bims-ginsta Biomed News
on Genome instability
Issue of 2026–05–03
37 papers selected by
Jinrong Hu, National University of Singapore
  1. TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
  2. A conserved motif tunes Sidekick condensate dynamics to control tricellular junction recruitment during epithelial remodeling.
  3. Scrib organizes cortical actomyosin clusters to maintain adherens junctions and angiogenic sprouting.
  4. Aged differentiated cells reverse into native stemness-like state by niche cytokines to sustain lifelong homeostasis and tissue repair.
  5. The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
  6. ATM counteracts chromatin-bound cGAS during DNA replication.
  7. Deciphering tRNA repertoires and translation coordination during mouse early embryogenesis by ORACLE-tRNAseq.
  8. Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
  9. Epitranscriptomic regulation of mRNA stability in pivotal transcription factors modulates the second cell fate decision.
  10. Cytoplasmic competition between separate parental pronuclei in zygotes.
  11. eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
  12. An in vitro menstrual cycle using organoids captures epithelial cell transitions during menstruation and regeneration of the human endometrium.
  13. Defective transcription of AAGAG satellite DNA causes sex-ratio meiotic drive in Drosophila.
  14. SIRT7 links H3K36ac epigenetic regulation with genome maintenance in the mouse testis.
  15. Nuclear envelope budding enables export of large transcripts in muscle cells.
  16. Developmental regulation of kinetochore phosphorylation determines mitotic fidelity.
  17. Spatially decoding genotype-associated epigenetic landscapes in human lymphoma FFPE tissues via epi-Patho-DBiT.
  18. Sensing endoplasmic reticulum redox state by ethylene receptors.
  19. MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth.
  20. ErbB family receptor dimerization dynamics and dysregulation via long-term single-molecule imaging.
  21. Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
  22. Mechanobiology of the Hippo-YAP Signaling Network.
  23. A Decline in Follicle Cell Function Is a Major Driver of Drosophila Ovarian Aging.
  24. Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton.
  25. NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
  26. Dynamic heterogeneity and hidden fluidity in dense epithelial tissues.
  27. DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development.
  28. Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.
  29. Cytokine Conversations: Fibroblasts Shape Macrophage Identity to Enhance Collagen Clearance.
  30. Hedgehog-driven adaxial cell constriction patterns slow muscle fate and somite boundary remodeling in the presomitic mesoderm.
  31. Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing.
  32. Somatic mutations distinguish melanocyte subpopulations in human skin.
  33. Sorcin couples Annexin A11 recruitment and ESCRT-III assembly during plasma membrane repair.
  34. Regulation of Tmem30b-mediated apical membrane homeostasis in auditory outer hair cells is critical for hearing.
  35. Ribosome dynamics during skeletal muscle repair and regeneration in mice and humans.
  36. Submicrometre sampling of living cells by macrophages.
  37. Purine metabolic adaptation protects the endothelium from disturbed flow-induced DNA damage and atherosclerosis.
  1. Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]
    TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
    Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.
      Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.
    Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2026.04.004
  2. Cell Rep. 2026 Apr 30. pii: S2211-1247(26)00414-6. [Epub ahead of print]45(5): 117336
    A conserved motif tunes Sidekick condensate dynamics to control tricellular junction recruitment during epithelial remodeling.
    Hiroyuki Uechi, Daxiao Sun, Yuki Saeki, Tetsuya Hiraiwa, Alf Honigmann, Anthony A Hyman, Erina Kuranaga.
      The tricellular junction, where three or more cells contact, comprises specific proteins regulating epithelial morphogenesis and homeostasis. It remains elusive how these proteins are confined to tricellular junctions to function. We reveal that the intracellular domain of the adhesive transmembrane protein Sidekick forms condensates and contributes to its accumulation at tricellular junctions. Fly genetics and in vitro reconstitution indicate that condensation alone is not sufficient for targeting but promotes stable accumulation of Sidekick at physiological concentrations. We identify a conserved motif whose deletion increases condensate dynamics and leads to mislocalization of Sidekick during epithelial junction remodeling. Mislocalization is accompanied by disturbed recruitment of Sidekick-associating proteins involved in junction dynamics to tricellular junctions and leads to delay in junction formation. These findings suggest that condensates with relatively low internal dynamics stabilize Sidekick localization under tissue dynamics, which assists recruitment of junction dynamics-regulating proteins and ensures epithelial remodeling.
    Keywords:  CP: cell biology; biomolecular condensation; epithelial morphogenesis; tricellular junctions
    DOI:  https://doi.org/10.1016/j.celrep.2026.117336
  3. J Cell Biol. 2026 Jun 01. pii: e202503146. [Epub ahead of print]225(6):
    Scrib organizes cortical actomyosin clusters to maintain adherens junctions and angiogenic sprouting.
    Lakyn N Mayo, Fiona Duong, Ana Mompeón, Kyle A Jacobs, M Luisa Iruela-Arispe, Matthew L Kutys.
      Spatiotemporal control of adherens junction fluidity and integrity is critical for angiogenesis, but underlying mechanisms are incompletely understood. To identify unappreciated regulators of endothelial adherens junctions, we performed VE-cadherin proximity ligation mass spectrometry, revealing significant interaction with the multifunctional scaffold Scrib. Utilizing a 3D angiogenesis-on-chip model, we find Scrib-depleted microvessels generate reduced intact sprouts and increased single-cell detachments. This defect was characterized by adherens junction instability and decreased actomyosin in the junctional cortex, yet was not caused by changes in catenin-dependent VE-cadherin coupling to actin. Instead, Scrib controls the formation of cortical actomyosin clusters, which critically organize the architecture and dynamics of the junctional actomyosin cortex to promote adherens junction stability. We further discovered that unconventional myosin-1c is a critical effector linking Scrib cortical dynamics and VE-cadherin to stabilize adherens junctions during angiogenic initiation. Our results demonstrate a new role for Scrib directing cortical actomyosin organization that is critical for precise control of adherens junctions during angiogenesis.
    DOI:  https://doi.org/10.1083/jcb.202503146
  4. Nat Commun. 2026 Apr 25.
    Aged differentiated cells reverse into native stemness-like state by niche cytokines to sustain lifelong homeostasis and tissue repair.
    Shalini Dimri-Wagh, Swarnabh Bhattacharya, Gharam Yassen, Ofir Shorer, Aya Amitai-Lange, Anna Altshuler, Shira Hadad-Porat, Keren Yizhak, Yuval Shaked, Michael Mimouni, Beatrice Tiosano, Ramez Barbara, Ruby Shalom-Feuerstein.
      Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that dedifferentiated corneal epithelial cells acquire a transcriptomic state closely resembling native stem cells, sustain tissue homeostasis across lifespan and efficiently repair repeated tissue injury. Transplantation of stage-specific genetically traceable aged differentiated epithelial cells onto a denuded niche reveals reversion into a stemness-like state, restoring both quiescent and active stem cell compartments. This plasticity operates within the epithelial lineage, allowing transitions along the differentiation axis, but remains restricted across lineages, as transplanted conjunctival cells fail to regenerate the corneal stem cell pool. Mechanistically, we identify niche-derived cytokines that trigger reprogramming in vivo and enhance stemness in primary human corneal epithelial cells, revealing a conserved and therapeutically exploitable pathway for epithelial regeneration.
