha B Larsen, Thomas Carroll, Douglas Barrows, Alexandra Mattei, Kevin A U Gonzales, Wei Wang, Kevin Li, Alexander Meissner, Helene Kretzmer, Dana Pe'er, Elaine Fuchs.
      Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
    DOI:  https://doi.org/10.1126/science.adz6830
  3. Nature. 2026 Mar 25.
    Epigenetic memory of colitis promotes tumour growth.
    Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang, Ena Oreskovic, Conrad Hock, Yan Hu, Daniel Zeve, Karina Sharma, Roni R Hyman, Qiming Zhang, Andrew Castillo, David T Breault, Ömer H Yilmaz, Jason D Buenrostro.
      Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41586-026-10258-4
  4. Nat Commun. 2026 Mar 26.
    Nucleolar migration regulates meiotic sex chromosome inactivation via phase separation during mammalian spermatogenesis.
    Mengjing Li, Zhenhai Du, Hanzhen Li, Mingyu Zhang, Yining Liu, Fengyu Zhang, Liangjun Hu, Lichuan Gu, Xiangfeng Chen, Tao Huang, Gang Lu, Wai-Yee Chan, Fei Gao, Zi-Jiang Chen, Wei Xie, Hongbin Liu.
      During spermatogenesis, the unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI) and form a heterochromatic XY body. Defects in MSCI lead to meiotic arrest and male infertility. Although DNA damage response (DDR) factors are established as key initiators of MSCI, how transcriptional silencing is subsequently achieved remains elusive. Here, we identify the nucleolar components NPM1, SENP3, and rRNA as essential downstream effectors of DDR signaling in MSCI. During pachytene, these components migrate to and transiently cover the XY body during MSCI establishment, before becoming restricted to a corner of the XY body. Genetic deletion of Npm1 or Senp3, or inhibition of rRNA transcription severely impairs MSCI. Mechanistically, SENP3-mediated deSUMOylation of NPM1 promotes its interaction with rRNA, enabling liquid-liquid phase separation, via which they exclude Pol II from the XY body. Together, these data reveal a critical role of nucleolar components in the transcriptional regulation of MSCI in mammalian spermatogenesis.
    DOI:  https://doi.org/10.1038/s41467-026-70932-z
  5. bioRxiv. 2026 Mar 05. pii: 2026.03.04.708749. [Epub ahead of print]
    Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions.
    Gibran Ali, Daniel Gibbard, Elisa Ghelfi, Aaron Olson, Junming Cai, Aidan Balagtas, Isaiah Klein, Emily Maccoux, Yulong Han, Akihiro Miura, Ming Guo, Ian Glass, Munemasa Mori, Douglas G Brownfield.
      Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP/TAZ nuclear entry for AT1 maturation. β-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8⁺ transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis.
    In Brief: We identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP/TAZ nuclear entry. We further show that intrinsic β-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and-in adult AT2s-inducing a KRT8⁺ transitional state associated with fibrosis.
    Highlights: Cell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition.Reduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification.Reduced tension permits architectural remodeling and YAP/TAZ nuclear entry required for AT1 maturation.Intrinsic β-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8⁺ transitional state associated with fibrosis.
    DOI:  https://doi.org/10.64898/2026.03.04.708749
  6. Protein Cell. 2026 Mar 24. pii: pwag020. [Epub ahead of print]
    Restoring the FOXO1 geroprotective pathway via seno-resistant mesenchymal progenitor cells alleviates primate epididymal aging.
    Huifen Lu, Linguo Cai, DongLiang Lv, Guoqiang Sun, Jinghui Lei, Taixin Ning, Zijuan Xin, Haoyan Huang, Ying Jing, Daoyuan Huang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Fei Gao, Rui Chen, Yingying Qin, Weihong Song, Andy Peng Xiang, Juan Carlos Izpisua Belmonte, Guang-Hui Liu, Jing Qu, Si Wang.
      Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcriptionally perturbed epithelial cell type. Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age. Functional studies in human epididymal epithelial cells demonstrated that FOXO1 deficiency drives cellular senescence. Mechanistically, FOXO1 transcriptionally activates LHX1, and this axis is essential for counteracting senescence. Furthermore, intervention with senescence-resistant mesenchymal progenitor cells or their exosomes mitigated epididymal aging phenotypes and restored FOXO1 expression in vivo and in vitro. Our study establishes the FOXO1-LHX1 axis as a key protective pathway against primate epididymal aging, providing mechanistic insights and potential therapeutic targets for preserving male reproductive health.
    Keywords:  FOXO1; aging; cell therapy; epididymis; longevity gene; primate; single-nucleus transcriptomics
    DOI:  https://doi.org/10.1093/procel/pwag020
  7. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00214-9. [Epub ahead of print]36(6): 1525-1540.e7
    Mechanical regulation of cuboidal-to-squamous epithelial transition in the Drosophila developing wing.
    Stefan Harmansa, Alexander Erlich, Thomas Lecuit.
      Growing tissues are constantly exposed to mechanical stresses that lead to deformations at cellular and tissue scales. In epithelial organs, cells form monolayers whose thickness can change dramatically during development. Here, we address how cell-shape changes in the peripodial epithelium of the Drosophila wing disc emerge from the interplay of basement membrane properties with tissue-extrinsic mechanical stress. We show that tissue-extrinsic stress arising from disc proper bending elastically deforms central peripodial cells and induces a cuboidal-to-squamous epithelial transition. In contrast, a rigid basement membrane shields peripheral margin cells from this bending stress and causes a cuboidal-to-columnar transition. These inverse shape transitions are further amplified by selective shearing of central cells due to coupling via the apical extracellular matrix protein Dumpy. These findings point to a pivotal role of the basement membrane and inter-tissue coupling in the emergence of stress patterns and cell deformations during organ growth.
    Keywords:  basement membrane; cell-shape transitions; epithelial cells; morphogenesis; squamous morphogenesis; tissue growth; tissue mechanics
    DOI:  https://doi.org/10.1016/j.cub.2026.02.035
  8. Nat Commun. 2026 Mar 24.
    Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
    Giulio Di Minin, Anna B Rüegg, Kevin Halter, Tobias Fuhrer, Tatjana Kleele, Nicola Zamboni, Anton Wutz.
      A hallmark of mammals is a diploid genome. Despite constraints from dosage compensation and imprinting, haploid embryonic stem cells can be established. However, rapid diploidization is observed in such cultures from mice, rats, and humans, limiting their use and indicating counterselection of a haploid genome. Here, we use metabolic profiling to discover that diploidization is triggered by an imbalance that arises from a smaller cytoplasmic volume and increased mitochondrial density. Reduced respiration causes a change in redox potential, leading to increased NADPH. Conversely, we demonstrate that NADPH oxidation in the mitochondria is sufficient to stabilize the haploid genome. We further show that the redox change leads to reduced AURORA kinase activation on chromosomes, connecting metabolic state to mitotic regulation. Our data, therefore, identify a mitochondrial metabolic imbalance as the root cause of diploidization and connect redox dysregulation to karyotypic instability.
    DOI:  https://doi.org/10.1038/s41467-026-70939-6
  9. bioRxiv. 2026 Mar 18. pii: 2026.03.18.712680. [Epub ahead of print]
    Midgestation metabolic constraint in purine metabolism drives distinct strategies for placenta and fetal growth.
    Weizhi Xu, Nancy De La Cruz, Andrea Woods, Dmitry Lokshtanov, Shihong Gao, Nawal Khan, Sylvia Wright, Maria E Florian-Rodriguez, Donald D McIntire, Elaine L Duryea, David B Nelson, Catherine Y Spong, Christina L Herrera, Jacob H Hanna, Sanjay Srivatsan, Alejandro Aguilera-Castrejon, Ashley Solmonson.
