bims-ginsta Biomed News
on Genome instability
Issue of 2026–09–06
forty-four papers selected by
Jinrong Hu, National University of Singapore
  1. Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
  2. Functional chimeric mRNAs encode proteins in mammalian immunity.
  3. De novo pan-rhodamine binders for fluorescence microscopy from mammalian cells to extremophiles.
  4. Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
  5. Lipid-mediated activation of BLT2 promotes membrane repair to prevent cell death.
  6. Tissue mitochondrial activity dictates the macrophage pool size.
  7. A single-amino-acid cleavage controls global mitochondrial complex integrity.
  8. Ratiometric transcriptional activation by protein degradation.
  9. Replication stress links Geminin depletion to centrosome amplification.
  10. The actomyosin cortex controls t-tubule remodeling in skeletal muscle.
  11. MAD2B guides chromosome stability in mitosis via the MAD2B-CIP2A signaling axis.
  12. Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration.
  13. Ribo-ITP enables identification of translons from limited input samples.
  14. ERH elicits cell lineage restriction in mammalian preimplantation development and differentiation from pluripotency via H3K9me3-heterochromatin.
  15. Dynamic control of cell state transitions during tissue morphogenesis.
  16. Sexual dimorphism in the complete Drosophila male central nervous system connectome.
  17. Direct visualization of MCM helicase activation and replisome coupling in situ.
  18. Conformational asymmetry of replicated human chromosomes.
  19. Upstream Regulation of the Hippo Pathway.
  20. An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin.
  21. Maternal PAN2 selectively maintains mRNA Poly(A) tail homeostasis to regulate RNA degradation during oocyte-to-early embryo transition in mice.
  22. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  23. Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction.
  24. Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state.
  25. Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.
  26. Adaptive motility enables neutrophils to rapidly navigate confined capillaries.
  27. Bridging-driven condensation by eukaryotic SMC complexes is a conserved feature of genome organization.
  28. Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
  29. An integrated landscape of mRNA and protein isoforms.
  30. A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation.
  31. Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
  32. Hijacking pre-tRNA enables LTR-retrotransposon-initiated constitutive heterochromatin formation.
  33. Multi-stromal organoid co-culture modelling reveals epithelial-fibroblast heterogeneity in pancreatic cancer and pancreatitis.
  34. Unbiased screen of human transcriptome reveals an unexpected role of 3'UTRs in translation initiation.
  35. Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases.
  36. Genome-wide chromatin recording resolves dynamic cell state changes.
  37. Spatial mapping of RNA turnover kinetics in the mouse brain.
  38. The molecular basis of transcription initiation by RNA polymerase II.
  39. CALIPERS: Cell cycle-aware live imaging for phenotyping experiments and regeneration studies.
  40. Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo.
  41. Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability.
  42. The regulatory logic linking inflammation and fibrosis.
  43. Rewiring the ribosome to translate proteins encoded in its own RNA.
  44. Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions.
  1. Nat Genet. 2026 Sep 02.
    Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
    Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Haoyu Wang, Tivadar Török, Juliano Ribeiro, Jessie Xue, Erik C Cardoso, Yao Rong, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Edridge D'Souza, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Min Dai, Giovanni Marrero, Vipin Kumar, Anjali Saqi, Benjamin Herzberg, Benjamin Izar, Howard Y Chang, Joo-Hyeon Lee, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang.
      Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Here we integrate high-resolution spatial transcriptomics and evolving lineage-tracing technologies to elucidate how tumor expansion, plasticity and metastasis co-evolve with microenvironmental remodeling in a Kras;Trp53-driven mouse model of lung adenocarcinoma. We find that subclonal expansion contributes to a hypoxic, immunosuppressive and fibrotic microenvironment that is associated with the emergence of prometastatic cancer cell states. We use tumor phylogeography to delineate intercellular interactions that are rewired in the expanding tumor niche and use co-culture systems to dissect how intercellular interactions and hypoxia influence cancer cell state. Furthermore, we find that metastases arise from spatially confined primary tumor subclones and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.
    DOI:  https://doi.org/10.1038/s41588-026-02739-z
  2. Nature. 2026 Sep 02.
    Functional chimeric mRNAs encode proteins in mammalian immunity.