    DOI:  https://doi.org/10.1038/s41467-026-72331-w
  5. Nat Cell Biol. 2026 Apr 30.
    The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
    Todd Douglas, Pengju Nie, Jiasheng Zhang, Kyrillos S Abdallah, Zhiping Wu, Meghan McReynolds, Kazuhiro Iwai, Junmin Peng, Wendy V Gilbert, Lawrence H Young, Craig M Crews.
      The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels.
    DOI:  https://doi.org/10.1038/s41556-026-01936-6
  6. Nat Cell Biol. 2026 Apr 29.
    ATM counteracts chromatin-bound cGAS during DNA replication.
    Yunhao Song, Xiaojuan Ran, Yu Xu, Kartik Subramanian, Chao Dai, Mavrakis Konstantinos, Li Lan, Vipin Yadav, Lee Zou.
      Cyclic GMP-AMP synthase (cGAS), a DNA sensor that activates type-I interferon responses, is restrained in the nucleus through chromatin binding, but its impact on DNA metabolism remains unknown. Here we show that chromatin-bound cGAS impedes DNA replication forks unless countered by ATM. Upon ATM loss, chromatin-bound cGAS slows replication forks, increases nascent DNA fragmentation and activates cytosolic cGAS. Remarkably, all these effects are alleviated upon the loss of cGAS chromatin binding, suggesting that ATM enables tolerance to chromatin-bound cGAS. Mechanistically, ATM, backed by ATR, releases cGAS from chromatin by phosphorylating MRE11. ATR inhibition in ATM-deficient cells exacerbates replication stress, causing synthetic lethality and stimulated interferon response. In ATM-deficient cancer cells, cGAS dictates replication stress and ATR inhibitor sensitivity, highlighting its potential as a biomarker for ATR-targeted therapy. Together, our findings uncover a regulatory circuit in which ATM and chromatin-bound cGAS jointly maintain the homeostasis of replication and cGAS signalling in cycling cells.
    DOI:  https://doi.org/10.1038/s41556-026-01931-x
  7. Nat Commun. 2026 Apr 30.
    Deciphering tRNA repertoires and translation coordination during mouse early embryogenesis by ORACLE-tRNAseq.
    Yun Li, Xin Wang, Ruofan Huang, Haoquan Yu, You Wu, Ze Shu, Wenlin Jiang, Zheng Cao, Zongyu Yu, Hongyan Li, Rushuang Yan, Yawei Gao, Xiao-Ou Zhang, Yunfang Zhang.
      Translational control is vital during the maternal-to-zygotic transition (MZT), yet the landscape of embryonic transfer RNA (tRNA) pools has been difficult to explore. Here, we develop Optimized Reaction for Accurate Capture of Low-input Entities tRNA Sequencing (ORACLE-tRNAseq), enabling robust tRNA profiling from as few as five mouse oocytes. We map tRNA landscapes from oocyte to blastocyst, identifying a distinct transition to embryonic tRNA repertoires and upregulation of tRNA pseudogenes at the 4-cell stage. Integrated multi-omics analyses reveal that zygotic tRNA gene activation coincides with zygotic genome activation (ZGA) and correlates with H3K4me3 establishment and chromatin remodeling. By coupling ORACLE-tRNAseq with Ribo-seq, we demonstrate that embryonic tRNA anticodon pools coordinate with high translation-efficiency gene pools to preferentially establish the zygotic translation machinery, particularly from major ZGA onwards. Collectively, these findings provide a resource for understanding translational regulatory networks during early embryogenesis.
    DOI:  https://doi.org/10.1038/s41467-026-72603-5
  8. bioRxiv. 2026 Feb 06. pii: 2026.02.04.703776. [Epub ahead of print]
    Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
    Xiaojuan Fan, Markus Hafner.
      Subcellular RNA localization is a fundamental layer of gene regulation, yet its heterogeneity across individual cells remains poorly understood. Here, we introduce the RNA Localization Profiler (RLP), a proximity-based RNA-editing strategy that maps compartment-specific RNAs in living cells. Across the cytoplasm, endoplasmic reticulum (ER), and plasma membrane, RLP identifies robust and highly specific RNA localization programs linked to translation and membrane organization. Single-cell RLP (scRLP) reveals that individual cells harbor roughly 5,000-7,000 cytoplasmic RNAs, with <10% associated with the ER. These measurements uncover pervasive subcellular heterogeneity in RNA localization that is undetectable by bulk assays. Spatial RNA patterns define an orthogonal axis of cell-state identity that is independent of gene expression. For example, ZWINT mRNA relocalizes to the cytoplasm in a cell cycle-dependent manner. These findings establish heterogeneous levels of subcellular RNA localization as a variable dimension of intracellular organization and cell identity.
    DOI:  https://doi.org/10.64898/2026.02.04.703776
  9. Nat Commun. 2026 Apr 28.
    Epitranscriptomic regulation of mRNA stability in pivotal transcription factors modulates the second cell fate decision.
    Weide Xiao, Li Tang, Mingli Ma, Kuisheng Liu, Jiaxu Lu, Wenqing Ding, Zhile Bai, Xuelian Liu, Xiaochen Kou, Yanhong Zhao, Hong Wang, Lei Yang, Shaorong Gao, Yawei Gao, Jun Liu.
      Embryonic development demands precise coordination of transcriptional and post-transcriptional mechanisms to ensure rapid cell fate transitions, yet the molecular mechanisms by which RNA influences these transitions remain unclear. Here, we observed a global increase in mRNA stability during the blastocyst formation, which precedes rapid lineage specification. Using both in vivo and mouse totipotent blastomere-like cells (TBLCs) or extended pluripotent stem cells (EPSCs) differentiation systems, we demonstrate that this transcriptome-wide stabilization is essential for the second cell fate decision, particularly in the formation of primitive endoderm (PrE). Mechanistically, VIRMA and METTL3, the components of methyltransferase complex (MTC) establish lineage specification by stabilizing the key PrE transcription factors, including Gata6, via the N6-methyladenosine (m6A) reader IGF2BP3. Knocked down of these regulatory proteins or targeted removal of m6A on Gata6, impacted the differentiation of PrE both in vivo and in vitro, and caused defects in blastulation and blastoid formation. Our results demonstrate that m6A-dependent post-transcriptional regulation plays a pivotal role in shaping lineage specification during peri-implantation and provided potential strategies for rescuing developmental defects.
    DOI:  https://doi.org/10.1038/s41467-026-72131-2
  10. Nature. 2026 Apr 29.
    Cytoplasmic competition between separate parental pronuclei in zygotes.
    Hirohisa Kyogoku, Mitsusuke Tarama, Masahiro Matsuwaka, Tappei Mishina, Akihito Harada, Reiko Nakagawa, Mami Kumon, Yoshihiro Shimizu, Yasuyuki Ohkawa, Tatsuo Shibata, Azusa Inoue, Tomoya S Kitajima.
