bims-ginsta Biomed News
on Genome instability
Issue of 2026–04–19
forty papers selected by
Jinrong Hu, National University of Singapore
  1. A spatial atlas of the healthy human liver from live donors.
  2. Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
  3. A transgene-free, human peri-gastrulation embryo model presents trilaminar embryonic disc-, amnion- and yolk sac-like structures.
  4. CHK2-USP37 axis stabilizes FOXO4 to sustain senescence and evade apoptosis.
  5. Single-mRNA imaging and modeling reveal coupled translation initiation and elongation rates.
  6. Chronic replication stress-mediated genomic instability disrupts placenta development in mice.
  7. Cytoplasmic lattices are megadalton storage complexes in mammalian oocytes.
  8. Lipid-trap mass spectrometry identifies lipid-protein interactions in cells.
  9. H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes.
  10. Stem cell control in the lung by an autocrine injury-activated Igf complex.
  11. Guidance of cellular nematic elastomers into shape-programmable living surfaces.
  12. Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
  13. Probing Proteoform Heterogeneity from Single Human Oocytes.
  14. p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
  15. Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation.
  16. Postmitotic transcription and 3D regulation show locus-specific and differentiation-specific sensitivity to cohesin depletion.
  17. FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated secretory phenotype.
  18. Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code.
  19. LC3-linked Golgi-bypass exocytosis fortifies epithelial barrier defense.
  20. Roles and Regulation of the Hippo Signaling Pathway in Mammalian Preimplantation Development.
  21. Synthetic control of implanted engineered liver tissue growth.
  22. Midzone bundles of the mammalian anaphase spindle are mechanically coupled both locally and globally.
  23. Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
  24. Mapping convergent regulators of melanoma drug resistance by PerturbFate.
  25. A recipe for chaos: Extrachromosomal DNA and the hallmarks of cancer.
  26. Cytoplasmic localization of pseudouridine synthase 7 facilitates a pseudouridine-dependent enhancement of cellular stress tolerance.
  27. Heterogeneity of Sonic Hedgehog response dynamics and fate specification in single neural progenitors.
  28. Restorative macrophage-derived RNAseT2 stimulates muscle stem cell fusion via an SLK/N-WASP/actin bundling dependent axis.
  29. HAK-actin, a U-ExM-compatible probe to image the actin cytoskeleton.
  30. Dependence of cell fate potential and cadherin switching on the coordinate within the primitive streak during differentiation of human pluripotent stem cells.
  31. Oscillatory gene expression in cell differentiation and tissue patterning.
  32. Condensate corona-nanoparticle complexes transfer functional biomolecules between cells.
  33. Pulling the Back to Steer Cell Migration: Mechanisms of Structural Polarity in Confining Signaling and Protrusion.
  34. Voltage-gated proton channel Hv1/VSOP regulates reciprocal interactions between F-actin and endosomes in microglia.
  35. MRE11 proximal polyadenylation site-mediated looping impacts transcription and genomic stability.
  36. The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death.
  37. 3D imaging of the pregnant uterus reveals an extensively invasive mouse placenta and early CXCL12-CXCR4 requirement.
  38. Aberrant laminin signaling drives melanocyte dedifferentiation and unveils a tractable therapeutic target in vitiligo.
  39. Distinct principles of genome compartmentalization in Drosophila and humans revealed by osmotic stress.
  40. Development of the fluorescent probe CenSpark for labeling centrioles and cilia.
  1. Nature. 2026 Apr 15.
    A spatial atlas of the healthy human liver from live donors.
    Oran Yakubovsky, Keren Bahar Halpern, Sapir Shir, Roy Novoselsky, Amichay Afriat, Adi Egozi, Tal Barkai, Yotam Harnik, Rouven Hoefflin, Yael Korem Kohanim, Ofra Golani, Inna Goliand, Yoseph Addadi, Merav Kedmi, Hadas Keren-Shaul, Liat Fellus-Alyagor, Lena Prichislov, Dana Hirsch, Chen Mayer, Ron Pery, Niv Pencovich, Timucin Taner, Ido Nachmany, Shalev Itzkovitz.
      Reconstructing gene expression atlases for human tissues is challenging due to limited access to healthy samples from live individuals. Neurologically deceased donors often show ischaemic changes, and tissues near diseased regions may have altered gene expression1,2. The liver, with its unique regenerative capacity, allows analysis from live healthy donors. Here, using spatial transcriptomics (Visium, Visium HD3, multiplexed error-robust fluorescence in situ hybridization (MERFISH)4 and PhenoCycler imaging5) and single-nucleus RNA sequencing6, we analysed 16 liver samples: 8 from young live healthy donors and 8 from individuals with liver pathology, sampling 'adjacent normal' tissue. Livers from live healthy donors displayed significant gene expression differences compared with the adjacent normal tissues from individuals with liver pathology. Hepatocytes and non-parenchymal cells exhibited marked zonation along the porto-central axis of the liver lobules, with key functions being pericentrally shifted compared to mice and other mammals. Our atlas identified dynamic programmes in early steatotic hepatocytes, including a decline in nuclear-encoded mitochondrial proteins and a compensatory increase in mitochondria-encoded transcripts. This study presents a spatial gene expression reference for the healthy human liver and insights into hepatocyte changes in early steatosis.
    DOI:  https://doi.org/10.1038/s41586-026-10377-y
  2. Cell. 2026 Apr 15. pii: S0092-8674(26)00333-8. [Epub ahead of print]
    Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
    José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Jin Park, Philipp Weiler, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masilionis, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.
      The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.
    Keywords:  KRAS inhibitors; benign-to-malignant transition; niche dynamics; p53; pancreatic cancer; single-cell biology; spatial transcriptomics; tumor initiation; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.03.032
  3. Nat Cell Biol. 2026 Apr 17.
    A transgene-free, human peri-gastrulation embryo model presents trilaminar embryonic disc-, amnion- and yolk sac-like structures.
    Shiyu Sun, Yi Zheng, Yung Su Kim, Zheng Zhong, Norio Kobayashi, Xufeng Xue, Yue Liu, Zhuowei Zhou, Yanhong Xu, Jinglei Zhai, Hongmei Wang, Jianping Fu.
      Human peri-gastrulation is a critical developmental stage, yet challenging to study directly. Stem cell-based embryo models have emerged as promising tools for probing early human embryogenesis. Here we report a transgene-free human embryo model, namely peri-gastrulation trilaminar embryonic disc (PTED) embryoid, derived exclusively from primed human pluripotent stem cells, recapitulating certain features of peri-gastrulation human development, which include the formation of trilaminar embryonic layers positioned between the dorsal amnion and ventral definitive yolk sac, as well as primitive haematopoiesis. Our lineage tracing showed that, in PTED embryoids, embryonic and extraembryonic mesoderm as well as embryonic and extraembryonic endoderm arise from gastrulating epiblast-like cells, which provides support for extraembryonic lineage potential of peri-gastrulation human epiblast. Notably, active haematopoiesis and blood-cell generation occurred within the definitive yolk sac-like structure of PTED embryoids. Together, PTED embryoids offer a tractable and ethically less complex model for investigating the self-organizing properties of human peri-gastrulation development.
    DOI:  https://doi.org/10.1038/s41556-026-01930-y
  4. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2526252123
    CHK2-USP37 axis stabilizes FOXO4 to sustain senescence and evade apoptosis.
    Jiahui Sun, Anke Geng, Zhiwei Song, Lingjiang Chen, Zhen-Ning Zhang, Ying Jiang, Zhiyong Mao.