      Purine nucleotides are essential for mammalian development 1,2 . Purine monophosphates support cell signaling and proliferation and are synthesized by cells through either de novo synthesis or a salvage pathway 3 . We previously identified a midgestational metabolic transition in mice (gestational days gd10.5-11.5) characterized by changes in purine metabolism 4 . Midgestation is a period of rapid growth for placenta and embryo, yet it remains unclear how the placental tissues expand without directly competing with the embryo for biosynthetic resources. Here, we show that this midgestational metabolic transition is associated with a marked reduction in embryonic expression of purine salvage enzymes, which constrains embryonic metabolism and leads to different strategies for purine synthesis between the placenta and embryo. Midgestation embryos are unable to engage the purine salvage pathway even when de novo purine synthesis is blocked either in vivo or in ex utero embryo culture, whereas placental tissue and trophoblasts retain the capacity to use either pathway. Disruption of de novo purine synthesis in mice causes reduced embryonic growth, impaired axial elongation, and abnormal brain and placental development, which are only partially rescued by supplementation with purine salvage precursors. In human placenta, trophoblast stem cells readily switch between the de novo and salvage pathways based on nutrient availability, and syncytiotrophoblasts (STB) preferentially rely on the salvage pathway. We identified guanosine monophosphate (GMP) as a metabolic checkpoint regulating STB differentiation, with insufficient GMP levels causing degradation of the small GTPase Rheb and failure of mTOR activation. Supplementation of purine salvage substrates restored GMP synthesis and STB differentiation in humans, but not mice. Further, in vivo measurements in humans revealed that maternal circulating hypoxanthine decreases during pregnancy and is further reduced in women with clinically small placentas, highlighting the role of hypoxanthine in supporting placental growth. These results uncover compartmentalized purine salvage between the embryo and placenta as a mechanism that limits competition for biosynthetic resources and enables coordinated growth during mammalian development.
    DOI:  https://doi.org/10.64898/2026.03.18.712680
  10. Sci Adv. 2026 Mar 27. 12(13): eaea2112
    Microtubules guide Aurora B substrate geometries for accurate chromosome segregation.
    Yiming Niu, Keith F DeLuca, Randall H Owen, Hide A Konishi, Rui Gong, Gregory M Alushin, Jennifer G DeLuca, Hironori Funabiki.
      Accurate chromosome segregation requires differential regulation of microtubule-binding substrates by Aurora B, the kinase subunit of the chromosomal passenger complex (CPC). How microtubules simultaneously up- and down-regulate Aurora B phosphorylation remains unclear. Devising a new cryo-electron microscopy workflow, we determined microtubule-bound structures of the CPC and key Aurora B substrates that resolve their phosphorylation sites, finding that microtubules can promote or restrict Aurora B-mediated phosphorylation depending upon binding geometry. The kinetochore Ndc80 complex oligomerizes on microtubules through multivalent interactions including its kinase recognition sites, sterically restricting kinase access to counteract phosphorylation-induced detachment. Attenuating this oligomerization compromised stable kinetochore-microtubule attachments and causes chromosome mis-segregation. Conversely, Aurora B recognition sites of the microtubule-depolymerase mitotic centromere-associated kinesin (MCAK) remain accessible on microtubules, explaining how microtubule-bound CPC can promote MCAK phosphorylation and inactivation. We propose that microtubule-guided substrate remodeling can serve as a general mechanism for controlling Aurora B-mediated phosphorylation during mitosis, which can coordinate diverse processes underlying faithful chromosome segregation.
    DOI:  https://doi.org/10.1126/sciadv.aea2112
  11. bioRxiv. 2026 Mar 03. pii: 2026.02.28.708733. [Epub ahead of print]
    Macrophages regulate meiotic initiation and germ cell clearance in the developing ovary.
    Xiaowei Gu, Satoko Matsuyama, Shu-Yun Li, Tony DeFalco.
      Tissue-resident macrophages are increasingly recognized for their roles in promoting organogenesis, yet how macrophages are involved in fetal ovarian development remains unclear. In particular, little is known about ovarian macrophage ontogeny and how it relates to germ cell entry into meiosis and establishment of the oocyte reserve. Here we combine temporally-controlled lineage tracing of yolk-sac erythro-myeloid progenitors, fetal HSC-derived progenitors, and postnatal monocytes to map multi-wave seeding and remodeling of ovarian macrophages across fetal and early postnatal life. We identify three major resident subsets defined by MHCII and CSF1R that display distinct expansion kinetics and persistence, and we show that CCR2-dependent monocyte recruitment is required for efficient maturation of postnatal macrophage populations. Functionally, transient or sustained depletion of CSF1R+ fetal macrophages perturbs ovarian vascular growth and triggers precocious meiotic initiation without overt loss of germ cells, leading to persistent, premature meiotic progression. Extending macrophage depletion into late gestation disrupts perinatal physiological germ cell attrition despite rapid postnatal macrophage repopulation. Together, our findings establish ovarian macrophages as stage-specific regulators that couple immune ontogeny to ovarian morphogenesis and germ cell quality control during establishment of the oocyte reserve.
    Keywords:  germ cell; macrophage; macrophage ontogeny; meiotic initiation; monocyte; oocyte; oocyte reserve; ovarian development; ovarian follicle; ovary
    DOI:  https://doi.org/10.64898/2026.02.28.708733
  12. Cell. 2026 Mar 20. pii: S0092-8674(26)00116-9. [Epub ahead of print]
    The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
    Ngee Kiat Chua, Tania J González-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J Peter, Mark A Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C Conaway, Gilbert G Privé, Alex N Bullock, Jeffrey J Babon, Rachel E Klevit, Sonja Lorenz, Alessio Ciulli, Eric S Fischer, Nicolas H Thomä, Radosław P Nowak, Brenda A Schulman, Michael Rapé, Katrin Rittinger, Julia K Pagan, Melanie Bahlo, Joel P Mackay, Peter D Mace, Christopher D Lima, Ronald T Hay, David Komander, Bernhard C Lechtenberg, Claudio A P Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham.
      To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.
    DOI:  https://doi.org/10.1016/j.cell.2026.01.029
  13. EMBO Rep. 2026 Mar 24.
    Transcription elongation can be sufficient, but is not necessary, to advance replication timing.
    Athanasios E Vouzas, Takayo Sasaki, Juan Carlos Rivera-Mulia, Jesse L Turner, Amber N Brown, Karen E Alexander, Laura Brueckner, Bas van Steensel, David M Gilbert.
      DNA replication timing (RT) often correlates with transcription during cell fate transitions, yet notable exceptions indicate a complex relationship. Using a reductionist system in mouse embryonic stem cells, we manipulate transcriptional length and strength at a single locus upstream of the silent, late-replicating Pleiotrophin (Ptn) gene. Small reporter genes driven by two of four promoters advance RT, whereas all promoters advance RT when driving the 96-kb endogenous Ptn gene. Inducible transcription of Ptn, but not the reporter, triggers a rapid and reversible RT advance, providing a system to manipulate RT independent of differentiation. Strikingly, deletion of the Ptn promoter and enhancers abolishes transcription yet does not prevent the developmental RT switch to early replication during neural differentiation. These findings, supported by parallel genome-wide analyses during differentiation, demonstrate that transcriptional elongation can causally advance RT in a rate-dependent and context-specific manner, but that transcription is neither necessary nor sufficient for RT advancement. Our results provide a solid empirical base with which to re-evaluate decades of seemingly contradictory literature.
    Keywords:  Cell Fate Transitions; DNA Replication Timing; Epigenomic Remodeling During Differentiation; Mouse Embryonic Stem Cells; Transcription Regulation
    DOI:  https://doi.org/10.1038/s44319-026-00735-2
  14. Mol Cell. 2026 Mar 23. pii: S1097-2765(26)00136-X. [Epub ahead of print]
    NAC promotes co-translational protein folding at the ribosomal tunnel exit.
    Jaime Santos, Manuel Günnigmann, Radoslaw J Gora, Marija Iljina, Masa Predin, Ilgin Eser Kotan, Pratiman De, Dhawal Choudhary, Juwon Jang, Frank Tippmann, Christopher Hins, Nenad Ban, Sander J Tans, Shu-Ou Shan, Günter Kramer, Bernd Bukau.