      Embryogenesis begins with a zygote-a single cell with two pronuclei that separately enclose maternal and paternal chromosomes. The functional significance of the separation of parental chromosomes into distinct pronuclei remains unexplored, despite the fact that one-pronuclear biparental zygotes are used clinically1-3. Here, using a combination of mouse zygote manipulation, quantitative imaging and theoretical approaches, we show a cytoplasm-mediated competition mechanism between separate parental pronuclei that ensures developmental potential. This mechanism limits pronuclear volume and prevents epigenetic mark dysregulation, including loss of trimethylated histones. One-pronuclear biparental zygotes lack this mechanism, resulting in a reduced rate of development to term. This low developmental potential can be partially rescued by competition-based or drug-based restoration of epigenetic marks. This study provides a spatial mechanism linking fertilization to the establishment of the full developmental potential for the next generation, highlighting caveats in clinical use of one-pronuclear biparental zygotes.
    DOI:  https://doi.org/10.1038/s41586-026-10417-7
  11. Cell Stem Cell. 2026 Apr 30. pii: S1934-5909(26)00146-3. [Epub ahead of print]
    eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
    Haruko Kunitomi, Aye Myat Khaine, Radia Jamee, Vanessa Arreola, Mariselle Lancero, Amba Raychaudhuri, Samuel Perli, Yoshiko Sato, Mio Iwasaki, Pedro Ruivo, Kiichiro Tomoda, Mari Mito, Yuichi Shichino, Shintaro Iwasaki, Shinya Yamanaka.
      eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5+ intestinal stem cell (ISC) and secretory maturation programs while preserving villus architecture. Transcriptomic and single-nucleus multiome analyses reveal a durable fetal-like/regenerative state with YAP-TEAD activation and regenerative absorptive cells. Ribosome profiling identifies selective translation-efficiency loss among chromatin regulators, especially the KAT3 coactivators CREBBP and EP300, resulting in reduced KAT3 abundance and global histone acetylation; chemical KAT3 inhibition phenocopies this state. CUT&Tag and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrate that reduced eIF4G2-KAT3 output drives locus-selective enhancer remodeling, with loss of adult ISC/Wnt-Notch elements and activation of TEAD-enriched fetal loci, without inflammatory or integrated stress response programs driving the transition. Fetal intestinal spheroids remain viable despite similar biochemical defects, highlighting a stage-specific requirement for translational buffering in maintaining adult identity.
    Keywords:  differentiation; eIF4G2 (NAT1/p97/DAP5); epigenetic gene regulation; histone modification; intestinal stem cell; translation initiation
    DOI:  https://doi.org/10.1016/j.stem.2026.04.006
  12. Cell Stem Cell. 2026 Apr 28. pii: S1934-5909(26)00145-1. [Epub ahead of print]
    An in vitro menstrual cycle using organoids captures epithelial cell transitions during menstruation and regeneration of the human endometrium.
    Konstantina Nikolakopoulou, Weand Ybañez, Lhéanna Klaeylé, Lisa Frugoli, Tereza Cindrova-Davies, Hans-Rudolf Hotz, Charlotte Soneson, Margherita Yayoi Turco.
      Menstruation is an unusual process in which the human endometrium undergoes cyclical shedding with scarless regeneration. Despite its pivotal role in reproductive health, the cellular states and interactions orchestrating this process remain poorly defined, largely due to the lack of in vitro systems that capture the inaccessible perimenstrual window. We use human endometrial organoids to establish an in vitro menstrual cycle (IVMC) protocol that recapitulates cyclical epithelial dynamics. We validate the IVMC by benchmarking against in vivo samples spanning the menstrual window through histology, transcriptomic, and multiplex secreted-protein analysis. During menstruation, the in vivo luminal epithelium acquires a distinct transcriptomic signature, characterized by WNT7A expression. Loss of WNT7A compromises long-term organoid survival, highlighting its functional importance. The regeneration-associated luminal epithelium acts as a signaling hub during regeneration through interactions with the vasculature. This work opens new avenues to dissect the unique regenerative program of the endometrium in health and disease.
    Keywords:  WNT7A; endometrium; epithelial cells; luminal epithelium; menstrual cycle; menstruation; organoids; regeneration; transcriptomics; wound healing
    DOI:  https://doi.org/10.1016/j.stem.2026.04.005
  13. Nat Commun. 2026 Apr 25.
    Defective transcription of AAGAG satellite DNA causes sex-ratio meiotic drive in Drosophila.
    Tomohiro Kumon, Mami Nakamizo-Dojo, Amelie A Raz, Romain Lannes, Jaclyn M Fingerhut, Yukiko M Yamashita.
      Male germ cells have complex transcriptomes, with a large fraction of the genome being transcribed. This includes protein-coding genes (often not translated), non-coding DNA, and repetitive DNA, such as transposons and satellite DNA, which are normally silenced as heterochromatin. The significance of such widespread transcription remains unknown. Here, we show that a heterochromatin protein, HP2, is required for the transcription of AAGAG satellite DNA in Drosophila spermatocytes. HP2 depletion leads to abnormal retention of heterochromatin histone marks (H3K9me3) and spermatid death during sperm DNA packaging, leading to a model that transcription of AAGAG satellite DNA facilitates the remodeling of its heterochromatic nature in preparation for sperm DNA packaging. Strikingly, the severity of the spermatid death correlates with the amount of AAGAG satellite DNA carried by the spermatids, leading to preferential death of Y-chromosome-containing spermatids over X-containing spermatids, and hence sex-ratio meiotic drive phenotype. We propose that widespread spermatocyte transcription may reflect the process of chromatin remodeling to allow sperm DNA packaging. We further propose that differential composition and amount of satellite DNA on chromosomes may underlie naturally occurring male meiotic drive.
    DOI:  https://doi.org/10.1038/s41467-026-72480-y
  14. Nat Commun. 2026 Apr 28.
    SIRT7 links H3K36ac epigenetic regulation with genome maintenance in the mouse testis.
    Anna Guitart-Solanes, Mayra Romero, Andres Gamez-Garcia, Irene Fernández-Duran, Bryan A Niedenberger, Cristina Madrid-Sandín, Norah Spears, Ignasi Roig, Christopher B Geyer, Alejandro Vaquero, Karen Schindler, Berta N Vazquez.
      Reproductive aging is an increasing health concern that affects family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here, we found that mammalian Sirtuin 7 sustains spermatogenesis in an age-dependent manner. Sirtuin 7 deficiency in mice increases histone H3 lysine 36 acetylation in spermatogonia and spermatocytes, a pattern also observed during natural aging, and leads to altered chromatin accessibility and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, required for continuous sperm production, become prematurely lost in Sirtuin 7 deficient mice and show increased genome damage accumulation during aging or environmental stress. These changes are concurrent with age-dependent defects in double-strand break repair and a meiotic delay. Taken together, our results indicate that Sirtuin 7 connects histone H3 lysine 36 acetylation epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.
    DOI:  https://doi.org/10.1038/s41467-026-72540-3
  15. Cell. 2026 Apr 24. pii: S0092-8674(26)00386-7. [Epub ahead of print]
    Nuclear envelope budding enables export of large transcripts in muscle cells.