      Cellular senescence, a state of permanent cell cycle arrest, contributes to tissue dysfunction and aging through the accumulation of apoptosis-resistant senescent cells. Although the transcription factor FOXO4 is known to enhance senescent cell survival, the mechanisms regulating its stability have remained unclear. Here, we identify a DNA damage response (DDR)-driven CHK2-USP37-FOXO4 axis essential for maintaining the apoptotic resistance of senescent cells. We demonstrate that FOXO4 protein stability is elevated in stress-induced senescent cells, resulting from reduced ubiquitin-proteasomal degradation. A deubiquitinase screen identified USP37 as the key enzyme stabilizing FOXO4 through direct interaction and removal of K48-linked polyubiquitin chains. Depletion of USP37 destabilizes FOXO4 and sensitizes senescent cells to apoptosis. Mechanistically, persistent DDR signaling during senescence activates CHK2, which phosphorylates USP37 at Thr589, thereby enhancing its binding to FOXO4. Importantly, ablation of USP37 in senescent cells increases the rate of apoptosis, a phenotype that is rescued by FOXO4 reexpression. Together, our work unveils USP37 as a CHK2-regulated stabilizer of FOXO4 that maintains the apoptotic resistance of senescent cells, suggesting the CHK2-USP37-FOXO4 axis as a therapeutic target for age-related pathologies.
    Keywords:  DNA damage response (DDR); FOXO4; USP37; apoptosis; cellular senescence
    DOI:  https://doi.org/10.1073/pnas.2526252123
  5. Elife. 2026 Apr 17. pii: RP107160. [Epub ahead of print]14
    Single-mRNA imaging and modeling reveal coupled translation initiation and elongation rates.
    Irene Lamberti, Jeffrey A Chao, Cédric Gobet, Felix Naef.
      mRNA translation involves multiple regulatory steps, but how translation elongation influences protein output remains unclear. Using SunTag live-cell imaging and mathematical modeling, we quantified translation dynamics in single mRNAs across diverse coding sequences. Our Totally Asymmetric Exclusion Process (TASEP)-based Hidden Markov Model revealed a strong coordination between initiation and elongation rates, resulting in consistently low ribosome density (≤12% occupancy) across all reporters. This coupling persisted under pharmacological inhibition of the elongation factor eIF5A, where proportional decreases in both initiation and elongation rates maintained homeostatic ribosome density. In contrast, eIF5A knockout cells exhibited a significant decrease in ribosome density, suggesting altered coordination. Together, these results highlight a dynamical coupling of initiation and elongation rates at the single-mRNA level, preventing ribosome crowding and maintaining translational homeostasis in mammalian cells.
    Keywords:  SunTag; TASEP; computational biology; eIF5A; human; single-molecule imaging; systems biology; translation elongation
    DOI:  https://doi.org/10.7554/eLife.107160
  6. PLoS Genet. 2026 Apr 13. 22(4): e1012111
    Chronic replication stress-mediated genomic instability disrupts placenta development in mice.
    Mumingjiang Munisha, Rui Huang, Jordan Khan, John C Schimenti.
      Abnormal placentation drives many pregnancy-related pathologies and poor fetal outcomes, but the underlying molecular causes are understudied. Here, we show that persistent replication stress due to mutations in the MCM2-7 replicative helicase disrupts placentation and reduces embryo viability in mice. MCM-deficient embryos exhibited normal morphology, but their placentae had a drastically diminished junctional zone (JZ). Whereas cell proliferation in the labyrinth zone (LZ) remained unaffected, it was reduced in the JZ during development. MCM2-7 deficient trophoblast stem cells (TSCs) failed to maintain stemness, suggesting that replication stress affects the initial trophoblast progenitor pool in a manner that preferentially impacts the developing JZ. In contrast, pluripotency of mouse embryonic stem cells (ESCs) with MCM2-7 deficiency were not affected. Developing female mice deficient for FANCM, a protein involved in replication-associated DNA repair, also had placentae with a diminished JZ. These findings indicate that replication stress-induced genomic instability compromises embryo outcomes by impairing placentation.
    DOI:  https://doi.org/10.1371/journal.pgen.1012111
  7. Nature. 2026 Apr 15.
    Cytoplasmic lattices are megadalton storage complexes in mammalian oocytes.
    Zeynep Ilgın Kılıç, Joyce van Loenhout, Marten Chaillet, Robert M van Es, Paula Sobrevals Alcaraz, Harmjan R Vos, Willem E M Noteborn, Miguel Ricardo Leung.
      Mammalian oocytes store proteins for embryonic development on abundant structures known as cytoplasmic lattices (CPLs)1; however, the mechanisms by which they achieve this are unclear, largely because the molecular composition of the lattices themselves is unknown. Here, we use cryo-electron microscopy and artificial intelligence-based modeling to elucidate the molecular architecture and protein composition of native CPLs from mouse oocytes. We find that CPLs are formed by at least 13 different proteins assembling into a megadalton-scale complex, including multiple copies of maternal effect factors such as PADI6 and the subcortical maternal complex (SCMC). We show that proteins essential for early embryonic development are in fact structural components of the CPLs, including the cytoskeletal proteins α- and β-tubulin, which are incorporated into CPLs as unpolymerized dimers; and an array of ubiquitination factors such as the epigenetic regulator and E3 ligase UHRF1, ubiquitin-conjugating E2 enzymes, and ubiquitin ligase substrate adaptors. This represents an elegant molecular mechanism by which oocytes stockpile vital proteins through direct incorporation into highly stable supramolecular assemblies. Our structures solve the decades-long mystery of the CPLs, thereby providing a structural framework for understanding how disrupting stored maternal factors leads to infertility and developmental defects.
    DOI:  https://doi.org/10.1038/s41586-026-10513-8
  8. Nat Cell Biol. 2026 Apr 13.
    Lipid-trap mass spectrometry identifies lipid-protein interactions in cells.
    Andrea Paquola, Clare E Benson, Smita Eknath Desale, Cagakan Ozbalci, Elisabeth M Storck, Stephen J Terry, Bhagyashree Dasari Rao, Kelechi N Nwite, Federica Ferrentino, Ulrike S Eggert.
      Cells actively maintain complex lipidomes that encompass thousands of lipids; however, many of the roles of these lipids remain unexplored. Specific interactions between lipids and membrane proteins are a likely reason for lipidome complexity. Here we report the development of a technique, named lipid-trap mass spectrometry (LTMS), to systematically study lipid-protein interactions directly captured from mammalian cells. LTMS uses immunoprecipitation of GFP-tagged proteins expressed in HeLa cells, followed by lipidomic analysis of lipids bound to the GFP-tagged protein. We applied LTMS to cell division to illustrate the technique. We chose this process because membranes regulate their lipid composition as they undergo major changes during cytokinesis, and many cytokinetic proteins, including RACGAP1 and ESCRT-III components CHMP4B and CHMP2A, are membrane-associated. Using LTMS, we found that RACGAP1 and CHMP4B associate with specific lipid species in dividing compared with non-dividing cells. We expand our understanding of lipid diversity during cell division and present a general approach to explore lipid-protein interactions to further our knowledge of the roles of lipids in mammalian cells.
    DOI:  https://doi.org/10.1038/s41556-026-01928-6
  9. Mol Cell. 2026 Apr 13. pii: S1097-2765(26)00190-5. [Epub ahead of print]
    H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes.
    Hailiang Mei, Chisayo Kozuka, Mami Kumon, Haruhiko Koseki, Azusa Inoue.