      The nascent polypeptide-associated complex (NAC) coordinates enzymatic modifications and membrane targeting of nascent chains during translation. While the role of NAC as a dynamic hub for other factors is well established, its direct role in co-translational folding is unclear. By proteome-wide profiling of co-translational NAC interactions in human cells, we found that NAC recognizes emerging segments enriched in hydrophobicity and α-helical propensity within folded domains of cytonuclear proteins. Single-molecule and structural analyses reveal that NAC, via its β-barrel domain, dynamically interacts with nascent chains at the ribosomal tunnel exit and is capable of promoting on-pathway folding. Compartment-specific nascent chain interactions of NAC further elucidate its role in targeting to the endoplasmic reticulum and in mitochondrial membrane protein biogenesis. Together, these findings show that human NAC acts as a bona fide co-translational chaperone that directly promotes early protein folding at the ribosomal tunnel exit, expanding its functional repertoire in protein biogenesis.
    Keywords:  NAC; chaperone; co-translational protein folding; cryo-electron microscopy; nascent chain; optical tweezers; proteostasis; ribosome; ribosome profiling; single-molecule microscopy
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.022
  15. Cell Stem Cell. 2026 Mar 23. pii: S1934-5909(26)00081-0. [Epub ahead of print]
    Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
    Ashley N Kamimae-Lanning, Jill M Brown, Matthias Günther, Franziska Esau, Holly Russell, Lise Larcher, Frédéric Langevin, Tomoya Isobe, Nicola K Wilson, Felix A Dingler, Rebecca L Cordell, Meng Wang, Christopher L Millington, Nina Claudino, Ewa Gogola, Matthew Nicholls, Verena Körber, Berthold Göttgens, Marella F T R de Bruijn, Juan I Garaycoechea, Jean Soulier, Thomas Höfer, Ketan J Patel.
      DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.
    Keywords:  Fanconi anemia; HSC attrition; bone marrow failure; clonal hematopoiesis; endogenous DNA damage; formaldehyde; neutral drift; somatic evolution; stem cell aging
    DOI:  https://doi.org/10.1016/j.stem.2026.02.011
  16. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00237-X. [Epub ahead of print]
    Drift of positional identity drives reproductive aging in a long-lived regenerative animal.
    Andrew Verdesca, Axel Poulet, Maxwell Bales, Josien C van Wolfswinkel.
      Most animals experience irreversibly declining health with advancing age, in part due to limitations in cell turnover and the accumulation of damage. The highly regenerative planarian Schmidtea mediterranea has abundant pluripotent stem cells that drive continuous cell turnover, yet it experiences an age-related loss of fertility, which can be restored through regeneration. We find that the source of planarian age-related infertility lies in the female reproductive system, accompanied by the formation of posterior ectopic ovaries and disrupted accessory reproductive structures, which are restored during regeneration. We further observe that the Notum/Wnt signaling gradient, which determines anterior-posterior polarity in planarians, is shifted posteriorly with age and that manipulating this gradient by RNAi was able to slow down or accelerate reproductive aging. These results indicate that in addition to a healthy stem cell pool, tissue polarity must be maintained to mitigate age-related decline and that resetting positional information could be a promising mechanism to promote tissue rejuvenation.
    Keywords:  Wnt; aging; female germline; fertility; planaria; polarity; regeneration; rejuvenation; spatial organization; turnover
    DOI:  https://doi.org/10.1016/j.cub.2026.02.050
  17. Cell Rep. 2026 Mar 19. pii: S2211-1247(26)00163-4. [Epub ahead of print]45(4): 117085
    Cellular and molecular landscapes of human tendons across the lifespan revealed by spatial and single-cell transcriptomics.
    Alina Kurjan, Jolet Y Mimpen, Lorenzo Ramos-Mucci, Ali C Aksu, Carla J Cohen, Mate Naszai, Christopher D Buckley, Adam P Cribbs, Mathew J Baldwin, Sarah J B Snelling.
      Tendon injuries are common and heal poorly, whereas developing tendons repair with minimal scarring; how this capacity declines with age remains poorly understood. Here, we combine histology, single-nucleus, single-cell, and spatial transcriptomic profiling of human Achilles and quadriceps tendons across embryonic, fetal, and adult stages, including ruptured adult tendons. We identify seven embryonic progenitor states that are predicted to contribute to three tendon-associated lineages-fibrillar, connective tissue, and chondrogenic-which diversify over development, occupy discrete spatial niches, and appear to acquire specialized roles in matrix synthesis, remodeling, and mechanical adaptation. While non-fibroblast populations remain transcriptionally stable with age, fibroblasts undergo marked reprogramming, shifting to homeostatic or injury-responsive states. In ruptured adult tendons, a subset of fibroblasts partially reactivates developmental programs yet remains transcriptionally distinct from developmental states that exhibit scarless healing. These findings define the cellular architecture of human tendon development and aging and reveal lineage-specific targets for therapeutic repair.
    Keywords:  CP: developmental biology; CP: genomics; fibroblasts; human tendon; single-cell RNA sequencing; single-nucleus RNA sequencing; spatial RNA sequencing; tendon aging; tendon development; tendon differentiation; tendon injury; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117085
  18. bioRxiv. 2026 Mar 16. pii: 2026.03.06.710140. [Epub ahead of print]
    Actin-membrane interface stress regulates Arp2/3-branched actin density during lamellipodial protrusion.
    Mitchell T Butler, Max A Hockenberry, Harrison H Truscott, Wesley R Legant, James E Bear.
      Motile cells can sense and exert forces on the extracellular environment through dynamic actin networks. Increased stress against the polymerizing barbed ends of branched actin networks has been shown to lead to an increase in the density of these networks through a force feedback mechanism, though this phenomenon has not been explored through the examination of real-time responses of endogenous actin networks in cells. Here, we utilize mouse embryonic fibroblast CRISPR knock-in lines with labeled ARP2/3 complex to identify cellular and extracellular conditions that regulate branched actin density and enrichment at the leading edge of lamellipodial protrusions. A common theme shared among all branched actin density-increasing conditions is higher levels of interface stress between the plasma membrane and the barbed ends of the lamellipodial actin network. Among these conditions, we find that ARP2/3 is specifically required for robust spreading and protrusion in response to increased extracellular viscosity. Interestingly, time-lapse traction force microscopy of ARP2/3-dependent viscosity responses show significantly reduced changes in strain energy applied to the substrate when compared to spreading and motility through cell-matrix adhesion. In addition, we find that increased extracellular viscosity can bypass the need for extracellular matrix proteins to support lamellipodial protrusion driven by optogenetic Rac activation. Our studies provide strong support for in vitro models of branched actin force feedback responses and further characterize an essential role for branched actin in mediating dramatic cell shape changes in response to increased extracellular viscosity.
    DOI:  https://doi.org/10.64898/2026.03.06.710140
  19. Cell. 2026 Mar 25. pii: S0092-8674(26)00267-9. [Epub ahead of print]
    STING signaling modulation by COPII cargo recognition.
    Heng Lyu, Cong Xing, Wanwan Huai, Kun Song, Devon Jeltema, Hui Zhang, Xuewu Zhang, Nan Yan.
      Stimulator of interferon genes (STING) activation requires coat protein complex II (COPII)-mediated endoplasmic reticulum (ER) exit, but the mechanism remains elusive. Here, we identify EEΦxΦ (339EEVTV343 in human STING) as the ER-exit motif recognized by SEC24 homolog C (SEC24C). Using AlphaFold3, we present a predicted structure of SEC24C binding to a STING dimer, revealing the EEΦxΦ motif in a previously structurally unresolved region. Mutations in this motif or the SEC24C cargo-binding site disrupt STING trafficking and signaling. Our findings support a STING oligomerization and avidity threshold model that explains regulated ER exit. The EEΦxΦ motif is conserved in vertebrate STING homologs and is sufficient to mediate ER exit of unrelated proteins. Interestingly, the STING ER-exit motif is suboptimal compared with known SEC24C cargos, which is crucial for preventing immune overactivation. An engineered "super-ER-exit" STING is constitutively active and induces potent antitumor immunity. Tandem repeats of this motif competitively inhibit endogenous STING signaling. Collectively, this study elucidates the STING-ER-exit mechanism and presents strategies for modulating STING signaling.