    Sofia Zaganelli, Janet B Meehl, Robert G Abrisch, Gia K Voeltz.
      Nuclear envelope (NE) budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet the significance of this unconventional export pathway for large endogenous cargoes in mammalian cells has remained largely unexplored. Here, we use a combination of electron and fluorescence microscopy to demonstrate that NEB events occur following myoblast differentiation into myotubes and concomitant with the expression of extremely long muscle-specific transcripts. We show that NE buds are derived from the inner nuclear membrane, contain internal vesicles, and are specifically enriched with long sarcomeric transcripts. We identify a role for the protein UAP56-interacting factor (UIF) in regulating mRNA cargo targeting into NE buds and show that this pathway requires the endosomal sorting complex required transport III (ESCRT-III) membrane remodeling machinery. Our findings uncover a non-canonical pathway for large transcript nuclear export in muscle cells and provide insight into its mechanism.
    Keywords:  ESCRT; RNA trafficking; membrane remodeling; nuclear envelope budding; nuclear export; sarcomeric transcripts
    DOI:  https://doi.org/10.1016/j.cell.2026.03.050
  16. bioRxiv. 2026 Apr 17. pii: 2026.04.15.718713. [Epub ahead of print]
    Developmental regulation of kinetochore phosphorylation determines mitotic fidelity.
    Brian Galaviz Sarmiento, Duane A Compton, Kristina M Godek.
      Accurate chromosome segregation relies on proper centromere and kinetochore formation and phospho-regulation. We previously demonstrated that a pluripotent state confers a low fidelity of chromosome segregation, however it is unknown how a pluripotent state impacts centromere and kinetochore function. Here, we demonstrate that both centromere and kinetochore structural organization and phosphorylation in mitosis are developmentally regulated. CENP-A, CENP-C, and HEC1 protein abundance is reduced at mitotic centromeres and kinetochores of human pluripotent stem cells (hPSCs) compared to isogenic somatic cells; however, elevating their levels does not improve chromosome segregation fidelity. Rather, we find that reduced phosphorylation of kinetochores is responsible for their low fidelity. HEC1 is hypophosphorylated at kinetochores of hPSCs compared to isogenic somatic cells at Cyclin B/Cdk1 and Aurora kinase phospho-sites. Inhibiting PP2A phosphatase activity or differentiation increases HEC1 phosphorylation at hPSC kinetochores decreasing chromosome segregation errors. Thus, mitotic fidelity in non-transformed human cells depends on the developmental regulation of the kinase and phosphatase networks controlling kinetochore phosphorylation.
    Summary: Galaviz Sarmiento et al show that the developmental regulation of kinetochore phosphorylation governs mitotic fidelity. HEC1 is hypophosphorylated at kinetochores of hPSCs during mitosis contributing to their high rate of chromosome segregation errors. While differentiation increases HEC1 phosphorylation improving chromosome segregation fidelity.
    DOI:  https://doi.org/10.64898/2026.04.15.718713
  17. Nat Commun. 2026 May 01.
    Spatially decoding genotype-associated epigenetic landscapes in human lymphoma FFPE tissues via epi-Patho-DBiT.
    Haikuo Li, Bo Tao, Archibald Enninful, Dingyao Zhang, Yi Dai, Fiona Oh, Negin Farzad, Keyi Li, Zhiliang Bai, Xiaoyu Qin, Mingyu Yang, Emily J Hwang, Jing Zhang, Jun Lu, Mark Gerstein, Jingtian Zhou, Mina L Xu, Rong Fan.
      While formalin-fixed paraffin-embedded (FFPE) samples are invaluable for human non-Hodgkin B-cell lymphoma translational research, effective methods for spatial profiling of chromatin accessibility and histone modifications in these tissues remain limited. Here, we introduce epi-Patho-DBiT, a platform that combines reverse crosslinking of FFPE tissues with spatially resolved assays for transposase-accessible chromatin using sequencing (spatial-FFPE-ATAC) or cleavage under targets and tagmentation (spatial-FFPE-CUT&Tag). Using spatial-FFPE-ATAC, we map epigenetic landscapes in mucosa-associated lymphoid tissue and follicular lymphoma, identifying chromatin variants linked to B-cell malignancy and resolving tumor karyotypes. Mitotic age inference reveals spatial tumor dynamics and uncovers cholesterol-mediated cell proliferation. Furthermore, spatial-FFPE-CUT&Tag elucidates genomic alterations during transformation of follicular lymphoma into diffuse large B-cell lymphoma and identifies DIP2C with dysregulated H3K4me3 and H3K27me3 levels. Unexpectedly, we observe elevated H3K27me3 occupancy at a chromosome 2 locus containing tumor-promoting genes, attributed to copy number amplification and thereby upregulation in transformed diffuse large B-cell lymphoma.
    DOI:  https://doi.org/10.1038/s41467-026-71576-9
  18. Cell. 2026 Apr 28. pii: S0092-8674(26)00393-4. [Epub ahead of print]
    Sensing endoplasmic reticulum redox state by ethylene receptors.
    Dongdong Hao, Zhina Xiao, Wei Yan, Chenliang Pan, Yanting Yang, Wen Song, Zhiren Chen, Ying Xing, Lian Jin, Yang Peng, Yuping Qiu, Kai Jiang, Xing Wen, Kai Huang, Shi Xiao, Haodong Chen, Hongwei Guo.
      Endoplasmic reticulum (ER) redox homeostasis is critical for ER functionality and is implicated in various human diseases, yet its physiological significance in plants remains largely elusive. Ethylene, a key phytohormone, is perceived and transduced at the ER, suggesting an underexplored connection between the ER and ethylene signaling. Here, we show that ethylene receptors sense the ER redox state via lumen-localized intermolecular disulfide bonds. ER reductive stress, rather than ethylene, disrupts the disulfide-linked dimers of the receptors, repressing their function and thereby activating downstream ethylene signaling. Moreover, modulating disulfide bond formation in the receptor ETHYLENE RESPONSE 1 (ETR1) through ER redox shifts supports plant resilience under hypoxia and during photomorphogenesis. Finally, our findings suggest that sensing ER redox may be an ancestral receptor function, predating the substantial emergence of ethylene biosynthesis. This study illuminates a deeper nexus between organelle homeostasis and hormone signaling.
    Keywords:  ETR1; disulfide bond; endoplasmic reticulum; ethylene receptor; redox state
    DOI:  https://doi.org/10.1016/j.cell.2026.04.004
  19. Nat Struct Mol Biol. 2026 Apr 29.
    MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth.
    Hector Flores-Romero, Aida Pena-Blanco, Jonas Aufdermauer, Shashank Dadsena, Philip Neubert, Lisa Hohorst, Eileen Cors, Cristiana Zollo, Alvaro Larrañaga-SanMiguel, Jone Zaldunbide, Maria Nenchova, Yasmin Carvalho-Schaefer, Thomas Langer, Georg Häcker, Ana J Garcia-Saez.