      Polycomb group (PcG) and Trithorax group (TrxG) proteins establish bivalent chromatin marked by H3K27me3, H2AK119ub1, and H3K4me3. However, how bivalent chromatin is formed in vivo in mammals is poorly understood. In mouse oocytes, it arises at thousands of promoters, including noncanonical imprinted loci whose H3K27me3 is intergenerationally inherited by early embryos. Here, we show that H3K27me3 is deposited at H3K4me3-premarked promoters in an H2AK119ub1-dependent manner during oogenesis. We find that H2AK119ub1 deficiency causes transcriptional derepression and loss of H3K27me3 proportional to preexisting H3K4me3 levels in oocytes. Importantly, concomitant deficiency of H2AK119ub1 and MLL2-mediated H3K4me3 substantially restores transcriptional silencing and H3K27me3 deposition, leading to partial restoration of noncanonical imprinting in offspring. Taken together, we propose that H2AK119ub1 antagonizes MLL2 function to repress bivalent genes during oogenesis, thereby conferring heritable H3K27me3. This study reveals how PcG and TrxG counteraction shapes the maternal epigenome for the next generation's development.
    Keywords:  MLL2; Polycomb; Trithorax; bivalent chromatin; epigenetic inheritance; genomic imprinting; mouse oocyte; placenta
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.014
  10. Science. 2026 Apr 16. 392(6795): eadt1310
    Stem cell control in the lung by an autocrine injury-activated Igf complex.
    Yue Zhang, Youcef Ouadah, Yin Liu, Maya E Kumar, Makenna M Morck, Mark A Krasnow.
      Stem cells proliferate after injury to repair damaged tissue, and chronic injury can promote cancer. However, the injury-activated signals and regulatory mechanisms, and their relationship to cancer, are poorly understood. Here, we identified insulin-like growth factor 2 (Igf2) as an injury-activated mitogen for lung neuroendocrine stem cells, which are facultative airway progenitors and a cell of origin of small-cell lung cancer in mice. Igf2 was constitutively produced by the stem cells but sequestered in the niche by coexpressed Igf binding proteins (Igfbps). Airway injury released Igf2 and induced proliferation by transiently activating Igf2 receptors and repressing retinoblastoma (Rb) tumor suppressor. Permanent pathway activation by Rb deletion initiated continuous stem cell division. Thus, beyond their classical hormonal roles in physiology, growth, and aging, Igf proteins operate locally and rapidly with Igfbp and Rb to control injury-induced stem cell proliferation and tumor initiation.
    DOI:  https://doi.org/10.1126/science.adt1310
  11. Science. 2026 Apr 16. 392(6795): 317-323
    Guidance of cellular nematic elastomers into shape-programmable living surfaces.
    Pau Guillamat, Waleed Mirza, Pradeep K Bal, Manuel Gómez-González, Pere Roca-Cusachs, Marino Arroyo, Xavier Trepat.
      Engineering living materials that autonomously morph into predetermined shapes holds potential for synthetic morphogenesis and soft robotics. Harnessing cellular tissues to self-organize and generate forces offers a promising route toward this goal. However, controlling tissue mechanics to direct morphogenesis remains challenging. We introduce a strategy to program tissue-shape transformations through nematic organization of cellular forces. By controlling nematic order and topological defects, we generate tissues programmed with specific stress fields. Using a theoretical framework coupling contractile nematics with thin-sheet mechanics, we show that nematically guided active stresses can drive morphogenesis through Gaussian morphing. Experimentally, detachment of nematic tissues triggers out-of-plane deformations, generating reproducible three-dimensional shapes. Integrating contractility and nematic patterning, our approach establishes a framework for designing shape-programmable living surfaces.
    DOI:  https://doi.org/10.1126/science.adz9174
  12. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12
    Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
    Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.
      Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.
    Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
  13. Mol Cell Proteomics. 2026 Apr 09. pii: S1535-9476(26)00062-9. [Epub ahead of print] 101566
    Probing Proteoform Heterogeneity from Single Human Oocytes.
    Nickolas P Fisher, Vijaya Lakshmi Kanchustambham, Elizabeth L Tsui, Chelsea Lock, Tian Xu, Hannah B McDowell, Indira Pla, Diane C Saunders, Jared O Kafader, Monica M Laronda, Neil L Kelleher.
      Ovarian tissue cryopreservation (OTC) is a fertility preservation strategy available to prepubertal patients undergoing gonadotoxic treatment who are at risk of developing premature ovarian insufficiency or for those whose treatment cannot be delayed. While cryopreserved tissue can be utilized for ovarian tissue transplantation (OTT) to restore hormone function and fertility in some of these individuals, those with a high risk of malignant cell reintroduction currently have no options. In vitro Maturation (IVM) of isolated immature oocytes from prepubertal patients is not yet successful enough for the clinic, necessitating study of the molecular factors influencing oocyte quality for IVM success. In this study, we characterized intact proteoforms from single human oocytes obtained from OTC and tissue donation in a donor cohort aged 2-33 years old to identify changes in the oocyte proteome across the pubertal transition. Utilizing single cell proteoform imaging mass spectrometry (scPiMS), which employs a sampling probe to raster over single cells coupled to individual ion mass spectrometry (I2MS) detection, we identified 559 proteins and 769 unique proteoforms across 28 oocytes from 8 donors, with an average of 78 unique proteoforms per oocyte. We used scPiMS to selectively sample oocytes and cumulus granulosa cells from single cumulus oocyte complexes (COCs) to identify proteoforms specific to these cell types. Finally, we determined proteoform landscapes for members of the oocyte-specific subcortical maternal complex (SCMC), KHDC3 and OOEP, and found new proteoforms that differ with donor age. Together, these first-in-class observations provide a foundation for understanding protein-level changes in oocyte biology across puberty to ultimately improve the efficiency of IVM and make fertility restoration options accessible for more patients.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101566
  14. Nat Aging. 2026 Apr 16.
    p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
    Ivan A Salladay-Perez, Itzetl Avila, Lizeth Estrada, Andreea C Alexandru, Cristian Ponce, Anika Dhingra, Grasiela Torres, Christina Y Deng, Ronak Hegde, Julia Gensheimer, Abhijit Kale, Indra Heckenbach, Simon Hui, Chantle Edillor, Jose A Soto, Alexander J Napior, Isaiah Little, Mark Larsen, Jacob Rose, Lia Farahi, Edwin D J Lopez Gonzalez, Matthew R Krieger, Kushan Chowdhury, Mridul Sharma, Yuming Jiang, Kevin Williams, Morten Scheibye-Knudsen, Carla M Koehler, Jesse G Meyer, Julia J Mack, Charles Brenner, Steven J Bensinger, Cyril Lagger, João Pedro de Magalhães, Birgit Schilling, Rajat Singh, Eric Verdin, Aldons J Lusis, Anthony J Covarrubias.
      Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01101-6
  15. J Biol Chem. 2026 Apr 09. pii: S0021-9258(26)00307-8. [Epub ahead of print] 111437
    Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation.
    Mariel Coradin, Elizabeth G Porter, Francisca Nathalia Vitorino, Richard M Searfoss, Joseph Cesare, Yemin Lan, Zhexin Zhu, Peder J Lund, Simone Sidoli, Yekaterina Perez, Congcong Lu, Justin Brumbaugh, Charles W M Roberts, Benjamin A Garcia.
      Histone proteolysis is an understudied phenomenon in which the N-terminal tails of histones are irreversibly cleaved by intracellular proteases. During development, histone post-translational modifications (PTMs) are known to orchestrate gene expression patterns that ultimately drive cell fate decisions. Therefore, deciphering the mechanisms of histone proteolysis is necessary to enhance the understanding of cellular differentiation. Here we show that histone H2A is cleaved by the lysosomal protease Cathepsin L during mouse ESC differentiation. Using quantitative mass spectrometry (MS), we identified L23 to be the primary cleavage site that gives rise to the main clipped form of H2A (cH2A), which reaches a maximum level of ∼1% of total H2A after four days of ESC differentiation. Using ChIP-seq, we found that preventing proteolysis leads to an increase in acetylated H2A at promoter regions in differentiated ES cells. We also identified novel readers of different acetylated forms of H2A in pluripotent ES cells, such as members of the PBAF remodeling complex, and show that H2A proteolysis abolishes this recognition. Analysis of the histone H3 PTM profiles of full-length (FL) H2A and cH2A containing nucleosomes demonstrate that cH2A is associated with marks found on active genes, consistent with ChIP-seq experiments. cH2A containing nucleosomes also are less stable or turned over at faster rates than nucleosomes containing FL H2A. Altogether, our data suggests that proteolysis serves as an efficient mechanism to silence pluripotency genes and destabilize the nucleosome core particle.