    Olivia Venezia, Harry Kane, Gang Du, Hannah D Coughlan, Timothy M Johanson, Hongshen Wang, Pathricia Tilstam, Samuel W Kazer, Georgia Gunner, Daisy A Hoagland, Megha G Basavappa, Kanchana Ravichandran, Eren Ada, Ademi Zhakyp, Sandhya Kumar, Coco Duizer, Owen Searle, Chris Geo Provido, Leonel Joannas, Shilong Yang, Liam B Healy, Qiankun Wang, Joia Capocchi, Bahawar Sharif Dhillon, Sarah Slavoff, Liang Shan, Jorge Henao-Mejia, Ruth A Franklin, Isaac M Chiu, Jose Ordovas-Montanes, Kate L Jeffrey, Judy Lieberman, Rhys S Allan, Jonathan C Kagan, Hao Wu, Ruaidhrí Jackson.
      Individual mammalian mRNAs and proteins are typically believed to originate from single genomic loci, with isoform diversity arising through cis-splicing of pre-mRNA. Whether mRNA from distant genes can undergo trans-splicing to generate functionally relevant chimeric transcripts has remained unclear. Here we develop a pipeline combining long-read direct RNA sequencing with non-targeted and targeted validation to identify chimeric transcripts in macrophages. Chromatin conformation capture studies reveal that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate the formation of chimeric mRNA. Notably, we identify a protein-coding chimeric mRNA representing a fusion between the pore-forming protein gasdermin D (GSDMD)1,2 and a C-terminal domain translated out of frame from Tmem106a (Gsdmd-Tmem106a) in mice. We show that inflammasome priming upregulates Gsdmd-Tmem106a, with the protein localizing to the plasma membrane. After activation of the inflammasome, GSDMD-TMEM106A directly interacts with canonical GSDMD N termini to accelerate and enhance pore formation and IL-1β release. Finally, we show that GSDMD-TMEM106A balances host defence and immunopathology in vivo: its loss protects against lethal sepsis but compromises antibacterial defence, whereas overexpression enhances host protection while increasing sepsis lethality. We establish that protein-coding chimeric mRNAs formed by regulated transcript fusion events are operative during inflammation and immunity.
    DOI:  https://doi.org/10.1038/s41586-026-10982-x
  3. Cell. 2026 Sep 01. pii: S0092-8674(26)00934-7. [Epub ahead of print]
    De novo pan-rhodamine binders for fluorescence microscopy from mammalian cells to extremophiles.
    Yuda Chen, Klaus Yserentant, Kibeom Hong, Kehan Chen, Yiming Kuang, Robert S Picardo, Arghya Bhowmick, Arthur Charles-Orszag, Samuel J Lord, Lei Lu, Kaipeng Hou, Samuel I Mann, Sagar Bhattacharya, Maggie Horst, Jonathan B Grimm, Luke D Lavis, R Dyche Mullins, William F DeGrado, Bo Huang.
      Fluorescent imaging in live cells is a cornerstone of life sciences. While natural fluorescent proteins have been engineered to enhance individual features, no existing tag combines ideal properties into a single system: high brightness, reversible binding, compact size, and stability across diverse conditions. Here, we achieve this through de novo design of rhodamine binders (Rhobin). To harness the broad repertoire of rhodamine fluorophores, we developed a generalizable design strategy for a pan-rhodamine binder compatible with diverse wavelengths and applications. Rhobin enables live- and fixed-cell imaging of various subcellular targets in mammalian cells, showing brightness surpassing existing tags. Its reversible fluorophore binding supports super-resolution stimulated emission depletion (STED) and live-cell single-molecule imaging for extended durations compared with HaloTag. Beyond conventional systems, Rhobin enables live imaging of the extremophile Sulfolobus acidocaldarius at 75°C, previously inaccessible with current tags. Together, these results establish Rhobin as a versatile platform for next-generation imaging and biosensor design.
    Keywords:  de novo protein design; fluorescence microscopy; fluorescent tag; rhodamines; single-molecule imaging; super-resolution imaging; thermophilic microorganisms
    DOI:  https://doi.org/10.1016/j.cell.2026.08.007
  4. Sci Adv. 2026 Sep 04. 12(36): eaec8606
    Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
    Kristina Bubb, Giovanni Rigoni, Polyxeni Papadea, Gianluigi Pironti, Jelena Misic, Shan Jiang, David Alsina, Diana Rubalcava-Gracia, Daniel C Andersson, Roberta Filograna, Camilla Koolmeister, Patrick Giavalisco, Anna Wredenberg, Matthias Mann, Florian A Rosenberger, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8606
  5. J Cell Biol. 2026 Oct 05. pii: e202510004. [Epub ahead of print]225(10):
    Lipid-mediated activation of BLT2 promotes membrane repair to prevent cell death.