    Keywords:  COPII; ER exit; SEC24C; STING; cancer; inflammation; vesicle trafficking
    DOI:  https://doi.org/10.1016/j.cell.2026.02.029
  20. Nat Commun. 2026 Mar 23.
    RF-SIRF reveals a replication stress-specific epigenetic code by spatio-temporal mapping of reversed forks.
    Sunetra Roy, Morgan M Fimreite, Yue Chen, Francesca Citron, Giulio Draetta, Katharina Schlacher.
      DNA replication stress responses are guardians of genomic stability critical during development, hematopoiesis, cancer therapy response, aging and disease suppression. Central to these responses are reversed forks (RF), which are distinct four-way DNA structures formed during DNA replication stalling to protect against toxic DNA lesions. Historically, RF detection relies on specialized electron microscopy, precluding studies within their native cellular context. By harnessing intrinsic bio-physical properties of RFs, we here present a quantitative method to map RFs with single-cell resolution (RF-SIRF). RF-SIRF reveals that RFs accumulate at the nuclear periphery during early-mid S-phase of the cell cycle. Crucially, RFs possess a specialized chromatin landscape and utilize an epigenetic replication stress code distinct from transcription, explaining the selective recruitment of DNA stress response proteins to RFs. Collectively, RF-SIRF enables robust quantitative, temporal, spatial and proteomic analyses of reversed forks, empowering advanced cellular and medical investigations of DNA replication stress responses.
    DOI:  https://doi.org/10.1038/s41467-026-70716-5
  21. Annu Rev Biochem. 2026 Mar 24.
    Cellular Repair and Removal of Protein-Damage Modifications.
    Abigail K D Porter, Christina M Woo.
      Protein aging, stress, or metabolism can lead to the accumulation of numerous nonenzymatic chemical alterations that can threaten protein stability and function, particularly in long-lived proteins. Eukaryotic cells recognize these protein-damage events through repair and removal pathways, whose loss can lead to adverse effects and contribute to age-related disease pathogenesis. Here, we review recent advances in understanding the formation, repair, and removal mechanisms of posttranslational modifications arising from protein damage, including dehydroamino acids, early-stage glycation, isoaspartate, C-terminal cyclic imides, and C-terminal amides. We emphasize the emerging role of E3 ubiquitin ligases in facilitating the degradation of proteins bearing these modifications, highlight the approaches used to make these discoveries, and discuss the potential functions of these modifications beyond protein damage. Mounting evidence that protein-damage events influence cellular signaling and metabolism suggests the existence of vast undiscovered regulatory networks, creating opportunities to uncover tissue-specific repair mechanisms and their roles in development, aging, and stress responses across diverse biological contexts.
    DOI:  https://doi.org/10.1146/annurev-biochem-051024-045733
  22. Curr Biol. 2026 Mar 24. pii: S0960-9822(26)00255-1. [Epub ahead of print]
    Mechanosensitive feedback organizes cell shape and motion during hindbrain neuropore morphogenesis.
    Fernanda Pérez-Verdugo, Eirini Maniou, Gabriel L Galea, Shiladitya Banerjee.
      Neural tube closure is a critical morphogenetic process in vertebrate development, and failure to close cranial regions such as the hindbrain neuropore (HNP) leads to severe congenital malformations. While mechanical forces such as actomyosin purse-string contraction and directional cell crawling have been implicated in driving HNP closure, how these forces organize local cell shape and motion to produce large-scale tissue remodeling remains poorly understood. Using live and fixed imaging of mouse embryos combined with cell-based biophysical modeling, we show that these force-generating mechanisms are insufficient to explain the reproducible patterns of cell elongation and nematic alignment observed at the HNP border. Instead, we show that local anisotropic stress and cytoskeletal organization are required to generate these patterns and promote midline cell motion. Our model captures key features of cell shape dynamics and emergent nematic order, which we confirm experimentally, including the alignment of actin fibers with cell shape and enhanced midline cell speed. Comparative analysis with chick embryos, which lack supracellular purse strings, supports a conserved link between tension generation and cellular patterning. These findings establish a physical framework connecting force generation, cell shape anisotropy, and tissue morphodynamics during epithelial gap closure.
    Keywords:  active nematic; actomyosin purse-string; cell shape; epithelial gap closure; hindbrain neuropore; mechanical feedback; mouse; neural tube closure; tissue mechanics; vertex model
    DOI:  https://doi.org/10.1016/j.cub.2026.02.068
  23. bioRxiv. 2026 Mar 09. pii: 2026.03.08.710403. [Epub ahead of print]
    Ribosome Molecular Aging Shapes Translation Dynamics.
    Jordy F Botello, Lifei Jiang, Peter J Metzger, Troy J Comi, Aya A Abu-Alfa, Qiwei Yu, Margaret S Ebert, Minkyu Lee, Lennard W Wiesner, Maya Butani, Claire J Weaver, Andrej Košmrlj, Ileana M Cristea, Clifford P Brangwynne.
      Cellular homeostasis relies on continual renewal of cellular components, yet some complexes like ribosomes persist for long periods, raising the question of whether extended molecular age impacts functional fidelity. Here, we introduce a spatiotemporal mapping strategy to resolve biomolecular life stages, and show that intracellular ribosome aging alters translational dynamics at specific transcripts. Molecularly aged ribosomes exhibit impaired elongation at basic amino acid-rich sequences, leading to increased pausing, premature termination, and ribosome collisions. By profiling ribosomal RNA modifications, we find that molecular aging increases the collision propensity of specific ribosome subpopulations. Consistent with our findings, enrichment of aged ribosomes in cells amplifies molecular age-dependent translation defects. In vivo labeling of ribosomes in aged C. elegans demonstrates that molecularly aged ribosomes shape translational dynamics during organismal aging. These findings identify ribosome molecular age as a determinant of translational dynamics, and link molecular aging of a core gene-expression complex to organismal aging.
    HIGHLIGHTS: A pulse-chase labeling strategy enables mapping subcellular demographics of macromolecular complexes in space and time.Molecular aging of ribosomes drives differential mRNA translation and shapes elongation dynamics.The collision propensity of specific ribosome subpopulations increases with molecular age.Older ribosomes shape translation dynamics during organismal aging.
    DOI:  https://doi.org/10.64898/2026.03.08.710403
  24. Nat Cell Biol. 2026 Mar 24.
    Nonsense-mediated mRNA decay safeguards telomeres in pluripotent stem cells.
    Marta Markiewicz-Potoczny, Si Young Lee, Soniya Chatterjee, Justin W Mabin, Anna Zinsser, Ranjodh Sandhu, Gianna Tricola, J Robert Hogg, Eros Lazzerini Denchi.
      Telomeres are protective DNA caps at chromosome ends that prevent cells from mistakenly recognizing them as broken DNA. These structures are safeguarded by a protein complex called Shelterin, particularly through the TRF2 protein encoded by Trf2. Surprisingly, in mouse embryonic stem cells, TRF2 is not essential for telomere protection, suggesting that other mechanisms compensate for its loss. Here we show that a cellular quality control system called nonsense-mediated mRNA decay (NMD), which normally eliminates defective RNA molecules, plays an unexpected role in maintaining telomere integrity in pluripotent cells. Through a genome-wide genetic screen, we discovered that NMD is essential for cell survival when TRF2 is absent. NMD accomplishes this by degrading an aberrant form of the messenger RNA encoded by Trf1, which produces the TRF1 protein, another Shelterin component. Without NMD, this aberrant RNA produces a truncated, harmful version of TRF1 that interferes with normal telomere protection. Our findings reveal that embryonic stem cells use a unique strategy for chromosome end protection, linking RNA quality control to genome stability in a previously unrecognized way.
    DOI:  https://doi.org/10.1038/s41556-026-01912-0
  25. Cell. 2026 Mar 20. pii: S0092-8674(26)00175-3. [Epub ahead of print]
    Deciphering mechanical determinants of morphological evolution.