    Keywords:  ChIP-seq; Proteolysis; chromatin remodeler; differentiation; epigenetic; histone; mass spectrometry; proteomics; stem cell
    DOI:  https://doi.org/10.1016/j.jbc.2026.111437
  16. Nat Genet. 2026 Apr;58(4): 892-902
    Postmitotic transcription and 3D regulation show locus-specific and differentiation-specific sensitivity to cohesin depletion.
    UkJin Lee, Alejandra Laguillo-Diego, Daniela Magliulo, Wilfred Wong, Kritika Kasliwal, Zhangli Ni, Lingling Cheng, Jieru Li, Bobbie Pelham-Webb, Alexandros Pertsinidis, Christina Leslie, Effie Apostolou.
      Acute cohesin loss causes widespread reorganization of three-dimensional (3D) chromatin architecture but has relatively minor effects on steady-state transcription. It remains unclear whether its role in gene regulation becomes more critical during mitotic exit, when 3D chromatin architecture and transcription are globally re-established. To address this, we acutely depleted RAD21 in mouse embryonic stem cells during mitotic exit under self-renewal or differentiation conditions. Here we show that, although most loops failed to reform without cohesin, the few cohesin-independent loops were linked to active promoters, strong enhancers and H3K27ac mitotic bookmarking. Transcriptional changes were only modest, indicating that gene reactivation largely bypasses cohesin. Sensitive genes showed RAD21 promoter binding, a higher number of structural loops and positioning within well-insulated, gene-poor topologically associating domains. During differentiation, cohesin loss impaired activation of a broader set of developmental genes, partly due to defective de novo regulatory interactions. Together, these findings demonstrate context-specific requirements for cohesin in gene activation.
    DOI:  https://doi.org/10.1038/s41588-026-02556-4
  17. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00196-6. [Epub ahead of print]86(8): 1441-1458.e7
    FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated secretory phenotype.
    Kan Etoh, Yuko Hino, Hideaki Morishita, Mitsuyoshi Nakao.
      The pro-inflammatory, senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells (SnCs) that exacerbates age-related pathophysiology and chronic diseases. Although unique gene regulation is essential for fulfilling the pro-inflammatory SASP, the epigenomic basis in SnCs remains largely unknown. Here, we show that FOXF1/2 define the senescence-specific enhancer landscape by shaping chromatin accessibility. FOXF1/2 interact with p300/CREB-binding protein (CBP) and stimulate H3K27 acetylation and chromatin opening at de novo enhancers of pro-inflammatory SASP genes, together with the recruitment of AP-1 c-JUN to these regions. FOXF1/2 depletion in SnCs significantly suppresses pro-inflammatory SASP, independent of persistent growth arrest, and diminishes the paracrine effect on surrounding cells. Notably, loss of FOXF1/2 leads to the redistribution of AP-1 c-JUN to regulatory elements of senescence-associated downregulated genes. Our results uncover that FOXF1/2 coordinate the pro-inflammatory SASP program, suggesting that FOXF1/2-mediated enhancer remodeling is a key target for modulating SnCs to promote healthy aging.
    Keywords:  AP-1 c-JUN; FOXF1; H3K27 acetylation; cellular senescence; chromatin opening; enhancer; gene expression; p300/CBP; pioneer transcription factor; pro-inflammatory SASP; senostatics or senomorphics
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.020
  18. Genome Res. 2026 Apr 15. pii: gr.281022.125. [Epub ahead of print]
    Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code.
    Marina Murillo, Marina Salvadores, Aina Vaquer Picó, Lina Tsapanou, Adrian Gabriel Torres, Fran Supek, Lluis Ribas de Pouplana.
      Transfer RNA genes (tDNAs) are essential genomic elements that safeguard translational fidelity. Using the T2T version of the human genome we have mapped the position of human tDNAs and analyzed their individual transcriptional activities. Then we have characterized, at single base resolution, the impact of somatic mutations in human tDNAs and its relationship to the transcriptional status of each gene. We confirm that tDNAs are hotspots for somatic mutagenesis, and show that they display mutational loads that are directly proportional to their transcription rates. Highly transcribed tDNAs in tumors or healthy tissues accumulate mutations at rates up to nine-fold higher than highly transcribed protein-coding genes. Mutational loads at tDNAs are tumor-specific, and increase with patient age. Mutations at structurally conserved tRNA positions appear to be under negative selection. Anticodon nucleotides crucial for decoding frequently acquire somatic mutations, readily generating chimeric tRNA species capable of systematically introducing amino acid substitutions across the proteome. Our results reveal a previously unrecognized source of somatic heterogeneity in human cancer and aging tissues that may directly impact upon translation efficiency and fidelity, and cause cell-specific proteostasis degeneration.
    DOI:  https://doi.org/10.1101/gr.281022.125
  19. Autophagy. 2026 Apr 12.
    LC3-linked Golgi-bypass exocytosis fortifies epithelial barrier defense.
    Jiabin Wang, Junkai Wang, Xinyu Xiao, Lingling Zheng, Xia Lu, Li Wang, Xin Bian, Long Lin.
      Cells dynamically regulate membrane protein delivery to meet physiological demands, yet how external cues rapidly mobilize unconventional Golgi-bypass exocytic routes in vivo remains unclear. Here we define LC3/Atg8-associated carrier exocytosis (LACES), a conserved program that couples microbial cues to accelerated surface delivery. In the Caenorhabditis elegans intestine, phenazine-1-carboxamide (PCN) triggers VPS-34-dependent PtdIns3P generation at ILE-1/ERGIC-53 subdomains, enabling Atg8ylation on preexisting single-membrane RAB-8 carriers. This route accelerates delivery of the ABC transporter PGP-1 and improves host survival during infection, while operating independently of the unfolded protein response, canonical macroautophagy/autophagy initiation modules, and LC3-associated phagocytosis regulators. The pathway is engaged by multiple extracellular bacteria and also functions in mammalian epithelia, where PCN increases apical ΔF508-CFTR delivery in polarized Caco-2 cysts with measurable functional improvement and enhances LC3-RAB8 interactions in mouse intestinal epithelium. These findings establish a conserved LC3-linked Golgi-bypass route and illustrate how microbial cues can rapidly rewire epithelial membrane trafficking to fortify barrier defense.
    Keywords:  Atg8ylation; LC3-linked Golgi-bypass secretion; RAB8 carriers; epithelial barrier defense; phenazine-1-carboxamide; unconventional protein secretion
    DOI:  https://doi.org/10.1080/15548627.2026.2659291
  20. Cold Spring Harb Perspect Biol. 2026 Apr 17. pii: a041908. [Epub ahead of print]
    Roles and Regulation of the Hippo Signaling Pathway in Mammalian Preimplantation Development.
    Hiroshi Sasaki.