    Yuan Chi, Kazuko Saeki, Ken Yasukawa, Soichiro Kakuta, Tomoaki Koga, Takehiko Yokomizo.
      Various pathogenic microorganisms produce toxins that create pores in cell membranes, causing cell damage and disrupting the host epithelial barrier. Recently, we reported that mice lacking the G protein-coupled receptor leukotriene B4 receptor 2 (BLT2), which is expressed in vascular endothelial and alveolar epithelial cells, are highly susceptible to pneumolysin (PLY), a pneumococci-generated toxin. Although we clarified the protective roles of BLT2 in vascular endothelial cells, those in alveolar epithelial cells have not been elucidated. Here, we report that lipid mediator 12-hydroxyheptadecatrienoic acid (12-HHT), which is produced by membrane-damaged epithelial cells, prevents cell death by promoting membrane repair through BLT2. BLT2 promoted the release of PLY-bound plasma membranes as extracellular vesicles in a sphingomyelinase-dependent manner. Additionally, BLT2 activated Rac1 and subsequent actin polymerization, leading to resistance to cell death. Furthermore, inhibition of 12-HHT production by aspirin and treatment with a BLT2 antagonist abolished the protective effect of BLT2. These findings provide a new therapeutic strategy for bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202510004
  6. Sci Immunol. 2026 Sep 04. 11(123): eaeb9244
    Tissue mitochondrial activity dictates the macrophage pool size.
    Laura Pena-Couso, Jon Sicilia, Sofía Vieto, Roberto Silva-Rojas, María Sánchez-Díaz, Enrique Calvo, Rafael Romero-Becerra, Cintia Folgueira, Leticia Herrera-Melle, Raquel Justo-Méndez, Xiaotong Hong, Silvia Campanario, Juan A López, Georgiana Crainiciuc, María Gil, Sandra Martín-Salamanca, Vera Lukesova, Jessica Segalés, Antonio L Serrano, Iván Ballesteros, Marta León, Macarena de Andrés-Laguillo, Sebastian A Stifter, Lorena Esteban-Martínez, Joan Isern, Jorge Alegre-Cebollada, Miguel Torres, Melanie Greter, Jesús Vázquez, José A Enríquez, Guadalupe Sabio-Buzo, Pura Muñoz-Cánoves, Andrés Hidalgo, José A Nicolás-Ávila.
      Removal of cellular waste from the extracellular space is fundamental for tissue health. Because the rate of material ejected by parenchymal cells varies across tissues, we searched for mechanisms that couple waste production and removal. Here, we show that the uptake of parenchyma-released mitochondria by macrophages is prominent across organs that rely on oxidative respiration-including heart, skeletal muscle, and brown adipose tissue-and that macrophage numbers closely align with the mitochondrial activity of each of these organs. We found that the mitochondrial activity of myofibers dictates the abundance of macrophages by modulating colony-stimulating factor 1 (CSF1) availability and the number of CSF1-producing fibroblasts in the tissue. Consequently, inhibition of CSF1-CSF1 receptor (CSF1R) signaling depleted macrophages and collapsed the mitochondrial activity of skeletal muscles. We propose that, by coupling macrophage abundance to the mitochondrial activity of their parenchyma, tissues ensure efficient waste disposal and fitness.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb9244
  7. Nat Struct Mol Biol. 2026 Aug 31.
    A single-amino-acid cleavage controls global mitochondrial complex integrity.
    Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle.
      Mitochondrial proteostasis depends on precise N-terminal processing of imported precursor proteins. Defects in this maturation step are implicated in disease, yet the functional impact in humans remains unclear. Here we show that the intermediate cleaving peptidase ICP55, which removes a single amino acid, acts as a key stabilizer of multimeric mitochondrial protein complexes. Using proteomics and complexome profiling, we identify over 100 human ICP55 substrates and demonstrate that loss of ICP55 triggers widespread destabilization of protein assemblies, with a global shift toward smaller subcomplexes. Thus, we uncover a conserved, post-translational mechanism that safeguards mitochondrial proteostasis by regulating complex integrity through a single amino-acid cleavage, and we reveal N-terminal proteoform control as an unexpected layer of organellar homeostasis.