    Richard Bailleul, Nicolas Cuny, Diana Khoromskaia, Soham Basu, Giulia Bergamini, Paolo Cucurachi, Florian Gabler, Sebastian Rupp, Annika Guse, Camille Curantz, Natalie Swinhoe, Phillip A Cleves, Jamie Craggs, Sosuke Fujita, Yu-Ichiro Nakajima, Petrus J Steenbergen, Alba Diz-Muñoz, Guillaume Salbreux, Aissam Ikmi.
      How morphological diversity arises from variations in biomechanical processes remains an open question. Although forces shape tissues, how force-generating systems differ across species to create diverse forms is unclear. Here, we combine comparative morphogenesis and active matter theory across six cnidarian species spanning 500 million years of divergence to identify the mechanical basis of larval shape diversity. We define species-specific configurations of mechanical modules-termed mechanotypes-that quantitatively predict larval shapes across taxa. We find that shape elongation is a simple trait at the mesoscale level, as its variation depends on one mechanical module, whereas shape polarity is a complex trait dependent on several modules. Perturbations mimicking interspecies regulatory differences reshape these modules, reprogramming larval morphology into forms resembling sister species. By establishing a mesoscale mechanical framework for cross-species comparison, this work reveals how variations in a limited set of tissue-scale parameters generate morphological diversity.
    Keywords:  active matter; cnidarian planulae; evo-devo; mechanobiology; mechanotype; mesoscale dynamics; morphogenesis; shape evolution; theoretical modeling; tissue mechanics
    DOI:  https://doi.org/10.1016/j.cell.2026.02.010
  26. Cell Rep. 2026 Mar 23. pii: S2211-1247(26)00248-2. [Epub ahead of print]45(4): 117170
    CDK1-dependent N-terminal NuMA phosphorylation promotes dynein-dynactin-NuMA assembly for accurate chromosome segregation.
    Marvin van Toorn, Merve Aslan, Keishi Shintomi, Ahmet Yildiz, Tomomi Kiyomitsu.
      The microtubule-based motor dynein and its cofactor dynactin are activated by various adaptors to fulfill essential functions throughout the cell cycle, including organelle transport and mitotic spindle assembly. NuMA is a mitotic adaptor that interacts with dynein-dynactin via its N-terminal region (NuMA-N). However, how NuMA-N binds and activates dynein-dynactin in mitosis remains unclear. Here, we combine a membrane-tethering assay, quantitative proteomics, and live-cell analyses to show that mitotic phosphorylation of NuMA-N drives dynein-dynactin-NuMA (DDN) assembly. We find that CDK1-Cyclin B1 phosphorylates NuMA-N, primarily at its conserved serine 203, which stimulates dynein activation in vitro. Replacing endogenous NuMA with phosphorylation-deficient mutants further reveals that NuMA-N phosphorylation, together with its dynein-binding site and Spindly-like motif, is required to form stable DDN complexes for functional spindle assembly. These results highlight CDK1-dependent N-terminal NuMA phosphorylation as a crucial mitotic phospho-switch that ensures stable multivalent interactions between dynein-dynactin and NuMA for accurate chromosome segregation.
    Keywords:  CDK1; CP: cell biology; CP: molecular biology; NuMA; cell cycle; dynein-dynactin; genome stability; microtubules; mitotic spindle; phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117170
  27. Nat Chem Biol. 2026 Mar 25.
    Biomolecular condensates mediate C-N bond formation.
    Xiaowei Song, Yuefeng Ma, Michael W Chen, Wen Yu, Xiao Yan, Jinheng Xu, Lecheng Lyu, Anthony A Hyman, Yifan Dai, Richard N Zare.
      We discover that biomolecular condensates, formed by intrinsically disordered proteins without inherent chemical activity, can spontaneously drive nonenzymatic reductive amination. These condensates facilitate reactions between amines and aldehydes or ketones, yielding imines, which are subsequently hydrogenated to form alkylated amines leading to C-N bond formation. Our experiments show that condensates modulate the reductive amination of diverse types of metabolite containing carbonyl groups. Using combinatorial metabolomics, we found that condensates generate previously unknown metabolites through the dimerization of natural amines with ketones and aldehydes. Metabolomics in living cells confirms that the ability of condensates in mediating C-N bond formation enables the synthesis of new metabolites and regulates cellular pathways. These findings uncover a previously unrecognized inherent function of biomolecular condensates, redefining their roles in metabolism. This further highlights the broader influence of condensates on chemical homeostasis and biochemical regulation in biological and prebiotic chemistry.
    DOI:  https://doi.org/10.1038/s41589-026-02169-2
  28. Nat Commun. 2026 Mar 23.
    Asymmetric histone inheritance regulates olfactory stem cell fates during regeneration.
    Binbin Ma, Guanghui Yang, Jonathan Yao, Charles Wu, Jean Pinckney Vega, Gabriel Manske, Saher Sue Hammoud, Satrajit Sinha, Abhyudai Singh, Haiqing Zhao, Xin Chen.
      The olfactory epithelium possesses an adult stem cell population, the horizontal basal cells (HBCs), to permit lifelong tissue regeneration. Here, we show that HBCs exhibit asymmetric inheritance of histone H4 but not H2A-H2B during olfactory epithelium regeneration in mice. Primary HBC cultures further revealed asymmetric histone inheritance for H3 and H3.3. Upon mitotic exit, asymmetric histone inheritance correlates with asynchronous transcription re-initiation and differential enrichment of p63, a key transcription factor for HBC cell fate. Disruption of asymmetric histone inheritance abolishes these asymmetric cellular features and attenuates olfactory epithelium regeneration and smell behavior recovery. Single-cell RNA sequencing of paired HBC daughters in culture further supports asymmetric multilineage cell fate priming. Together, these findings reveal asymmetric histone inheritance in a mammalian adult stem cell lineage and highlight its biological significance in neural tissue regeneration and animal behavior.
    DOI:  https://doi.org/10.1038/s41467-026-70987-y
  29. Mol Cell. 2026 Mar 23. pii: S1097-2765(26)00138-3. [Epub ahead of print]
    RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
    Shubo Zhao, Chloe S Palma-Chaundler, Carla M Engel, Jacqueline Cordes, Daniel Nixdorf, Michael Y Luo, Selay Kaya, Aldwin Suryo Rahmanto, Diana van den Heuvel, Timur Mackens-Kiani, Pedro Weickert, Simon Lam, Vipul Gupta, Julia Philippou-Massier, Ivan Bagarić, Jonathan Bohlen, Graeme Hewitt, Martijn S Luijsterburg, Roland Beckmann, Petra Beli, Danny D Nedialkova, Christopher J Carnie, Marion Subklewe, Stephen P Jackson, Julian Stingele.
      Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.
    Keywords:  GCN1; GCN2; RNA damage; RNF25; acute myeloid leukemia; azacytidine; chemotherapy; integrated stress response; ribosome collisions; ubiquitylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.024
  30. EMBO J. 2026 Mar 25.
    The coordinated action of UFMylation and the RQC pathways clears arrested polypeptides at the ER.
    Milica Mihailovic, Aleksandra S Anisimova, Bu Erte, Ni Zhan, Ioanna Styliara, Yasin Dagdas, Gülsün Elif Karagöz.
      Clearance of arrested nascent polypeptides resulting from ribosomal stalling is essential for proteostasis. Stalled endoplasmic reticulum (ER)-bound ribosomes are marked by ubiquitin-fold modifier 1 (UFM1) on the large ribosomal subunit protein RPL26, but the precise role of this modification in ribosome-associated quality control (RQC) remains poorly understood. Here, we define the interplay between the UFMylation machinery and the RQC in clearing arrested polypeptides upon ribosome stalling at the ER. Proteomic analysis shows that RQC factors associate with UFMylated ribosomes. Functional assays demonstrate that ribosome rescue factors ZNF598 and ASC-1 recognize and split stalled ribosomes at the ER, a prerequisite for RPL26 UFMylation. The UFM1 E3 ligase complex then binds and UFMylates the post-split 60S-peptidyl-tRNA complex, facilitating access of RQC factors. Depletion of the NEMF/LTN1 complex leads to accumulation of UFMylated ribosomes, whereas impaired UFMylation weakens NEMF/LTN1 binding to ER-stalled ribosomes, supporting a physical link between these pathways. These findings demonstrate that RQC cooperates with the UFMylation machinery to overcome the topological constraints of clearing the arrested polypeptides at the ER.