      During preimplantation development, mammalian embryos form blastocysts. Studies in mouse embryos have revealed multiple roles of the Hippo signaling pathway in this process. Among them, the process of TEA domain transcription factor 4 (TEAD4)-Yes-associated protein (YAP) control of trophectoderm (TE) and inner cell mass fate is the most extensively characterized. The major mechanism of YAP regulation is the activation of Hippo signaling by adherens junctions and inhibition by cell polarization or the apical domain. Several additional mechanisms further modulate Hippo signaling and/or YAP, including polarity regulation by Rho-associated coiled-coil-containing protein kinase (ROCK) and transcription factor AP-2γ (TFAP2C), angiomotin (AMOT) regulation by Ras homolog (RHO), asymmetric inheritance of the apical domain, mechanical regulation, and glucose metabolism. Hippo signaling also regulates other processes during embryogenesis, including zygotic gene activation by maternal YAP, cell state transition at the 8-cell stage, and maturation and quality control of the epiblast via cell competition. The TE fate regulatory role of the Hippo pathway is evolutionarily conserved among mammalian species, including human and bovine embryos, but some details differ.
    DOI:  https://doi.org/10.1101/cshperspect.a041908
  21. Sci Adv. 2026 Apr 17. 12(16): eadz8362
    Synthetic control of implanted engineered liver tissue growth.
    Amy E Stoddard, Vardhman Kumar, Constantine N Tzouanas, Veronica Hui, Jeffrey Li, Anisha Jain, Alanna Farrell, Sangeeta N Bhatia, Christopher S Chen.
      Despite the promise of engineered tissue implants for the treatment of organ failure, scaling of these constructs to sizes of therapeutic relevance remains a barrier to clinical translation. Here, we propose a strategy to circumvent this limitation: to instead implant a small-scale construct and then induce it to grow in situ after its engraftment into a host. Using engineered liver tissue as a proof-of-concept application, we integrated synthetic biology and tissue engineering tools to build liver tissues that can be expanded on-demand after implantation in vivo. To achieve this goal, we first identified the combination of Yes-associated protein (YAP) and growth factor (GF) signaling as sufficient to drive human hepatocyte proliferation in dense, three-dimensional engineered tissues. We then engineered control of these signaling axes using synthetic biology tools to drive human liver tissue expansion both in vitro and in vivo. As such, this work establishes a genetic strategy for generating large organ implants through bioengineered on-demand outgrowth via synthetic biology triggering (BOOST).
    DOI:  https://doi.org/10.1126/sciadv.adz8362
  22. bioRxiv. 2026 Apr 10. pii: 2026.04.08.716168. [Epub ahead of print]
    Midzone bundles of the mammalian anaphase spindle are mechanically coupled both locally and globally.
    Zachary Mullin-Bernstein, Sterre van Wierst, Carly Garrison, Nathan Cho, Sophie Dumont.
      Robust chromosome segregation requires the anaphase spindle to both preserve and remodel its structure under force. How it does so remains unclear as probing mechanics during anaphase's short lifetime is challenging. Here, we use microneedles to pull on mammalian anaphase midzone bundles and ask how they respond to and transmit force across space and time. We find that midzone bundles locally transmit force to each other in the spindle's short axis over multiple timescales. Along the spindle's long axis, midzone bundles globally transmit force: rather than bundles sliding apart or detaching under force, the spindle shortens. This reveals strong anchorage and resistance to outward sliding, and that spindle elongation requires all midzone bundles to elongate. This global force transmission is stronger for short-lived forces and is strictly PRC1-dependent, indicating limited mechanistic redundancy. In sum, the anaphase spindle acts as a single mechanical unit over short timescales to resist and transmit force, while remodeling over long timescales to segregate chromosomes.
    Summary: Using microneedle manipulation, Mullin-Bernstein et al. show that microtubule bundles of the mammalian anaphase spindle are mechanically coupled, transmitting force both laterally and between spindle poles. These strong connections may help ensure coordinated and error-free chromosome segregation.
    DOI:  https://doi.org/10.64898/2026.04.08.716168
  23. Nature. 2026 Apr 15.
    Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
    Temurkhan Ayupov, Verónica Moreno-Juan, Serena Curtoni, Alex Fratzl, Upnishad Sharma, Susana Posada-Céspedes, Ramona Ratiu, Rei Morikawa, Alexandra Graff Meyer, Margherita Pezzoli, Glenn Bantug, Morgan Chevalier, Yanyan Hou, Sarah A Nadeau, Álvaro Herrero-Navarro, Vikram Ayinampudi, Elizabeth Kastanaki, Natasha Whitehead, Rebecca A Siwicki, Mariana M Ribeiro, Ji Hoon Han, Annalisa Bucci, Christoph Hess, Simone Picelli, Magdalena Renner, Daniel J Müller, Cameron S Cowan, Simon Hansen, Botond Roska.
      A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy1-3. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here we developed MitoCatch as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells by cell-surface-displayed monospecific binders, mitochondrion-displayed monospecific binders or bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondrial delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons and cardiac, endothelial and immune cells in humans and mice. Transplanted mitochondria promoted the survival of damaged neurons from an individual with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a potential strategy to target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41586-026-10391-0
  24. Nature. 2026 Apr 15.
    Mapping convergent regulators of melanoma drug resistance by PerturbFate.
    Zihan Xu, Ziyu Lu, Aileen Ugurbil, Abdulraouf Abdulraouf, Andrew Liao, Jianxiang Zhang, Wei Zhou, Junyue Cao.
      High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.
    DOI:  https://doi.org/10.1038/s41586-026-10367-0
  25. Cell. 2026 Apr 16. pii: S0092-8674(26)00278-3. [Epub ahead of print]189(8): 2307-2321
    A recipe for chaos: Extrachromosomal DNA and the hallmarks of cancer.
    Ivy Tsz-Lo Wong, Chris Bailey, Sihan Wu, Anton G Henssen, Benjamin F Cravatt, Zhijian J Chen, Vineet Bafna, Mariam Jamal-Hanjani, Charlie Swanton, Howard Y Chang, Paul S Mischel.
      Some aggressive cancers exhibit a level of rapid genome change and therapy resistance that is difficult to explain. Research over the past decade has shown that extrachromosomal DNA (ecDNA) can be the cause. When oncogenic genetic elements untether from chromosomes and no longer follow Mendelian inheritance, genomic chaos and accelerated evolution ensue, generating unique ecDNA biology and non-traditional therapeutic vulnerabilities distinct from traditional mutation-targeting approaches. Here, we put forward a holistic view where ecDNA is integrated into the broader Hallmarks of Cancer framework to better understand the problem and chart a path forward.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.011
  26. Nat Commun. 2026 Apr 17.
    Cytoplasmic localization of pseudouridine synthase 7 facilitates a pseudouridine-dependent enhancement of cellular stress tolerance.
    Minli Ruan, Sean M Engels, Matthew R Burroughs, Xiaoyan Li, Rosella Stower, Talia Tzadikario, Connor Powell, Dylan Bloch, Oleksandra Fanari, Stuart Akeson, Daniel E Eyler, Chase A Weidmann, Sara Rouhanifard, Miten Jain, Lydia M Contreras, Kristin S Koutmou.
      Pseudouridine (Ψ) is an abundant post-transcriptional modification found across all classes of RNA. It is widely speculated that Ψ inclusion in messenger RNAs (mRNAs) might provide an avenue for cells to control gene expression post-transcriptionally. Here we demonstrate that one of the principal mRNA pseudouridylating enzymes, pseudouridine synthase 7 (PUS7), exhibits a stress-induced accumulation in the cytoplasm of yeast and human epithelial lung cells. Stress-induced and cytoplasmic localization of PUS7 promotes Ψ-incorporation into hundreds of mRNA targets. In contrast, the modification status of tRNA sites targeted by PUS7 (Ψ13 and Ψ35) is unperturbed. Furthermore, engineered PUS7 cytoplasmic localization increases cellular fitness under reactive oxygen species (ROS) and divalent metal ion stress. Quantitative proteomics reveal a reshaping of the proteome upon PUS7 relocalization under stress. Collectively, our data demonstrate that PUS7 localization alters mRNA pseudouridylation patterns, reshapes the proteome, and influences cellular fitness.