    DOI:  https://doi.org/10.1038/s41594-026-01876-7
  8. Cell. 2026 Sep 01. pii: S0092-8674(26)00936-0. [Epub ahead of print]
    Ratiometric transcriptional activation by protein degradation.
    Melissa A Gray, Katelyn L Randal, Jennifer A Co, Michelle T Tang, Athena Z Xue, Sophia W Chen, Hlib Razumkov, Qusay Q Omran, David E Solow-Cordero, Jeonghye Yu, Stephanie A Robinson, Cara A Starnbach, Nathanael S Gray, Steven M Corsello, Steven M Banik.
      Cells can respond to alterations in the abundances of specific proteins through transcriptional outputs. Synthetic approaches inspired by native post-transcriptional circuits that convert protein abundance changes into programmable gene expression would be transformative. Here, we discover and describe design principles that effectively convert protein degradation into transcriptional outputs in live cells. We define ratiometric transcriptional activation, where control over the ratio between a transcription factor and a protein of interest fused to its inhibitor enables detection of abundance changes with high sensitivity at scale. We show that ratiometric transcriptional activation can be implemented in single cells using triply orthogonal circuits or in multicellular pools, operating independently of the mechanism of protein downregulation and enabling simultaneous detection of multiple protein downregulation events through outputs such as cell survival, fluorescent protein expression, or barcode sequencing. These circuits can be applied to oncogenic targets and enable discovery of new molecular glue degraders.
    Keywords:  CRISPR; PROTAC; amplification; anti-CRISPR; gene circuits; high-throughput; molecular glue; multiplexed circuits; proteostasis detection; synthetic biology; synthetic circuits; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.cell.2026.08.009
  9. bioRxiv. 2026 Jul 02. pii: 2026.06.30.735730. [Epub ahead of print]
    Replication stress links Geminin depletion to centrosome amplification.
    Inês B Santos, David M Glover.
      The timing of DNA replication and centrosome duplication is tightly regulated with cell cycle progression to ensure the faithful duplication of the genome during cell division. Both DNA and centrosomes are licensed for replication in late telophase/early G1, replicated in S phase and segregated during mitosis; yet how defects in DNA replication licensing are coupled to centrosome homeostasis remains poorly understood. Here, we show that depletion of the replication licensing inhibitor Geminin in proliferating mouse embryonic fibroblasts induces robust centrosome amplification together with impaired primary cilium assembly. Rather than promoting whole-genome reduplication, knockdown of Geminin triggers a replication stress response, characterized by DNA damage accumulation throughout the cycle, and activation of an ATR-dependent DNA damage response. Mechanistically, Geminin depletion-induced replication stress activates the ATR-Chk1-Wee1 checkpoint axis prolonging G2 and leading to premature centriole disengagement and centrosome amplification. These findings identify replication stress as the signaling module that couples defective DNA replication licensing to centrosome amplification.
    DOI:  https://doi.org/10.64898/2026.06.30.735730
  10. Sci Adv. 2026 Sep 04. 12(36): eaeb3209
    The actomyosin cortex controls t-tubule remodeling in skeletal muscle.
    Ana Raquel Pereira, Silvia Di Francescantonio, Ana da Rosa Soares, Tianyang Liu, Filomena A Carvalho, Josie Liane Ferreira, Graciano Leal, Inês Faleiro, Naoko Kogata, Beatrice Labella, Teresinha Evangelista, Nuno C Santos, Michael Way, Carolyn A Moores, Edgar R Gomes.
      A network of plasma membrane invaginations called t-tubules plays an essential role in controlling calcium release from the endoplasmic reticulum at the triads during muscle contraction. Although the importance of t-tubules for muscle physiology is well established, and abnormalities are found in muscle disorders, the mechanisms that mediate t-tubule growth are unknown. We show that the actomyosin cortex beneath the plasma membrane, regulated by Arp2/3 complexes containing Arpc5, acts as a gatekeeper for the membrane availability during t-tubule growth. Enlarged t-tubules are formed upon disruption of Arpc5, impairing the synchronization between plasma membrane depolarization and calcium release. Knockout of Arpc5 in mouse skeletal muscle results in impaired locomotion and posture. Furthermore, we show that human triadopathy patients and Arpc5 knockout mice accumulate enlarged t-tubules. We propose that cortex-dependent membrane availability affects muscle function, offering a potential pathophysiological mechanism for muscle disorders.