    Keywords:  Endoplasmic Reticulum; Ribosome Stalling; Ribosome-associated Quality Control; Translation; UFMylation
    DOI:  https://doi.org/10.1038/s44318-026-00753-9
  31. Genome Biol. 2026 Mar 24.
    ER tethering and active transport govern condensate diffusion during hyperosmotic stress.
    Bisal Halder, Guoming Gao, Armin Ahnoud, Shelby Stakenas, Emily R Sumrall, Nils G Walter.
       BACKGROUND: Hyperosmotic shock and the resulting cell volume compression are commonly experienced by organs such as the kidneys, causing rapid formation of hyperosmotic phase separation (HOPS) condensates in the cytoplasm and nucleoplasm. Although the causal relationship between hyperosmotic shock and condensation has been characterized, the diffusion dynamics of biomolecular condensates in hyperosmotically compressed cells and their underlying mechanisms remain largely unknown.
    RESULTS: We systematically characterize the dynamics of HOPS condensates formed by model protein mRNA decapping enzyme 1A (DCP1A) through live-cell fluorescent single-particle tracking (SPT) across timescales. We find that HOPS condensates predominantly exhibit sub-diffusion rather than free diffusion, while a small fraction undergo bursts of super-diffusion. Using imaging to measure spatial accessibility inside cells and fluorescence labels for specific cellular organelles, we show that sub-diffusion arises from endoplasmic reticulum (ER) attachment, whereas super-diffusion reflects microtubule-dependent active transport. We further reconstruct spatial accessibility within hyperosmotically compressed cells using trajectories of genetically encoded multimeric nanoparticles (GEMs) and find that, despite compression, the cytoplasm remains accessible via diffusion and does not exhibit physical corralling. This indicates that restricted condensate mobility arises primarily from specific molecular interactions rather than from physical barriers.
    CONCLUSIONS: Our findings challenge the view that the cytosol becomes static and constrained during hyperosmotic compression. Instead, it remains dynamic, while condensates are spatially organized through docking to membrane structures with intermittent episodes of long-range transport. This model reshapes our understanding of the physical environment within stressed cells and provides a framework for how condensates achieve spatiotemporal organization through interactions with cellular structures and active processes.
    DOI:  https://doi.org/10.1186/s13059-026-04042-w
  32. Curr Opin Genet Dev. 2026 Mar 24. pii: S0959-437X(26)00029-8. [Epub ahead of print]98 102462
    At the tip of regeneration.
    Camille E Dumas, Lauren Connolly, Mekayla A Storer.
      Regeneration requires coordinated cellular responses that restore tissue structure and function following injury, yet regenerative capacity varies widely across vertebrates. In mammals, regeneration is restricted to specific contexts, including the digit tip, where local tissue environments permit blastema formation and patterned repair. Here, we review emerging insights into the local cues governing mammalian digit tip regeneration, focusing on the roles of the nail organ, inflammatory dynamics, fibroblast heterogeneity, and extracellular matrix mechanics. We then place these mechanisms within a broader systemic context, highlighting how immune, endocrine, and neuroendocrine signals shape regenerative outcomes in diverse models. Together, these studies emphasise regeneration as an organism-wide process integrating local repair programmes with systemic physiological regulation.
    DOI:  https://doi.org/10.1016/j.gde.2026.102462
  33. Sci Adv. 2026 Mar 27. 12(13): eaee2473
    Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center.
    Jue Wang, Man Wu, Le Xiao, Gang Du, Muyuan Chen, Venkat G Magupalli, Peter D Dahlberg, Hao Wu, Grant J Jensen.
      The NLRP3 inflammasome is a multiprotein molecular machine that drives inflammatory responses in innate immunity. Although its dysregulation is implicated in numerous human diseases, its structural organization in cells remains poorly understood. Here, we used precise fluorescence-guided cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) to visualize NLRP3 inflammasomes in situ within human macrophages at various stages of activation. After priming and activation, we observed expansion and dispersion of Golgi cisternae, along with the emergence of 50-nanometer NLRP3-associated vesicles, which likely transport NLRP3 to the MTOC. Dense NLRP3-containing condensates then formed in and around the MTOC. In later stages, the condensates solidified, coincident with widespread mitochondrial damage, autophagy, and pyroptotic cell death.
    DOI:  https://doi.org/10.1126/sciadv.aee2473
  34. EMBO J. 2026 Mar 24.
    Ki-67 shapes the nucleolus by anchoring chromatin via its amphiphilic properties.
    Daja Schichler, Yuki Hayashi, Letitia Fernandez, Mariam Chupanova, Alberto Hernandez-Armendariz, Beate Neumann, Sara Cuylen-Haering.
      The nucleolus, a membrane-less organelle essential for ribosome biogenesis, adopts variable shapes across cell types and in response to environmental conditions, yet the mechanisms regulating its morphology and functional implications remain unclear. Using a high-throughput screen, we identify the proliferation marker Ki-67 as a central regulator of nucleolar shape. Ki-67 localises to the chromatin-nucleolus interface, where its depletion induces nucleolar rounding and reduces chromatin enrichment both at the nucleolar rim and within internal invaginations. This effect is driven by Ki-67's amphiphilic properties conferred by two distinct affinity domains separated by a spacer. Given that chromatin loss is a common feature of rounded nucleoli in our screen, and acute chromatin digestion also induces rounding, we propose that the chromatin environment in and around the nucleolus plays a key role in determining nucleolar shape. Our study elucidates a novel Ki-67-mediated chromatin anchoring mechanism, tightly linking nucleolar shape to genome organisation and expanding our understanding of condensate morphology.
    Keywords:  Amphiphilic properties; Biomolecular condensates; Heterochromatin; Ki-67; Nucleolus
    DOI:  https://doi.org/10.1038/s44318-026-00747-7
  35. Nat Cell Biol. 2026 Mar 25.
    Active size control of condensates by a kinase-based mechanism.
      
    DOI:  https://doi.org/10.1038/s41556-026-01917-9
  36. Nat Commun. 2026 Mar 26.
    A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR.
    Yang Yi, Yanqiang Li, Rui Wang, Xufen Yu, Qi Liu, Chaehyun Yum, Yang Zhang, Yuanyuan Qiao, Aileen Szczepanski, Siqi Wu, Qiaqia Li, Ladan Fazli, Jiangchuan Shen, Xin Wang, Xiaoling Li, Ping Mu, Edward M Schaeffer, Heather A Hundley, Hengyao Niu, Arul M Chinnaiyan, Lu Wang, Jinjun Shi, Jian Jin, Xuesen Dong, Wei Zhao, Kaifu Chen, Qi Cao.
      Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a widespread modification in metazoans. Cumulative evidence has revealed the altered A-to-I editing profiles in cancers, but the underlying mechanism remains unclear. Here, we discover the well-known histone lysine methyltransferase enhancer of zeste homologue 2 (EZH2) as an unexplored ADAR interactor and editing regulator in prostate cancer (PCa). Through competing with interleukin enhancer binding factor 2 (ILF2) for ADAR1 binding, EZH2 reshapes the substrate selectivity of ADAR1 and thus exhibits a bidirectional role in editing regulation. Moreover, EZH2 depletion induces the translational repression of transportin-1 (TRN1), which further results in the accumulation of cytoplasmic ADAR1p110 isoform to protect many oncogenic transcripts from degradation. Consistently, depletion of ADAR1 dramatically enhances the sensitivity of cancer cells and tumors to EZH2 selective degraders. Collectively, our study sheds new light on a link between two layers of epigenetic regulations at histone modification and RNA editing levels, demonstrates a previously uncharacterized role of EZH2 in RNA editing and mRNA stability independently of its lysine methyltransferase activity, and reveals the significance of EZH2-ADAR1 cascade in governing RNA editing and mRNA stability, which may provide additional perspectives for the advancement of EZH2-targeting cancer therapies.