      During apoptosis, the BCL-2 family members BAX and BAK oligomerize and form a pore to mediate the decisive step of mitochondrial outer membrane permeabilization. However, the contribution of additional cellular components to apoptotic pore dynamics remains poorly understood. Here we map the protein environment of the apoptotic pore using in situ proximity labeling and identify the mitochondrial carrier homolog protein MTCH2 localizing nearby BAX and BAK assemblies specifically under apoptotic conditions. We show that cells lacking MTCH2 exhibit delayed BAX and BAK oligomerization at the single-particle level, which can be rescued by addition of lysophosphatidic acid. Accordingly, MTCH2 depletion decreases not only apoptosis sensitivity but also sublethal mitochondrial permeabilization during bacterial infection, mitochondrial DNA release into the cytosol and cGAS-STING activation under impaired caspases. Our findings uncover a key role of MTCH2 in promoting BAX and BAK high-order assembly with functional consequences for apoptotic pore growth and downstream responses.
    DOI:  https://doi.org/10.1038/s41594-026-01805-8
  20. Cell. 2026 Apr 28. pii: S0092-8674(26)00399-5. [Epub ahead of print]
    ErbB family receptor dimerization dynamics and dysregulation via long-term single-molecule imaging.
    Kaibo Ma, Xiaojie Ma, João F Shida, Zijian Niu, Yuzhu Karlie Lin, Saptarshi Mandal, Alexandra Dobbins, Lior Golomb, Michael J Eck, Heidi Greulich, Matthew Meyerson, Chunte Sam Peng.
      Dimerization is crucial for the activation of ErbB family receptors, yet the real-time dynamics and effects of oncogenic mutations remain unclear. Here, we performed long-term, multicolor single-particle tracking (SPT) of EGFR, HER2, and HER3 in living cells using upconverting nanoparticles (UCNPs), which do not photobleach. Our technique enables continuous observation of receptor interactions, revealing details of their dimerization dynamics. Oncogenic EGFR mutations promote stable, ligand-independent dimerization. Unexpectedly, both HER2 and HER3 exhibit constitutive homodimerization, prompting a revised model for their activation mechanisms. HER2 mutations modestly enhance homodimer stability compared with EGFR mutations, while HER3 mutations destabilize homodimers, suggesting that HER3 homodimerization sequesters HER3 and limits heterodimerization with other receptors. We also identified stable, ligand-independent heterodimers among all three receptors, further stabilized by ligand stimulation. These insights offer a comprehensive ErbB interaction network, elucidating diverse dimerization mechanisms and implications for oncogenic signaling.
    Keywords:  ErbB receptor family; dimerization network; long-term single-particle tracking; oncogenic signaling; upconverting nanoparticles
    DOI:  https://doi.org/10.1016/j.cell.2026.04.010
  21. J Clin Invest. 2026 May 01. pii: e202528. [Epub ahead of print]136(9):
    Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
    Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G McDonald, Chongshan Dai, Chao Li, Zhao V Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R Malloy, Stanislaw Deja, Shawn C Burgess, Matthew A Mitsche, Jay D Horton.
      Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.
    Keywords:  Cardiology; Fatty acid oxidation; Heart failure; Metabolism
    DOI:  https://doi.org/10.1172/JCI202528
  22. Cold Spring Harb Perspect Biol. 2026 Apr 27. pii: a041902. [Epub ahead of print]
    Mechanobiology of the Hippo-YAP Signaling Network.
    Bipin Kumar Tripathi, Kenneth D Irvine.
      Cells are not only biochemical machines but also mechanical entities, which experience physical cues ranging from extracellular matrix (ECM) stiffness to cytoskeletal tension and intercellular adhesion. The Hippo signaling network is a key interpreter of these cues, responding to multiple, intertwined inputs including filamentous actin (F-actin) abundance and architecture, actomyosin contractility, integrin-focal adhesion signaling, junctional complexes, and nuclear mechanics, to modulate Yorkie (Yki)/Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) activity and ultimately cell fate, organ growth, and tissue homeostasis. Mechanoregulation can be Hippo-dependent (via regulation of Wts/LATS kinases) or Hippo-independent. Hippo signaling and YAP/TAZ also feed back on mechanics, modulating F-actin levels, focal adhesions, and actomyosin contractility. Links between tissue mechanics and Hippo signaling have important physiological roles in development and homeostasis. Conversely, in disease states including cancer and fibrosis altered mechanics can chronically activate YAP/TAZ, creating feedforward tissue stiffening and maladaptive remodeling. Understanding Hippo mechanobiology can thus inform strategies that restore balance between adaptive and pathological responses to tissue mechanics.
    DOI:  https://doi.org/10.1101/cshperspect.a041902
  23. Aging Cell. 2026 May;25(5): e70529
    A Decline in Follicle Cell Function Is a Major Driver of Drosophila Ovarian Aging.
    Emily A Wolfgram, Todd G Nystul.
      The ovary is one of the first organs to lose functionality with age. We found that aging of the Drosophila ovary is characterized by an accumulation of phenotypes in the somatic compartment, including failure of the follicle cells to encapsulate germ-cell cysts, an extended S phase, and increased DNA damage. In aged ovaries, follicle encapsulation defects are associated with the lack of a germ-cell cyst checkpoint in early oogenesis. Single-cell RNA sequencing revealed that, across all cell types in the ovary, cells in the follicle lineage have the highest number of differentially expressed genes. Overexpression of Atg8a, a key autophagy machinery gene homologous to mammalian LC3, specifically in follicle cells prevents age-associated decline in the follicle epithelium and loss of reproductive capacity. Collectively, these findings demonstrate that genetic manipulation of a small population of ovarian somatic cells is sufficient to improve both cell-autonomous and non-autonomous features of reproductive aging.
    Keywords:   drosophila ; aging; cell biology; ovary; reproduction
    DOI:  https://doi.org/10.1111/acel.70529
  24. Nat Mater. 2026 Apr 29.
    Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton.
    Amy E M Beedle, Vivek Sharma, Jorge Oliver-De La Cruz, Anuja Jaganathan, Aina Albajar-Sigalés, F Max Yavitt, Kaustav Bera, Ion Andreu, Ignasi Granero-Moya, Dobryna Zalvidea, Zanetta Kechagia, Gerhard Wiche, Xavier Trepat, Johanna Ivaska, Kristi S Anseth, Vivek B Shenoy, Pere Roca-Cusachs.
      The cell nucleus is continuously exposed to external signals, of both chemical and mechanical nature. To ensure proper cellular response, cells need to regulate the transmission, timing and duration of these signals. Although such timescale regulation is well described for chemical signals, whether and how it applies to mechanical signals reaching the nucleus is still not fully understood. Here we demonstrate that the formation of fibrillar adhesions locks the nucleus in a mechanically deformed conformation, setting the mechano-response timescale to that of fibrillar adhesion remodelling (~1 h). This process encompasses both mechanical deformation and associated mechanotransduction (such as via YAP), in response to both increased and decreased mechanical stimulation. The underlying mechanism is the anchoring of the vimentin cytoskeleton to fibrillar adhesions and the extracellular matrix through plectin 1f, which maintains nuclear deformation. Our results reveal a mechanism to regulate the timescale of mechanical adaptation, effectively setting a low-pass filter to mechanotransduction.