    DOI:  https://doi.org/10.1126/sciadv.aeb3209
  11. J Mol Cell Biol. 2026 Aug 29. pii: mjag034. [Epub ahead of print]
    MAD2B guides chromosome stability in mitosis via the MAD2B-CIP2A signaling axis.
    Umer Ejaz, Fangyuan Xiong, Hengyi Shao, Tahir Ullah, Xuebiao Yao, Liangyu Zhang, Zhen Dou.
      Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, monitored by the spindle assembly checkpoint machinery, which prevents precocious chromosome segregation and reduces the risk of aneuploidy. MAD2B, a homologue of MAD2, is critical for mitotic quality control and DNA damage repair. However, it remains elusive how MAD2B guides genome surveillance during the cell cycle. Here, we show that MAD2B safeguards genome integrity through interactions with CIP2A in a context-dependent manner. To delineate the molecular mechanisms underlying MAD2B-dependent signaling in mitosis, we carried out affinity purification of FLAG-MAD2B followed by mass spectrometry to identify MAD2B-associated proteins. Our biochemical characterization uncovered a previously uncharacterized interaction between MAD2B and CIP2A, mediated by the N-terminus of CIP2A. Importantly, MAD2B depletion resulted in DNA damage response and replication stress phenotypes, leading to aberrant mitotic DNA synthesis primarily in HeLa cells. Notably, loss of MAD2B disrupted CIP2A recruitment to γH2AX-marked DNA lesions and attenuated DNA damage repair. Together, these results establish MAD2B as a context-sensitive regulator of genome stability that links replication stress surveillance to mitotic chromosome repair via the MAD2B-CIP2A signaling axis.
    Keywords:  CIP2A; DNA damage repair; MAD2B; genome stability; mitosis
    DOI:  https://doi.org/10.1093/jmcb/mjag034
  12. Nat Aging. 2026 Aug 31.
    Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration.
    Anamika Yadav, Kyle Alvarez, Anna Chechenina, Kevin Y Yip, Eytan Ruppin, Alexandre Colas, Jacqueline C Yano Maher, Veronica Gomez-Lobo, Caroline Kumsta, Sanju Sinha.
      Organ structure, including the organization of cells, vasculature and extracellular matrix, underpins its function, yet how structure changes with age remains mostly unknown. Here we developed PathStAR, a framework that quantifies tissue structural aging from routine histopathology images, without being trained to predict chronological age. Applying PathStAR to 25,306 post-mortem biopsies from 40 tissues in 970 donors aged 21-70 years revealed that organ structural aging progresses via distinct, nonlinear temporal trajectories: vascular tissue structural aging accelerates early, uterus and vagina structural aging accelerates late (around menopause) and certain tissues including digestive and male reproductive organs show biphasic accelerations. We show that accelerations of structural aging are characterized across organs by increased inflammation alongside reduced energy production, repair and quality control. Cross-organ analysis reveals coordinated deterioration within individuals, including digestive and male reproductive tissues, linked by sex hormones. Together, our analysis provides a systematic map of structural aging across the human body.
    DOI:  https://doi.org/10.1038/s43587-026-01200-4
  13. Nat Commun. 2026 07 31. pii: 9264. [Epub ahead of print]17(1):
    Ribo-ITP enables identification of translons from limited input samples.
    Vighnesh Ghatpande, Uma Paul, Logan Persyn, Yifan Tian, MacKenzie A Howard, Can Cenik.
      In the last decade, an unexpectedly large number of translated regions (translons) have been discovered using ribosome profiling and proteomics. Translons can act as regulatory elements or encode functional micropeptides. However, identification of translons has been limited to cell lines or large organs due to high input requirements for conventional ribosome profiling and mass spectrometry. Here, we address this input limitation using Ribo-ITP on difficult-to-collect samples such as microdissected hippocampal tissues and single preimplantation embryos to identify thousands of translons. To test the translational capacity of the identified translons, we engineer a translon-dependent GFP reporter system and detect expression of translons initiating at ATG and near-cognate start codons in mouse embryonic stem cells (mESCs). We identify distinct expression patterns of translons using a comparative analysis of more than a thousand ribosome profiling datasets across a wide range of cell types. Further, using a machine learning model, we predict that specific upstream translons in synaptically enriched mRNAs regulate translation efficiency of the annotated coding region. Taken together, we present a proof-of-concept study to identify non-canonical translation events from low input samples which can be applied to cell and tissue types inaccessible to conventional methods.