    DOI:  https://doi.org/10.1038/s41467-026-71207-3
  37. Mol Cell. 2026 Mar 24. pii: S1097-2765(26)00156-5. [Epub ahead of print]
    A cytomegalovirus-encoded lncRNA blocks cell-cycle progression.
    Tal Fisher, Orel Mizrahi, Julie Tai-Schmiedel, Aharon Nachshon, Michal Schwartz, Meidva Patrick, Avraham Gluck, Einav Aharon, Sharon Karniely, Noam Stern-Ginossar.
      During infection with human cytomegalovirus (HCMV), the viral long non-coding RNA RNA2.7 becomes the most abundant polyadenylated transcript in the cell, yet its function has remained enigmatic. By combining RNA sequencing, metabolic labeling of newly synthesized RNA, and ribosome profiling, we define how RNA2.7 modulates host gene expression and promotes viral propagation. We show that RNA2.7 stabilizes numerous host mRNAs by sequestering a broad array of RNA-binding proteins, reshaping the cellular transcriptome. Accordingly, RNA2.7 is essential for HCMV-induced cell-cycle arrest at the G1-S transition specifically when infection occurs in G1, thereby enhancing viral replication in actively cycling cells. Notably, RNA2.7 expression alone is sufficient to block cell-cycle progression, and screening RNA2.7 fragments identifies a region containing an extended polyadenosine stretch that is required for this activity. Our findings reveal how RNA2.7 promotes viral replication by modulating host mRNA stability and enforcing cell-cycle arrest, creating favorable conditions for infection.
    Keywords:  Cytomegalovirus; RNA2.7; cell cycle; host-virus interaction; lncRNA
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.025
  38. Dev Biol. 2026 Mar 19. pii: S0012-1606(26)00069-2. [Epub ahead of print]534 152-159
    Dynamic remodeling of epithelial junctions in trophoblast cells of the mammalian blastocyst.
    Xinjian Doris He, Caroline McCaffrey, Kimberly D Tremblay, Jesse Mager.
      Proper junction organization within the trophectoderm is essential for blastocyst integrity and implantation. Epithelial junctions are well characterized in many somatic cell types with a typical apical-basal arrangement of junction type: tight junctions, adherens junctions, and then desmosomes. Here, we reveal that the early mural trophoblast of both mouse and human blastocysts exhibit a distinct junction arrangement in which desmosomes are positioned medially within adherens junctions, leaving a basal E-cadherin "tail", which colocalizes with ATP1A1, a marker for Na+/K+-ATPase pumps. As blastocysts develop and expand approaching hatching and implantation, the organization of junctions in mural trophoblast shifts to the canonical arrangement, and we show that this reorganization requires the ATPase pump function. Together, these data uncover a dynamic remodeling of trophoblast junctions, suggesting a novel connection between junction organization, blastocyst maturation, hatching, and successful implantation.
    Keywords:  Blastocyst; Epithelial junctions; Trophectoderm
    DOI:  https://doi.org/10.1016/j.ydbio.2026.03.013
  39. Nat Commun. 2026 Mar 24.
    Tuft cells shape airway remodeling by eliciting OXGR1- and SOX9-dependent stem cell programs.
    Minkyu Lee, Xin Wang, Qihua Ye, George X Huang, Michael V Mandanas, Nils R Hallen, Laura Cho, Joshua A Boyce, Tanya M Laidlaw, Nora A Barrett.
      Tissue-resident stem cells play an essential role in repairing barrier tissues subjected to frequent insults. However, the local cues that coordinate successful barrier repair or lead to tissue remodeling are largely unknown. Here we use murine models of airway injury, fate mapping, and null strains to identify a role for rare tuft epithelial cells in signaling to submucosal stem cells through the generation of cysteinyl leukotrienes (CysLTs) and activation of the CysLT receptor OXGR1. This results in mobilization of SOX9+ submucosal gland progenitors, aberrant repair of the surface airway epithelium, and durable features of airway remodeling including submucosal gland hyperplasia and collagen deposition. Remarkably, selective deletion of SOX9 from the airway stem compartment allows epithelial restoration and prevents tissue remodeling. These findings demonstrate a tuft cell- OXGR1- and SOX9- circuit that remodels the airway after injury and is detected in the human sinus mucosa.
    DOI:  https://doi.org/10.1038/s41467-026-70763-y
  40. Science. 2026 Mar 26. 391(6792): 1332-1338
    Systems-level organization of extracellular proteostasis.
    Cláudio M Gomes, Michele Vendruscolo.
      One defining feature of complex organisms is the ability to maintain protein homeostasis beyond cellular boundaries. We review how extracellular proteostasis is organized as a hierarchical network spanning pericellular, tissue, and systemic tiers. At each tier, secreted chaperones, proteases, vesicles, receptors, immune sentinels, and clearance organs cooperate to recognize, buffer, and eliminate misfolded proteins. Feedback through immune signaling, stress-induced protein secretion, and glymphatic and lymphatic transport adjusts capacity to proteotoxic load. We illustrate how failures in this stratified defense underlie neurodegenerative disorders and systemic amyloidoses, and we highlight strategies that stabilize extracellular proteins, augment clearance pathways, or enhance fluid transport. Viewing extracellular proteostasis as an integrated systems-level network reveals opportunities for combinatorial and preventive therapies.
    DOI:  https://doi.org/10.1126/science.aed3712
  41. J Cell Biol. 2026 Apr 06. pii: e202603041. [Epub ahead of print]225(4):
    Export or explode: Export defects cause micronucleus membrane rupture.
    Hiba Baaziz, Daniela Cimini.
      Micronucleus membrane rupture drives genome instability; however, the mechanisms governing this phenomenon remain unclear. Zych and colleagues reveal that impaired protein export, caused by reduced levels of the transport protein RCC1, drives micronucleus expansion, leading to nuclear envelope rupture.
    DOI:  https://doi.org/10.1083/jcb.202603041
  42. Cell Stem Cell. 2026 Mar 23. pii: S1934-5909(26)00080-9. [Epub ahead of print]
    Decoding the spatiotemporal development of the blood-brain barrier in human cortex.
    Zhongqiu Li, Yanxin Li, Ziqing He, Changliang Wang, Yuehong Zhang, Rong Li, Lei Jin, Jin Jiao, Fen Ji, Bing Zhu, Jingjing Zhang, Peng Du, Ji Dong, Jianwei Jiao.
      The blood-brain barrier (BBB) is essential for maintaining the homeostasis of the central nervous system. However, the processes of BBB formation in humans remain unclear. Here, using single-cell spatiotemporal transcriptomics, we investigate human BBB development from 6 to 21 gestational weeks (GWs) and observe widespread expression of BBB-specific transporters in all brain-endothelial subclusters during development. We determine the onset of the human BBB-like transcriptional signature at GW8 and prove that neural cells can induce the expression of BBB-specific transporters in brain endothelial cells (ECs) via CADHERIN-2 (CDH2). We also demonstrate that neural progenitor cells promote the proliferation of mural cells. Concomitant with the initiation of the BBB-like transcriptional signature, communication signals between ECs and mural cells begin to intensify. In addition, we reveal conserved BBB development between humans and mice and demonstrate that H2A.Z.1 regulates angiogenesis and BBB development. Collectively, these findings provide unique insights into understanding human BBB ontogeny and identifying therapeutic targets for BBB-related disorders.
    Keywords:  BBB; MERFISH; blood-brain barrier; cerebrovascular; endothelial cells; mural cells; neural progenitor cells; neurons; scRNA-seq; scStereo-seq
    DOI:  https://doi.org/10.1016/j.stem.2026.02.010
  43. bioRxiv. 2026 Mar 20. pii: 2026.03.19.712957. [Epub ahead of print]
    SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis.
    Aya Nassereddine, Kerri Davidson, Sandra Sandria, Jyot D Antani, Shreyasi Das, Rachel Rivera, Van Anh Tran, Monique Hinchcliff, Megan King, Valerie Horsley.