    DOI:  https://doi.org/10.1038/s41563-026-02590-x
  25. Cell Metab. 2026 Apr 29. pii: S1550-4131(26)00142-7. [Epub ahead of print]
    NAD-dependent redox control enables endothelial quiescence and vascular stabilization during angiogenesis.
    Wencao Zhao, Wenkai Zhu, Trace Thome, Ioana Soaita, Jae Woo Jung, Michael C Noji, Jian Li, Huajun Bai, Yansen Xiao, Yifan Yang, Chelsea Thorsheim, Wei Zhou, Yijun Yang, Kristina Li, Jonathan J Edwards, Ivan A Kuznetsov, Boa Kim, Joseph A Baur, Zoltan Arany.
      Angiogenesis requires endothelial cells (ECs) to toggle between quiescence versus proliferation, migration, and invasion. While activation from quiescence is well characterized, mechanisms governing the return from proliferation to quiescence (PtoQ) remain unclear. We show here that metabolic rewiring during PtoQ renders ECs sensitive to oxidative stress, requiring nicotinamide adenine dinucleotide (NAD) turnover for protection. Limiting EC NAD does not affect proliferation or migration but prevents cell-cell contact formation and quiescence acquisition during PtoQ. In vivo and ex vivo, limiting EC NAD permits initial sprouting but impairs vascular stabilization and plexus formation. Mechanistically, NAD suppresses mitochondria-derived hydrogen peroxide (H2O2) during PtoQ. Exogenous H2O2 mimics NAD deficiency, whereas its removal rescues PtoQ. In pathological settings, inhibiting NAD synthesis limits exuberant angiogenesis of retinopathy and tumors. In summary, we unveil metabolic events critical for PtoQ, a poorly studied component of angiogenesis, and point to new ways to suppress pathological angiogenesis.
    Keywords:  H(2)O(2); NAD; NADPH; NAMPT; angiogenesis; endothelial cells; metabolism; quiescence
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.004
  26. Sci Adv. 2026 May;12(18): eaec3773
    Dynamic heterogeneity and hidden fluidity in dense epithelial tissues.
    Yuan Shen, Wang Xi, René-Marc Mège, Walter Kob, Benoit Ladoux.
      Epithelial tissues maintain organ integrity while continuously remodeling during morphogenesis, repair, and disease. At high cell densities, these tissues often appear mechanically arrested in a disordered, solid-like state, raising the question of how they retain the ability to reorganize. Here, we show that, unlike thermal glasses, dense epithelial tissues do not exhibit caging behavior but instead behave as a complex fluid. Cells display subdiffusive creep together with Fickian yet non-Gaussian dynamics and compressed exponential relaxation, hallmarks of stress-driven fluidity. This fluidity arises from the tissue's structural and mechanical organization rather than from cell division or extrusion, which only transiently enhance local dynamics. Fast-moving cells organize into collective, anisotropic clusters whose spatial heterogeneity correlates with local structural entropy and soft vibrational modes. Together, these findings reveal a hidden fluidity in densely packed epithelia that supports mechanical stability while preserving the capacity for remodeling during development, wound healing, and early tumor invasion.
    DOI:  https://doi.org/10.1126/sciadv.aec3773
  27. Genes Dev. 2026 Apr 27.
    DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development.
    Kayla K Mason, Seohyun K Park, James I Emerson, Yao Wei Lu, Da-Zhi Wang, William F Marzluff, Frank L Conlon.
      Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5' untranslated regions (UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at midgestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5' UTRs and requires DDX3X. These findings uncover a sex-specific posttranscriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.
    Keywords:  DDX3X; cardiac; heart; posttranscription; sex differences; translation
    DOI:  https://doi.org/10.1101/gad.353320.125
  28. Nat Commun. 2026 Apr 27.
    Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.
    Jie Yao, Su Fang, Miao Lei, Zexian Ou, Chuanfei Zeng, Wanli Peng, Na He, Lian Yang, Bingpeng Guo, Mingmeng Fang, Cuihua Wang, Jie Lv, Shuang Wu, Wei Kevin Zhang, Huimin Huang, Yang Peng, Wei Rao, Zhili Rong, Penghui Yang, Chaoqun Wang, Qian Han, Wenxiang Hu.
      Idiopathic pulmonary fibrosis is a progressive and fatal disorder characterized by abnormal activation of alveolar fibroblasts. However, the metabolic reprogramming of alveolar fibroblasts during lung injury remains unclear. Here we show that uptake of branched-chain amino acids is increased, whereas their catabolism is significantly impaired in fibrotic lung fibroblasts and mouse lung tissues. Branched-chain amino acids promote lung fibroblast activation and bleomycin-induced lung fibrosis. Genetic inactivation of branched-chain amino acid transaminase 2 exacerbates fibrosis, whereas inhibition of the corresponding transporter SLC7A5 or enhancement of catabolism attenuates pulmonary fibrosis in male mice. Mechanistically, ATF4 and PPARγ regulate the expression of SLC7A5 and BCAA catabolic genes, respectively. We identify KDM4A as a key mediator of the epigenetic regulation of fibrotic genes. Notably, dysregulated BCAA metabolism is associated with disease severity in patients, suggesting that targeting BCAA metabolism may serve as a promising therapeutic strategy for idiopathic pulmonary fibrosis.
    DOI:  https://doi.org/10.1038/s41467-026-72273-3
  29. Matrix Biol. 2026 Apr 24. pii: S0945-053X(26)00052-1. [Epub ahead of print] 102010
    Cytokine Conversations: Fibroblasts Shape Macrophage Identity to Enhance Collagen Clearance.
    Signe Spliid Heltberg, Sander van Putten, Oliver Krigslund, Kirstine Sandal Nørregaard, David Højland Ipsen, Niels Behrendt, Lars Henning Engelholm, Henrik Jessen Jürgensen.
      Tissue remodeling critically depends on fibroblasts and macrophages, but the timely and coordinated induction of phenotypes that promote remodeling-associated extracellular matrix (ECM) and interstitial collagen degradation is poorly understood. Here, we exploit the potency of activated dermal fibroblasts and macrophage plasticity to study cell-cell interplay. We identify fibroblasts as vigorous stimulators of co-cultured macrophages' differentiation towards a collagen-clearing phenotype. Fibroblasts secrete several soluble factors with macrophage recruitment and stimulation potential, including M-CSF, CXCL-1, CCL2, IL-6, and TIMP-1. IL-6-driven upregulation of Mannose Receptor (MR, CD206), an endocytic collagen-clearance receptor, is identified as a key macrophage effector-response. Mouse dermal in situ collagen turnover models demonstrate that macrophage MR-dependent collagen-uptake constitutes a recruitable pathway that can readily facilitate collagen degradation and links IL-6 macrophage-stimulation to the process. Importantly, a novel fibroblast depleter system reveals that fibroblasts dictate macrophage differentiation and collagen-clearance in vivo. Our study establishes activated fibroblasts as critical orchestrators of macrophage functions with potential impact on physiological tissue remodeling and fibrosis.