    DOI:  https://doi.org/10.1038/s41467-026-71654-y
  27. Elife. 2026 Apr 15. pii: RP96980. [Epub ahead of print]13
    Heterogeneity of Sonic Hedgehog response dynamics and fate specification in single neural progenitors.
    Fengzhu Xiong, Andrea R Tentner, Sandy Nandagopal, Tom W Hiscock, Peng Huang, Sean G Tsung-Megason.
      During neural tube patterning, a gradient of Sonic hedgehog (Shh) signaling specifies ventral progenitor fates. The cellular response to Shh is processed through a genetic regulatory network (GRN) to specify distinct fate decisions. This process integrates Shh response level, duration, and other inputs and is affected by noise in signaling and cell position. How reliably the Shh response profile predicts the fate choice of a single cell remains unclear. Here, we use live imaging to track neural progenitors in developing zebrafish and quantify both Shh and fate reporters in single cells over time. We found that there is significant heterogeneity between Shh response and fate choice in single cells. We quantitatively modeled reporter intensities to obtain single-cell response levels over time and systematically evaluated their correlation with cell fate specification. Motor neuron progenitors (pMNs) exhibit a high degree of variability in their Shh responses, which is particularly prominent in the posterior neural tube where the Shh response dynamics are similar to those of the more ventrally fated lateral floor plate cells (LFPs). Our results highlight the precision limit of morphogen-interpretation GRNs in small and dynamic target cell fields.
    Keywords:  cell fate; developmental biology; heterogeneity; morphogen; neural tube; single-cell tracking; zebrafish
    DOI:  https://doi.org/10.7554/eLife.96980
  28. Nat Commun. 2026 Apr 14.
    Restorative macrophage-derived RNAseT2 stimulates muscle stem cell fusion via an SLK/N-WASP/actin bundling dependent axis.
    Michéle Weiss-Gayet, Gaëtan Juban, Emmeran Le Moal, Antonio Moretta, Camilla Farnetani, Christelle Gobet, Jules Guillemaud, Marie-Catherine Le Bihan, Oded Shoseyov, Annie Adrait, Katharina Ternka, Odile Boespflug-Tanguy, Matthias Kettwig, Yohann Couté, Rémi Mounier, Francesco Acquati, Robert D Knight, Bénédicte Chazaud.
      Muscle stem cells (MuSCs) fuse to form myofibers to repair skeletal muscle after injury. Within the regenerative MuSC niche, restorative macrophages stimulate MuSC fusion, although the molecular mechanisms involved are largely unknown. Here, we show that restorative macrophages secrete ribonuclease T2 (RNAseT2) to stimulate MuSC fusion. RNAseT2 enters MuSCs via the mannose receptor and induces the formation of actin bundles in MuSCs, enabling cell/cell fusion. Mechanistically, RNAseT2 binds to Ste20-like kinase (SLK), which itself triggers the phosphorylation-mediated activation of N-WASP, through Paxillin phosphorylation, allowing actin bundling necessary for MuSC fusion. In vivo, overexpressing RNAseT2 in regenerating muscle increases fusion in newly formed myofibers in mouse and zebrafish while macrophages deficient for RNAseT2 gene lead to fusion defect and smaller myofibers. This study reveals a new function for the highly conserved RNAseT2 and provides a new molecular mechanism by which restorative macrophages support MuSC fusion during muscle repair.
    DOI:  https://doi.org/10.1038/s41467-026-71990-z
  29. Cell Rep Methods. 2026 Apr 16. pii: S2667-2375(26)00108-6. [Epub ahead of print] 101408
    HAK-actin, a U-ExM-compatible probe to image the actin cytoskeleton.
    Olivier Mercey, Luc Reymond, Florent Lemaître, Isabelle Mean, Marine H Laporte, Marine Olivetta, Karin Sadoul, Omaya Dudin, Virginie Hamel, Paul Guichard.
      Expansion microscopy (ExM) enables super-resolution imaging by physically enlarging biological samples. While ExM has been successfully applied to study the intracellular microtubule cytoskeleton, reliable probes for visualizing actin fibers remain limited. Here, we present HAK-actin, an engineered actin probe compatible with ultrastructure expansion microscopy (U-ExM). We show that HAK-actin delivers robust and uniform actin staining across diverse systems, including human cells, microbial eukaryotes, and mouse retinal tissue. This tool provides a simple, versatile, and reproducible solution for actin cytoskeleton visualization, addressing a critical need in cell biology.
    Keywords:  CP: imaging; actin; cryo-ExM; cytoskeleton; expansion microscopy; iU-ExM; super resolution
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101408
  30. Development. 2026 Apr 01. pii: dev204807. [Epub ahead of print]153(7):
    Dependence of cell fate potential and cadherin switching on the coordinate within the primitive streak during differentiation of human pluripotent stem cells.
    Ye Zhu, Aryeh Warmflash.
      During gastrulation, mesendoderm originates in the primitive streak (PS) where cells undergo an epithelial-mesenchymal transition and an expression switch from E- to N-cadherin. We made measurements of these processes during differentiation of human pluripotent stem cells to PS and downstream mesendoderm subtypes using established protocols and variants in which signaling through key pathways, including activin, BMP and Wnt, were modulated. The anterior-to-posterior identity of cells within the PS had little impact on the subsequent differentiation potential but impacted the degree of cadherin switching. During switching, E-cadherin downregulation and N-cadherin upregulation were uncorrelated and had different dependence on signaling. The exception to the broad potential of cells was the loss of definitive endoderm potential in mid-to-posterior PS. Thus, cells induced to different PS coordinates had similar potential within the mesoderm but differed in cadherin switching. Consistent with this, E-cadherin knockout or overexpression did not alter outcomes during differentiation. Overall, although all processes are regulated by the same set of signaling pathways, the extent of cadherin switching and epithelial-mesenchymal transition can vary substantially within cells adopting the same cell fate.
    Keywords:  Cadherin switching; EMT; Gastrulation; Pluripotent stem cells; Primitive streak; Signaling
    DOI:  https://doi.org/10.1242/dev.204807
  31. Curr Opin Genet Dev. 2026 Apr 11. pii: S0959-437X(26)00037-7. [Epub ahead of print]98 102470
    Oscillatory gene expression in cell differentiation and tissue patterning.
    Hiromi Shimojo, Ryoichiro Kageyama.
      Recent advances in imaging techniques and single-cell transcriptomics have revealed that many genes exhibit ultradian rhythms across diverse developmental processes and in tissue homeostasis, underscoring the importance of rhythmic gene expression in the regulation of cell fate determination, cellular competence, and tissue patterning. Although the biological functions of gene expression dynamics have long remained unclear, researchers have begun to elucidate the mechanisms by which distinct dynamic gene expression patterns regulate cell proliferation, cell differentiation, cell survival, cell death, and cell-cell interactions. In this review, we discuss recent advances in our understanding of the functional roles of oscillatory gene expression in cell fate regulation, with a particular focus on the timing of cell fate decisions.
    DOI:  https://doi.org/10.1016/j.gde.2026.102470
  32. Nat Mater. 2026 Apr 16.
    Condensate corona-nanoparticle complexes transfer functional biomolecules between cells.