    DOI:  https://doi.org/10.1038/s41467-026-75571-y
  14. Nat Commun. 2026 07 30. pii: 9262. [Epub ahead of print]17(1):
    ERH elicits cell lineage restriction in mammalian preimplantation development and differentiation from pluripotency via H3K9me3-heterochromatin.
    Andrew Katznelson, Blake Hernandez, Kylea Tapia, Holly Fahning, Adam Burton, Jingchao Zhang, Maria-Elena Torres-Padilla, Nicolas Plachta, Kenneth S Zaret, Ryan L McCarthy.
      Enhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized as promoting fission yeast heterochromatin and recently shown to maintain H3K9me3 heterochromatin in human fibroblasts. Here, we find that ERH depletion in fibroblasts reverts the somatic cell H3K9me3 landscape of broad megabase size domains to an embryonic stem cell (ESC) state composed of mainly H3K9me3 peaks and enables activation of naïve and pluripotency genes and transposable elements during induced pluripotent stem cell (iPSC) reprogramming. Concordantly, we find that ERH represses totipotent and alternative lineage programs during mouse preimplantation development and is required for proper segregation of the inner cell mass and trophectoderm cell lineages. During human ESC differentiation into germ layer lineages, ERH silences naïve and pluripotency genes, transposable elements, and alternative lineage somatic genes. As in fission yeast, we find that mammalian ERH interacts with RNA-binding proteins to engage and repress its chromatin targets. Our findings reveal a conserved, fundamental role for ERH in mammalian cell fate specification via the initiation and maintenance of early developmental gene repression.
    DOI:  https://doi.org/10.1038/s41467-026-76015-3
  15. EMBO J. 2026 Sep 04.
    Dynamic control of cell state transitions during tissue morphogenesis.
    Joana E Saraiva, Sandra Edwards-Jorquera, Elias H Barriga.
      Morphogenesis, the process by which cells, tissues, and organs acquire and maintain their form, is essential for embryogenesis, regeneration, and disease progression. During morphogenesis, cells within tissues dynamically interact with biophysical and biochemical signals from their environment by modifying their shape, gene expression, and function. These modifications often lead to transitions between cell states, and with that, to the establishment of functional programs that will in turn define embryonic stages or tissue states. Here, we discuss how the interplay of gene expression programs, chromatin modifications, and biophysical factors from the microenvironment contributes to the robust coordination of morphogenesis by allowing cells within tissues to dynamically transit across functional stages.
    DOI:  https://doi.org/10.1038/s44318-026-00905-x
  16. Cell. 2026 Sep 03. pii: S0092-8674(26)00942-6. [Epub ahead of print]189(18): 5504-5526.e15
    Sexual dimorphism in the complete Drosophila male central nervous system connectome.
    Stuart Berg, Isabella R Beckett, Marta Costa, Philipp Schlegel, Michał Januszewski, Elizabeth C Marin, Aljoscha Nern, Stephan Preibisch, Wei Qiu, Shin-Ya Takemura, Alexandra M C Fragniere, Andrew S Champion, Diane-Yayra Adjavon, Michael Cook, Marina Gkantia, Kenneth J Hayworth, Gary B Huang, William T Katz, Florian Kämpf, Zhiyuan Lu, Christopher Ordish, Tyler Paterson, Tomke Stürner, Eric T Trautman, Catherine R Whittle, Laura E Burnett, Judith Hoeller, Feng Li, Frank Loesche, Billy J Morris, Tobias Pietzsch, Markus W Pleijzier, Valeria Silva, Yijie Yin, Iris Ali, Griffin Badalamente, Alexander Shakeel Bates, Rory J Beresford, John Bogovic, Paul Brooks, Sebastian Cachero, Brandon S Canino, Bhumpanya Chaisrisawatsuk, Jody Clements, Arthur Crowe, Inês de Haan Vicente, Georgia Dempsey, Erika Donà, Márcia Dos Santos, Marisa Dreher, Christopher R Dunne, Katharina Eichler, Samantha Finley-May, Miriam A Flynn, Imran Hameed, Gary Patrick Hopkins, Philip M Hubbard, Ladann Kiassat, Julie Kovalyak, Shirley A Lauchie, Meghan Leonard, Alanna Lohff, Kit D Longden, Charli A Maldonado, Ilina Moitra, Sung Soo Moon, Caroline Mooney, Eva J Munnelly, Nneoma Okeoma, Donald J Olbris, Anika Pai, Birava Patel, Emily M Phillips, Stephen M Plaza, Alana Richards, Jennifer Rivas Salinas, Ruairí J V Roberts, Edward M Rogers, Ashley L Scott, Louis A Scuderi, Pavithraa Seenivasan, Laia Serratosa Capdevila, Claire Smith, Rob Svirskas, Satoko Takemura, Ibrahim Tastekin, Alexander Thomson, Lowell Umayam, John J Walsh, Holly Whittome, C Shan Xu, Emily A Yakal, Tansy Yang, Arthur Zhao, Reed George, Viren Jain, Vivek Jayaraman, Wyatt Korff, Geoffrey W Meissner, Sandro Romani, Jan Funke, Christopher Knecht, Stephan Saalfeld, Louis K Scheffer, Scott Waddell, Gwyneth M Card, Carlos Ribeiro, Michael B Reiser, Harald F Hess, Gerald M Rubin, Gregory S X E Jefferis.