    Keywords:  Extracellular matrix degradation; Fibroblast-macrophage crosstalk; Interleukin-6; Macrophage phenotype; Mannose receptor; collagen endocytosis
    DOI:  https://doi.org/10.1016/j.matbio.2026.102010
  30. Cell Rep. 2026 Apr 29. pii: S2211-1247(26)00397-9. [Epub ahead of print]45(5): 117319
    Hedgehog-driven adaxial cell constriction patterns slow muscle fate and somite boundary remodeling in the presomitic mesoderm.
    Yawen Wang, Xiang Li, Rui Xia, Yinan Wan, Jingao Lu, Zhonghua Zhao, Wenqing Zhang, Qiang Wang, Timothy E Saunders, Jianmin Yin.
      How morphogen signaling interfaces with cell behaviors and mechanics to coordinate body axis patterning has remained largely unclear. Here, we uncover a mechanochemical program that directs slow muscle fate commitment and somite boundary remodeling in the presomitic mesoderm (PSM). Hedgehog, secreted from the underlying notochord, triggers cytoskeletal remodeling and basal constriction in adaxial cells, progressively reducing notochord contact and allowing adjacent cells to engage the morphogen source. Concurrently, directional rearrangements of dorsal and ventral medial cells shift prospective somite boundaries posteriorly, converting straight borders into V-shaped patterns before segmentation. Vertex modeling and mutant analyses indicate that Hedgehog-dependent constriction of adaxial cells initiates the tissue deformation, while somite segmentation stabilizes this architecture. Using an integrative multi-omics approach with targeted gene validation, we identified acta1a (a major skeletal muscle actin isoform) and arhgef25a (a RhoGEF) as key participants in adaxial cell morphogenesis in the PSM.
    Keywords:  CP: developmental biology; Hedgehog signaling; acta1a; adaxial cell; arhgef25a; cell constriction; presomitic mesoderm; somite boundary; tissue mechanics; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117319
  31. Nat Cell Biol. 2026 Apr 27.
    Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing.
    Nina Kozlova, Kayla A Cruz, Antoine A Ruzette, Hanna M Doh, Nicholas A Willis, Su Min Hong, Raul S Gonzalez, Monika Vyas, Laura M Selfors, Stephan Dreyer, Rosie Upstill-Goddard, Kerrie L Faia, Steve Wenglowsky, Josh Close, Alica Beutel, Zeljka Jutric, Michael U J Oliphant, Larysa Poluben, Byanjana Thapa, Martin S Taylor, Venla Mustonen, Pradeep Mangalath, Christopher J Halbrook, Joseph E Grossman, Rosa F Hwang, John G Clohessy, Salla Ruskamo, Petri Kursula, Boryana Petrova, Naama Kanarek, Philip A Cole, David K Chang, Conor L Evans, Simon F Nørrelykke, Ralph Scully, Taru Muranen.
      Pancreatic ductal adenocarcinomas (PDACs) are aggressive, stroma-rich tumours. They are unresponsive to treatments, and patients relapse quickly on DNA-damaging chemotherapies. PDAC stroma consists of extracellular matrix proteins (ECM), secreted by cancer-associated fibroblasts (CAFs). Here we show an unexpected link between CAF-secreted ECM proteins and enhanced DNA repair. We identify NDRG1 (N-myc downstream-regulated gene 1) as a key mediator that senses signals from the ECM via adhesion receptors and serum and glucocorticoid-activated kinase. We establish NDRG1 as a DNA repair factor that physically associates with replication forks, maintains DNA replication, resolves stalled forks caused by chemotherapies and is involved in reducing R-loops, RNA-DNA hybrids known to cause genomic instability. NDRG1 is highly expressed in PDAC tumours and its high expression correlates with poor disease-specific survival and poor response to chemotherapy. In conclusion, our data reveal an unexpected role for CAF-secreted ECM proteins in promoting DNA repair via NDRG1, mechanistically linking tumour stroma to replication fork homeostasis and R-loop regulation.
    DOI:  https://doi.org/10.1038/s41556-026-01938-4
  32. Nat Cell Biol. 2026 Apr 27.
    Somatic mutations distinguish melanocyte subpopulations in human skin.
    Bishal Tandukar, Delahny Deivendran, Limin Chen, Neda Bahrani, Defne Baskurt, Beatrice Weier, Harsh Sharma, Noel Cruz-Pacheco, Min Hu, Kayla Marks, Rebecca G Zitnay, Aravind K Bandari, Barbara Rentroia-Pacheco, Rojina Nekoonam, Boris C Bastian, Iwei Yeh, Robert Judson-Torres, A Hunter Shain.
      Here, to understand the homeostatic mechanisms governing melanocytes, we interrogate the mutational landscapes, gene-expression profiles and morphological features of 297 clonal expansions of epidermal melanocytes from 31 donors. We show that a population of melanocytes with low mutation burden persists in sun-exposed epidermis. These cells are smaller, less dendritic, and exhibit stem-like expression profiles when compared to melanocytes carrying high mutation burdens. Using single-cell spatial transcriptomics, we show that melanocytes inferred to have low mutation burdens localize to both hair follicles and interfollicular epidermis, whereas melanocytes with high mutation burdens are largely restricted to epidermis. We propose that melanocytes in the hair follicle occupy a privileged niche, protected from ultraviolet radiation, but replenish the epidermis following photodamage. This study highlights the value of incorporating mutational information into cell atlases. Cells can change their positions over time, but mutations provide a historical record of processes that were operative on each cell.
    DOI:  https://doi.org/10.1038/s41556-026-01943-7
  33. bioRxiv. 2026 Apr 13. pii: 2026.04.10.717788. [Epub ahead of print]
    Sorcin couples Annexin A11 recruitment and ESCRT-III assembly during plasma membrane repair.
    Jordan Matthew Ngo, Justin Krish Williams, Abinayaa Murugupandiyan, Randy Schekman.
      The absence of a cell wall affords animal cells diverse functionality at the cost of acute sensitization to plasma membrane (PM) damage. Thus, animal cells tightly monitor and maintain the integrity of their PM to prevent cell death. Genetic loss of PM repair factors is associated with human diseases including muscular dystrophy and neurodegeneration. Despite evidence that annexin and endosomal sorting complex required for transport (ESCRT) proteins are required for PM repair, the extent to which their recruitment is coordinated at sites of membrane damage is unclear. Here, we identify sorcin as a new PM repair factor that directly couples annexin A11 (ANXA11)-mediated sensing of PM damage and ESCRT-III assembly. We demonstrate that ANXA11, recruited to the PM upon damage-induced calcium influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Our data highlight mechanistic and topological similarities between the budding of membrane-enveloped viruses and damage-induced microvesicles. We propose that they share a common mechanism of membrane budding and speculate that membrane-enveloped viruses may have co-opted this host pathway of PM ESCRT recruitment to facilitate virion assembly and propagation.
    DOI:  https://doi.org/10.64898/2026.04.10.717788
  34. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2531557123
    Regulation of Tmem30b-mediated apical membrane homeostasis in auditory outer hair cells is critical for hearing.