    Laurent Adumeau, Yuchen Lin, Mura M McCafferty, Silvia Vercellino, Yi-Feng Wang, Xiaoliang Yang, Wei Zhang, David Garry, Filippo Bertoli, Cara Gaffney, Ying Ling Dee, Linlin Song, Ester Canepa, Xia Xiao, Yanqiu Ye, Guohui Huang, Qiwei Wang, Liufang Liao, Zixu Zhao, Koen Evers, Lorenzo Cursi, Vanya Petseva, Zengchun Xie, Aisling Fleming, Emily Sheridan, Ingrid Morera, Kai Liu, Yingxin Li, Marta Saccomanno, Andrea Marcantognini, Yan Yan, Kenneth A Dawson.
      Biological nanoscale assemblies transfer proteins and RNAs between cells and cellular compartments. Nonetheless, it is unclear if exogenous and synthetic nanostructures affect these molecular assemblies and processes. Here we report nanostructure-biological hybrid complexes that are formed by synthetic nanoparticles after being internalized by cells. These nanoparticles, in rare events, acquire an overlaid cell-derived biomolecular condensate corona, afterwards being exported to the extracellular space to be internalized by other cells. The condensate corona is compositionally distinct from extracellular vesicles, containing intact proteins, mRNAs and long RNAs. The condensate corona is mechanically robust in extracellular conditions, becoming fluid within endosomes, where it detaches from the particle core and escapes the endo-lysosomal pathway, redistributing its protein and RNA components to cytosolic and nuclear compartments. Grafting short peptides onto the surface of purified corona-nanoparticle complexes prevents detachment and endo-lysosomal escape, suggesting that recognition interactions at the condensate-endosome lumen interface control intracellular access. Overall, these findings reveal a natural, condensate-mediated route for the transfer of biomolecular machinery including RNA between cells, which could inspire design principles for future delivery systems.
    DOI:  https://doi.org/10.1038/s41563-026-02534-5
  33. Cold Spring Harb Perspect Biol. 2026 Apr 13. pii: a041740. [Epub ahead of print]
    Pulling the Back to Steer Cell Migration: Mechanisms of Structural Polarity in Confining Signaling and Protrusion.
    Bo Gong, Tobias Meyer.
      Directed cell migration is a coordinated process mediated by membrane protrusion at the front and contractile retraction at the back. This review compares a local excitation and global inhibition (LEGI) model and an emerging structural polarity of receptor activation (SPRA) model. The LEGI model posits that locally excitable signals generate membrane protrusions that become a single front through uncharacterized global inhibition that suppress competing protrusions. In contrast, the SPRA model proposes a central role of structural polarization, particularly membrane proximal F-actin, endoplasmic reticulum (ER)-plasma membrane (PM) contact sites, as well as actomyosin and nuclear positioning. In this model, the structural asymmetry ultimately sets up a stable front-to-back signal gradient, by enhancing receptor activity at the front and diminishing it at the back. Local differences in receptor sensitivity explains how uniform receptor stimuli initiate protrusions and trigger persistent cell migration. We discuss the mechanistic evidence for the two directed migration models and key open questions.
    DOI:  https://doi.org/10.1101/cshperspect.a041740
  34. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2521977123
    Voltage-gated proton channel Hv1/VSOP regulates reciprocal interactions between F-actin and endosomes in microglia.
    Takafumi Kawai, Daisuke Yoshioka, Pattama Wiriyasermkul, Risa Mori-Kreiner, Rizki Tsari Andriani, Megumi Kobayashi, Manabu Abe, Kenji Sakimura, Kazuki Nagayasu, Shushi Nagamori, Yasushi Okamura.
      Voltage-gated proton channel Hv1/VSOP has long been regarded as a plasma membrane protein that modulates intracellular pH and membrane potential to support immune cell function. Here, we reveal an unexpected intracellular pool of Hv1 on endosomal membranes in microglia, where it orchestrates a reciprocal interplay between endosomal trafficking and the actin cytoskeleton. Combining endosome patch-clamp recordings with high-resolution imaging, we demonstrate that functional endosomal Hv1 forms tight and dynamic associations with F-actin. Genetic deletion of Hv1 markedly elongates actin filaments, a phenotype that appears to depend on intracellular rather than plasma membrane Hv1 activity. Heterologous expression of wild-type Hv1, but not a proton-non-conducting mutant, reduced the F-actin staining, indicating that the ion-conducting function is required for this regulation. Live-cell imaging reveals that Hv1-positive endosomes move in concert with F-actin networks and frequently engage with their terminal regions, suggesting that filament barbed ends are trapped at Hv1-positive endosomes. Proximity-labeling proteomics identifies the actin-capping protein CAPZ as a critical mediator of Hv1-dependent actin remodeling, and genetic ablation of CAPZ abolishes the actin phenotype in Hv1-deficient microglia. These findings uncover a previously unrecognized ion channel-cytoskeleton crosstalk that shapes endosomal function and microglial physiology, redefining the functional landscape of voltage-gated proton channels.
    Keywords:  F-actin; endosome; microglia; voltage-gated proton channel
    DOI:  https://doi.org/10.1073/pnas.2521977123
  35. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00208-X. [Epub ahead of print]
    MRE11 proximal polyadenylation site-mediated looping impacts transcription and genomic stability.
    Kaimeng Huang, Marie Eve Brault, Ke Cong, Narmen Azazmeh, Sarah Collins, Siyun Lee, George A Lantz, Gregory Raskind, Gaëlle Legube, Rameen Beroukhim, Dipanjan Chowdhury.
      Alternative polyadenylation (APA) generates transcript isoforms with variable 3' untranslated regions (UTR) lengths, yet its role in DNA damage response (DDR) genes is poorly understood. Here, we demonstrate that the proximal polyadenylation site (pPAS) of MRE11 engages in PAS-promoter looping to facilitate RNA polymerase recycling and sustain high promoter activity-a mechanism not well characterized in mammals. Deletion of the MRE11 pPAS disrupts this looping, reduces MRE11 transcription, impairs MRE11-RAD50-NBS1 (MRN) complex levels, and phenocopies hypomorphic MRE11 mutations. MRE11pPAS-/- cells exhibit ectopic DNA replication and reduced viability under overgrowth conditions. 5-ethynyl-2'-deoxyuridine sequencing (EdU-seq) revealed aberrant DNA synthesis occurring primarily at intronic and intergenic regions, where MRE11 chromatin immunoprecipitation sequencing (ChIP-seq) showed decreased binding correlating with elevated replication. Furthermore, multiple DDR genes with several PASs also form PAS-promoter loops, suggesting a broader regulatory mechanism. Together these findings identify the MRE11 pPAS as a critical noncoding element that maintains genome stability through transcriptional regulation via PAS-promoter looping.
    Keywords:  DNA repair; DNA replication; MRE11; RNA Pol II recycling; alternative polyadenylation; chromatin looping; genome stability; promoter-3′ UTR looping; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.032
  36. Sci Immunol. 2026 Apr 17. 11(118): eads9680
    The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death.
    Esther L Jones Evans, Benjamin Demarco, Han Cai, Madelon M E de Jong, Sarah Hill, Marcus A Widdess, Joannah R Fergusson, Ryan E Glass, Gemma Harris, Gracie J Mead, Yavuz F Yazicioglu, Saba Nayar, Benjamin A Fisher, Mark S Cragg, Alexander J Clarke, Audrey Gérard, Jelena S Bezbradica, Lynn B Dustin.