      Sex differences in behavior exist across all animals, typically under strong genetic regulation. In Drosophila, fruitless/doublesex transcription factors identify dimorphic neurons, but their organization into functional circuits remains unclear. We present the connectome of the entire Drosophila male central nervous system. This contains 166,700 neurons spanning the brain and nerve cord, fully proofread and annotated, including fruitless/doublesex expression and 11,710 neuron types. We provide the first comprehensive comparison between male and female brain connectomes to synaptic resolution, finding 8,069 isomorphic, 138 dimorphic, 289 male-specific, and 71 female-specific types. This resource enables analysis of full sensory-to-motor circuits underlying complex behaviors and the impact of dimorphic elements. Sex-specific/dimorphic neurons are concentrated in higher brain centers, while the sensory and motor periphery is largely isomorphic. Within higher centers, male-specific connections are organized into hotspots defined by male-specific neurons or arbors. Dimorphic neurons reroute information across sexes.
    Keywords:  Drosophila; central nervous system; connectome; dimorphic circuits; neural circuits; sex differences
    DOI:  https://doi.org/10.1016/j.cell.2026.08.015
  17. bioRxiv. 2026 Aug 24. pii: 2026.08.21.746258. [Epub ahead of print]
    Direct visualization of MCM helicase activation and replisome coupling in situ.
    Oraya J Zinder, Jonas Zähringer, Hana Polasek-Sedlackova, Kannanganattu V Prasanth, Taekjip Ha, Supriya G Prasanth.
      Deciphering the spatial organization of molecular machines that copy the genome remains a fundamental challenge in biology. Essential for eukaryotic DNA replication, Mini-Chromosome Maintenance (MCM2-7) helicases are loaded during G1 as double hexamers (DHs) to license replication origins. Upon activation in S phase, each DH is thought to split into two single hexamers (SHs) that form the active CMG helicases and travel bidirectionally. However, the field has long been divided: biochemical and structural studies define CMG helicases as autonomous, independent motors, while genomic and cellular imaging assays suggest sister replisomes remain physically coupled within replication factories. Here, we use MINFLUX nanoscopy to localize individual MCM complexes down to nanometer precision in situ, directly resolving DHs in human cells and capturing their separation into SHs upon origin firing. We find that the resulting sister replisomes do not diffuse apart: they remain coupled at a characteristic distance of ∼40 nm throughout S phase. Depletion experiments identify two distinct contributions to this coupling: local, protein-mediated tethering by the AND1 scaffold, and higher-order spatial confinement dependent on cohesin, which is dispensable for MCM loading in G1 but required to maintain coupling in S phase. By linking the nanometer-scale architecture of the replisome to the genome-wide topology of replication fountains, these findings provide direct spatial evidence that sister forks are coupled during DNA synthesis and define the molecular forces that organize replisomes within their native nuclear context.
    DOI:  https://doi.org/10.64898/2026.08.21.746258
  18. Science. 2026 Sep 03. 393(6815): eaea4611
    Conformational asymmetry of replicated human chromosomes.
    Flavia Corsi, Thomas L Steinacker, Sofia Kolesnikova, Zsuzsanna Takács, Paul Batty, Michael Mitter, Daniel W Gerlich, Anton Goloborodko.