    Miao Chang, Guodong Hong, Shan Gao, Cheng Cheng, Jia Yuan, Yu Xiao, Ruifeng Qiao, Jing Ke, Xinhao Wu, Tiancheng Zhang, Siwei Guo, Runze Jiang, Ziyi Liu, Jing Zhou, Xiaohan Zhang, Yunhao Wu, Xiaoxu Zhao, Wen Li, Shuyuan Shen, Zuhong He, Xiuli Bi, Renjie Chai, Xiaolong Fu.
      Mechanotransduction within the cochlea depends on the precise architecture of hair bundles, yet our comprehension of the mechanisms that govern the formation and maintenance of the sound-receptive structure is still limited. Here, we identify Tmem30b, a phospholipid-flippase chaperone, as a critical regulator expressed in outer hair cells (OHCs). Although initially localized to the nuclear membrane at P5, Tmem30b translocates to and stabilizes within the stereocilia and the underlying cuticular plate during maturation. The Tmem30b-/- mice exhibit an early-onset hearing loss with preserved vestibular and retinal functions. Notably, the disorganization of OHC stereocilia in mutants initiates at P7, coinciding with the initial presence of Tmem30b in stereocilia. Mechanistically, Tmem30b partners with Atp8b1 to regulate phospholipid asymmetry; disruption of this complex destabilizes OHC bundles. Crucially, AAV-mediated delivery of Tmem30b to hair cells alleviates stereocilia defects in both Tmem30b-/- and Atp8b1-/- mice. Furthermore, hair cell specific overexpression of Tmem30b protects mice from noise-induced and aminoglycoside-induced hearing loss. In summary, our findings establish Tmem30b as a pivotal organizer of OHC hair bundles and highlight Tmem30b-Atp8b1-mediated lipid regulation as a therapeutic target for hearing loss.
    Keywords:  Tmem30b; hair bundle; outer hair cells; phosphatidylserine flippase
    DOI:  https://doi.org/10.1073/pnas.2531557123
  35. Am J Physiol Cell Physiol. 2026 May 01.
    Ribosome dynamics during skeletal muscle repair and regeneration in mice and humans.
    Minying Cui, Sebastian Edman, Baptiste Jude, Paulo R Jannig, Oscar Horwath, Emily Shorter, Pieter J Koopmans, Toby L Chambers, Ronald G Jones, Abraham Nilsson, Johanna T Lanner, Thomas Sejersen, Eva Pontén, Kevin A Murach, Jörg Schilcher, Ferdinand von Walden.
      Skeletal muscle repair requires coordinated regulation of inflammation and protein synthesis, but the roles of ribosome biogenesis and protein composition remain poorly defined. To address this, mice underwent femoral artery ligation (FAL) to induce muscle regeneration over 28 days. In humans, tibialis anterior biopsies from traumatic tibial fracture patients were subjected to RNA sequencing. Following FAL, c-Myc mRNA increased transiently, followed by increased ribosomal DNA transcription, leading to elevated total RNA levels. Skeletal muscle-specific ribosomal protein paralog RPL3L was replaced by the ubiquitously expressed RPL3 during the initial phases of recovery, but this shift was reversed by day 28. A substantial transcriptomic response was observed in human muscle injury, with heavy emphasis on MYC-induced anabolism and inflammation. This supports a model in which MYC-driven changes in ribosomal content and composition form a core anabolic module in skeletal muscle repair, potentially representing a targetable axis to enhance recovery after muscle injury.
    Keywords:  Ribosome heterogeneity; Skeletal muscle; regeneration; ribosomen biogenesis
    DOI:  https://doi.org/10.1152/ajpcell.00184.2026
  36. Nature. 2026 Apr 29.
    Submicrometre sampling of living cells by macrophages.
    Amy C Fan, Rukman R Thota, Nina Serwas, Vivasvan S Vykunta, Kyle Marchuk, Megan K Ruhland, Lauren Liu, Grace Johnson, Austin Edwards, Matthew F Krummel.
      An effective immune system must sample and develop healthy self-identity to prevent autoimmunity and to discern pathogenic insults1-3. Self-proteins are presented to T cells in the thymus during immune cell development2,3 and must be presented throughout the body to maintain regulatory T cell populations4-6 and to provide tonic signals to sustain conventional T cells over time7-9. Observations of continuous apoptosis in some organs together with the ingestion of that material by myeloid populations has led to a conventional understanding of ongoing cell death as a major source of self-antigens10. Here we used a series of companion imaging and vesicular labelling technologies to reveal an alternative process undertaken by macrophages that results in non-destructive, direct sampling of living cells. This process requires cell-cell contact, does not require caspase activation and occurs via trogocytosis-like stretching of the target cell into the macrophage, which leads to the generation of submicrometre-sized vesicles that contain cytoplasm. Using a high-dimensional flow-based method for labelling vesicles, we demonstrate that live-sampled material is distinctly processed and is poorly subjected to fusion with lysosomes. The material also produces differential effects on the presentation of antigen to CD4 T cells compared with CD8 T cells. Disruption of this trafficking by redirecting antigen to the lysosome significantly reduced the associated macrophage-mediated priming of CD8 T cells. These results demonstrate an important and substantial sampling of living cells by the immune system, with clear consequences for maintaining the border of immunity.
    DOI:  https://doi.org/10.1038/s41586-026-10435-5
  37. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2526299123
    Purine metabolic adaptation protects the endothelium from disturbed flow-induced DNA damage and atherosclerosis.
    Qian Ma, Yongfeng Cai, Zhidan Zhang, Dingwei Zhao, Yuan Zhao, Peishan Xu, Tammy Lu, Wendy Zhang, Qiuhua Yang, Yaqi Zhou, Varadarajan Sudhahar, Tohru Fukai, Hanjoong Jo, Yiming Xu, Yuqing Huo.
      Despite effective lipid-lowering therapies, atherosclerosis continues to be a leading cause of death, with considerable residual cardiovascular risk. Atherosclerotic lesions develop preferentially at arterial regions exposed to disturbed flow (d-flow), which induces genomic stress, endothelial injury, and barrier dysfunction. Hemodynamic forces are known to reprogram endothelial metabolism, but the role of de novo purine synthesis (DNPS), which supplies nucleotides for genome maintenance and whose terminal steps are catalyzed by the bifunctional enzyme ATIC, remains undefined in atherosclerosis. By integrating bulk and single-cell multiomics with in vitro flow systems and in vivo models, we show that d-flow upregulates DNPS and ATIC genes in vitro and in vivo, in concert with a DNA damage/repair state. Endothelial-specific Atic deletion exacerbates DNA damage, apoptosis, barrier dysfunction, and accelerates atherogenesis, while purine-base supplementation rescues repair defects. We further identify MYC as a mechanosensitive driver of ATIC induction. These findings establish a d-flow-MYC-ATIC-DNPS axis that sustains nucleotide sufficiency for DNA repair and maintains endothelial barrier integrity, suggesting potential endothelial-targeted therapeutic strategies for atherosclerosis.
    Keywords:  ATIC; DNA damage; atherosclerosis; de novo purine synthesis; endothelial cells
    DOI:  https://doi.org/10.1073/pnas.2526299123
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