      Sjögren's disease (SjD) causes localized and systemic inflammation and autoantibody production against intracellular proteins such as TRIM21/Ro52 (tripartite motif-containing protein 21). TRIM21, an E3 ubiquitin ligase, binds antibody Fc domains on opsonized pathogens that have escaped extracellular immunity and entered the cytosol. TRIM21 then ubiquitinates these pathogens, driving their proteasomal degradation. How TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis or necroptosis) but not apoptosis. Although many cytosolic proteins are released by dead cells, liberated TRIM21 is distinct: Its high antibody affinity enables binding to Fc domains of circulating immunoglobulins, forming large immune complexes (ICs). These ICs increase in SjD, where anti-TRIM21 autoantibodies interact with released TRIM21 via Fc and F(ab')2. TRIM21 ICs are taken up by macrophages, which drive proinflammatory responses, antigen presentation, and metabolic changes in high interferon environments. Thus, TRIM21 may perpetuate inflammation and autoantigen presentation, resulting in high immunogenicity.
    DOI:  https://doi.org/10.1126/sciimmunol.ads9680
  37. bioRxiv. 2026 Apr 09. pii: 2026.04.06.716785. [Epub ahead of print]
    3D imaging of the pregnant uterus reveals an extensively invasive mouse placenta and early CXCL12-CXCR4 requirement.
    James B Zwierzynski, Mira N Moufarrej, Kristy Red-Horse.
      Successful pregnancy requires exquisite balance: the placenta must invade just enough to access maternal blood but not so deep it remains attached at birth. Disrupting this balance causes life-threatening pregnancy complications, for which treatments remain limited. Animal models are desperately needed to discover mechanisms underlying balanced uteroplacental development and how pregnancy complications arise, but this is hampered by the view that mouse placentation lacks human characteristics such as extensive trophoblast invasion and targeting of uterine spiral arteries. Here, we utilize 3D imaging, mouse genetics, and pharmacological perturbations to demonstrate that: (1) The mouse placenta invades more extensively than previously recognized with most spiral arteries heavily enveloped by fetal trophoblasts, (2) This process is disrupted without CXCL12-CXCR4 signaling specifically during early pregnancy, and (3) Disrupting early uteroplacental development ultimately results in excessively deep trophoblast invasion, closely mimicking the pregnancy complication placenta accreta. Mechanistically, uterine epithelium, stroma, and arteries activate CXCR4 signaling in early pregnancy, and inhibition causes decidualization failure, followed by dissolution of spiral artery development. Trophoblasts consequently migrate deep into uterine muscle and its arteries, reproducing hallmarks of human accreta. Thus, with 3D imaging, the mouse more effectively models human uteroplacental development and defines an early etiological window for intervention.
    DOI:  https://doi.org/10.64898/2026.04.06.716785
  38. Nat Commun. 2026 Apr 17.
    Aberrant laminin signaling drives melanocyte dedifferentiation and unveils a tractable therapeutic target in vitiligo.
    Fei Yang, Lingli Yang, Sylvia Lai, Masafumi Yokota, Yasutaka Kuroda, Takuo Yuki, Yoshito Takahashi, Tetsuya Sayo, Takeshi Namiki, Hiroyuki Goto, Sho Hiroyasu, Shigetoshi Sano, Shintaro Inoue, Yoichi Mizukami, Daisuke Tsuruta, Ichiro Katayama.
      Vitiligo is an acquired depigmenting disorder characterized by progressive melanocyte loss, yet its cellular mechanisms remain incompletely understood. Here, we identify a melanocyte dedifferentiation-like shift as a potentially reversible pathogenic mechanism. In healthy skin, melanocytes reside within a basement membrane niche defined by dystroglycan-laminin-211 adhesion. In vitiligo, extracellular matrix remodeling with reduced laminin-211 and increased laminin-332 is associated with a shift toward integrin α3β1-laminin-332 interactions. This alteration correlates with melanocyte dedifferentiation-like changes, together with Rho-F-actin remodeling, and coordinated alterations in Hippo, MAPK, and c-Jun signaling. Affected melanocytes exhibit reduced pigmentation and features of neural crest-like states, including multilineage potential. Importantly, these changes are partially reversible. Pharmacological modulation restored melanocyte differentiation and pigmentation in mouse models and ex vivo human skin, with JAK inhibition also promoting redifferentiation. These findings identify a microenvironment-driven mechanism in vitiligo and suggest potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-72064-w
  39. bioRxiv. 2026 Apr 06. pii: 2026.04.02.716189. [Epub ahead of print]
    Distinct principles of genome compartmentalization in Drosophila and humans revealed by osmotic stress.
    Bright Amankwaa, Christopher Playter, Emily Stow, Jacob T Sanders, Tianchun Xue, Rachel Patton McCord, Mariano Labrador.
      The three-dimensional organization of eukaryotic genomes into compartments, topologically associating domains, and loops is mediated by architectural proteins whose organizational principles vary across species. In Drosophila , insulator proteins including Su(Hw) and the histone variant γH2Av form liquid-liquid phase separation (LLPS) condensates, yet how this phase separation capacity relates to genome compartmentalization has remained unclear. Here we use hyperosmotic stress to simultaneously displace architectural proteins from chromatin in both Drosophila and human cells, enabling a comparative dissection of genome organization principles across species. We find that although human CTCF shares predicted LLPS properties with Drosophila insulator proteins, it does not form condensates upon osmotic stress, while Drosophila insulator proteins do. Hi-C analysis reveals that osmotic stress causes loss of compartments, TAD boundary strength, and loops in both organisms, but genome recovery after stress is rapid and near-complete in human cells while remaining substantially incomplete in Drosophila after one hour. Analysis of this recovery asymmetry reveals a fundamental difference in compartment organization: whereas human A and B compartments engage in robust homotypic long-range interactions, Drosophila B compartments rarely participate in long-range B-to-B contacts, indicating that the Drosophila genome does not replicate canonical A/B compartment organization. Instead, Drosophila genome architecture is dominated by A-to-A interactions, and A compartments are specifically enriched in γH2Av and Su(Hw), with moderate enrichment of cohesin subunits. Furthermore, loops in Drosophila are mechanistically independent from compartments and TADs, recovering before compartment structure is restored, and are anchored by Su(Hw) and cohesin rather than by dCTCF. Together, these findings suggest that the LLPS properties of γH2Av and Su(Hw) underlie A compartment formation in Drosophila through a mechanism distinct from the heterochromatin-driven B compartment interactions that predominate in vertebrates, revealing fundamentally different organizational principles between fly and human genomes.
    DOI:  https://doi.org/10.64898/2026.04.02.716189
  40. Nat Chem Biol. 2026 Apr 15.
    Development of the fluorescent probe CenSpark for labeling centrioles and cilia.
    Cédric Pourroy, Georgios N Hatzopoulos, Luc Reymond, Friso E Douma, Tatiana Favez, Marie Croisier, Sara Cascais, Caroline Arber, Benita Wolf, Daphne M Laan, Guillermina R Ramirez-San-Juan, François Kuonen, Saishree S Iyer, Ilya Grigoriev, Anna Akhmanova, Pierre Gönczy.
      Small-molecule probes are transformative for cell biology, offering unprecedented insights into subcellular structures, including in systems without molecular genetic tools. Centrioles are fundamental for generating the axoneme of cilia and flagella, as well as centrosomes, but a generic small-molecule probe allowing selective visualization of centriolar and axonemal microtubules is lacking. We engineered CenSpark as a cell-permeable dual-ligand fluorescent probe exploiting the juxtaposition of inner and outer microtubule-binding sites of microtubule triplets and doublets present exclusively in centriolar and axonemal microtubules. This design endows CenSpark high selectivity in live and fixed specimen analysis of centrioles, cilia and flagella across systems. We deployed CenSpark to uncover the rate of primary cilium formation and track centrioles in chimeric antigen receptor T cells during polarization at the immunological synapse with unprecedented resolution. Overall, CenSpark is a novel versatile small-molecule fluorescent probe to monitor centrioles, cilia and flagella without the need for genetic manipulation.
    DOI:  https://doi.org/10.1038/s41589-026-02186-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒09 at 4:43.