      Fibrosis involves sustained changes in fibroblast gene expression, leading to excessive extracellular matrix (ECM) deposition and progressive tissue stiffening. Although matrix stiffness is a potent regulator of cell fate and transcription, it is not clear how nuclear mechanosensing contributes to fibrosis. Here, we define a central role for SUN2, a component of linker of nucleoskeleton and cytoskeleton (LINC) complexes, as a mediator of stiffness-dependent nuclear and chromatin responses during skin fibrosis. SUN2 transcripts are upregulated in dermal fibroblasts of patients with systemic sclerosis and Sun2 protein is elevated in fibrotic mouse skin. Nuclear size, A-type lamins and Sun2 are elevated in dermal fibroblasts plated on stiff substrates. Loss of Sun2 protects against bleomycin-induced skin fibrosis in vivo and abolishes stiffness-induced changes in nuclear size and fibrotic gene expression in vitro. Mechanistically, we identify three Sun2 -dependent mechanosensitive chromatin states and show that mechanical induction of the histone methyltransferase Ezh2 requires Sun2 . These findings define SUN2 as a nuclear mechanosensor that couples matrix stiffness to chromatin regulation and transcriptional programs that drive fibrosis, identifying it as a potential therapeutic target pathway in fibrotic disease.
    DOI:  https://doi.org/10.64898/2026.03.19.712957
  44. Cell Metab. 2026 Mar 24. pii: S1550-4131(26)00093-8. [Epub ahead of print]
    Mitochondrial lactate venting limits oxidative stress.
    Daniela Rauseo, Yasna Contreras-Baeza, Mildreth Salazar, Abigail J Galarza, Sebastián Holtheuer-Gallardo, Hugo Faurand, Natali Cárcamo-Lemus, Raibel Suárez, Joel L Asenjo, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Jan Dernic, Luca Ravotto, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.
      Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix lactate dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and reactive oxygen species.
    Keywords:  genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.020
  45. Cell. 2026 Mar 23. pii: S0092-8674(26)00233-3. [Epub ahead of print]
    Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures.
    Him K Shrestha, Huan Sun, Jay M Yarbro, DongGeun Lee, Danting Liu, Erming Wang, Meghan McReynolds, Nan Zhang, Boer Xie, Shu Yang, Kaiwen Yu, Suresh Poudel, Yuxin Li, Zuo-Fei Yuan, Dehui Kong, Minghui Wang, Zhen Wang, Mingming Niu, Hong Wang, Masihuz Zaman, Ju Wang, David R Vanderwall, Yu Sun, Zhiping Wu, Ping-Chung Chen, Bing Bai, Anthony A High, Júlia Faura, Chunyu Liu, David A Bennett, Erik C B Johnson, Nicholas T Seyfried, Allan I Levey, Vahram Haroutunian, Geidy E Serrano, Thomas G Beach, Michael DeTure, Takahisa Kanekiyo, Ronald C Petersen, Guojun Bu, Pamela J McLean, Dennis W Dickson, Rosa Rademakers, Gang Yu, Xusheng Wang, Bin Zhang, Junmin Peng.
      Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity. Here, we present a pan-neurodegeneration atlas (PanNDA) from multilayer, deep proteomic analysis of 2,279 human brain samples spanning 6 major NDs: Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration with TDP-43 pathology, progressive supranuclear palsy with tau pathology, vascular dementia, and Parkinson's disease. PanNDA integrates data from whole proteome, detergent-insoluble proteome, and posttranslational modifications (phosphorylation and ubiquitination), enabling intra- and inter-disease comparisons. Intra-disease analyses uncover distinct molecular subtypes (e.g., three in AD and four in LBD), reveal dysregulated pathways, and prioritize top-ranked proteins. Inter-disease comparisons identify shared alterations in NDs, such as GPNMB in microglial and lysosomal activation and NPTX2 in synaptic regulation, alongside disease-specific changes and hub regulators within protein networks. Overall, PanNDA provides a systems-level framework for understanding ND mechanisms and serves as a foundational resource that is accessible via an interactive website: https://penglab.shinyapps.io/pannda.
    Keywords:  Alzheimer's disease; Lewy body dementia; Parkinson’s disease; frontotemporal lobar degeneration; mass spectrometry; neurodegenerative diseases; posttranslational modifications; progressive supranuclear palsy; proteomics; vascular dementia
    DOI:  https://doi.org/10.1016/j.cell.2026.02.026
  46. EMBO J. 2026 Mar 24.
    Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
    Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.
      Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.
    Keywords:  AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis
    DOI:  https://doi.org/10.1038/s44318-026-00734-y
  47. Protein Cell. 2026 Mar 25. pii: pwag024. [Epub ahead of print]
    DNA-triggered AIM2 condensation orchestrates immune activation and regulation.
    Quanjin Li, Xiaohan Geng, Huiwen Yan, Zhaolong Li, Miao Shi, Ziqi Zhu, Tongxin Niu, Chunqiu Zhao, Kaile Shu, Yina Gao, Han Feng, Songqing Liu, Qiuyao Jiang, Pengcheng Bu, Dong Li, Pu Gao.
      The innate immune sensor AIM2 detects cytosolic DNA and initiates inflammatory responses, yet its activation mechanism remains incompletely understood. Here, we show that AIM2 undergoes liquid-liquid phase separation upon DNA binding, forming dynamic condensates both in vitro and in cells. These condensates serve as platforms for inflammasome and PANoptosome assembly, promoting immune activation across multiple pathways. Direct structural determination from condensates reveals the assembly of active-form ASC filaments. Mechanistically, liquid-phase condensation is governed by multivalent interactions involving different AIM2 domains, including previously uncharacterized regions and species-specific elements. In vitro and in vivo assays show that mutants specifically disrupting condensation impair immune complex assembly, cell death initiation, antimicrobial defense, and intestinal homeostasis. Moreover, AIM2-DNA condensates function as regulatory hubs targeted by host- and pathogen-derived factors to balance immune homeostasis or facilitate immune evasion. These findings establish liquid-phase condensation as a fundamental mechanism of AIM2 activation and a potential therapeutic target.
    DOI:  https://doi.org/10.1093/procel/pwag024
  48. EMBO Rep. 2026 Mar 26.
    YAP1 and QSER1 are key modulators of embryonic signaling pathways in the mammalian epiblast.
    Elizabeth Abraham, Thomas Roule, Aidan Douglas, Emily Megill, Olivia M Pericak, Jordan E Howe, Carmen Choya-Foces, Joanne F Garbincius, Henry M Cohen, Paula Roig-Flórez, Mikel Zubillaga, Mark D Andrake, Seonhee Kim, John W Elrod, Naiara Akizu, Conchi Estaras.
      YAP1 signaling is essential for development but its specific roles in early embryogenesis remain poorly understood. To shed light on this, we analyze YAP1's role in regulating the pluripotency of the mammalian epiblast, using scRNAseq approaches. Conditional deletion of Yap1 in the mouse epiblast (Sox2-Cre) alters the expression of signaling genes, including Nodal, Wnt3, and Fgf8. Accordingly, Yap1 loss leads to enhanced differentiation of the epiblast toward primitive streak lineages, as evidenced by the upregulation of T/Brachyury and Eomes genes. A proximity labeling assay in human pluripotent stem cells, followed by biochemical assays and molecular modeling predictions, reveals that YAP1 cooperates with QSER1 protein to regulate lineage genes. Our analysis shows that YAP1:TEAD4 enhancers recruit QSER1 to prevent RNA Polymerase II recruitment. QSER1 depletion, similar to YAP1, increases NODAL gene expression and leads to hyperactive NODAL signaling during human embryonic stem cells differentiation. Overall, our findings define a role of YAP1 in the epiblast in vivo and uncover an interplay with QSER1 controlling the activity of developmental signaling pathways in pluripotent cells.
    Keywords:  Epiblast; Nodal Signaling; Pluripotency; QSER1; YAP1
    DOI:  https://doi.org/10.1038/s44319-026-00746-z
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