      DNA replication generates sister chromatids with identical sequence, yet its mechanism is fundamentally asymmetric: Chromatids inherit strands of opposite orientation, whereas forks synthesize new strands by distinct leading- and lagging-strand mechanisms. How this replication asymmetry affects chromosome organization is unknown. Using sister chromatid-sensitive conformation analysis, we found that human sister chromatids are consistently misaligned in the 5'→3' direction of inherited DNA strands. This shift persisted without cohesin-mediated loop extrusion but was lost upon disruption of cohesion. Polymer modeling showed that modest directional misalignment of cohesive cohesins can explain the observed shift, and we propose two models for how such misalignment could originate from replication fork asymmetry. This register shift between sister chromatids has implications for homology search during DNA repair.
    DOI:  https://doi.org/10.1126/science.aea4611
  19. Cold Spring Harb Perspect Biol. 2026 Sep 04. pii: a041897. [Epub ahead of print]
    Upstream Regulation of the Hippo Pathway.
    Sherzod A Tokamov, Richard G Fehon.
      Studies of the Hippo signaling pathway have revealed a highly complex network of interacting regulatory mechanisms that together control pathway output and tissue growth. An overriding theme of this regulation is that it functions to link basic cellular architecture and processes to pathway function, thereby allowing tissue growth to be coordinated with cell shape and tissue morphogenesis. One such mechanism involves the transmembrane protein Crumbs and its partner Expanded, which recruit and activate the core kinases, Tao-1, Hippo, and Warts, to the junctional cortex. In parallel, Kibra and its partner Merlin recruit and activate pathway components at the apicomedial cell cortex. Both mechanisms physically and functionally interact with apical and basolateral polarity components, leading to significant cross talk between these pathways. Importantly, mechanical tension, generated within cells by actomyosin contractile networks and transmitted between cells through intercellular junctions, controls pathway output via multiple mechanisms in distinct cellular domains. In this review, we discuss these regulatory mechanisms, with particular attention to those that function upstream of the core kinases, their organization within epithelial cells, and how this organization allows cells to sense mechanical tension to shape growth in developing tissues.
    DOI:  https://doi.org/10.1101/cshperspect.a041897
  20. Mol Cell. 2026 Aug 31. pii: S1097-2765(26)00553-8. [Epub ahead of print]
    An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin.
    Chen Nie, Wanchang Liu, Lei Zhang, Sai Ge, Mingyang Ma, Jundi Wang, Zhanzhan Xu, Yingyu Qin, Xiao Albert Zhou, Yang Liu, Weibin Wang, Jiadong Wang.
      Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a "transcription repair bridge" to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity.
    Keywords:  ATM; DNA damage response; IRAK1; MRE11-RAD50-NBS1 complex; active transcription; homologous recombination repair; snRNA
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.006
  21. Sci Bull (Beijing). 2026 Aug 24. pii: S2095-9273(26)00941-2. [Epub ahead of print]
    Maternal PAN2 selectively maintains mRNA Poly(A) tail homeostasis to regulate RNA degradation during oocyte-to-early embryo transition in mice.
    Xuan Wu, Hua Zhang, Yu-Ke Wu, Zhuo-Yue Niu, Jing-Wen Liu, Lu Chen, Jia-Jia Cao, Yu-Ling Chen, Shu-Yan Ji, Fa-Long Lu, Heng-Yu Fan.
      In mammals, the precise degradation of maternal mRNAs is essential for oocyte maturation and early embryonic development, as it facilitates the "maternal-to-zygotic transition (MZT)" by eliminating maternal transcripts and enabling zygotic genome activation (ZGA). However, the physiological role of the poly(A)-specific nuclease 2 (PAN2), a deadenylase that initiates cascade degradation of long-tailed transcripts, remains unknown. Here, we generated oocyte-specific Pan2 conditional knockout (cKO) mice to investigate its role. We found that Pan2 cKO females exhibit severe female subfertility despite normal oocyte maturation and ovulation, with embryos arresting at the 2-cell stage. PAIso-seq2 and transcriptome sequencing reveal that PAN2 coordinates maternal mRNA deadenylation and decay. Mechanistically, PAN2 recognizes its substrates through a PAN3-PABPC1 bridging complex, and it preferentially targets transcripts whose poly(A) tails lack guanosine (G) but are enriched for uridine (U). PAN2 deficiency causes poly(A) tail dyshomeostasis, leading to global accumulation of maternal mRNAs, impaired zygotic genome activation, and abnormal protein accumulation in 2-cell embryos. Overexpression of these proteins phenocopies developmental defects. Notably, the PAN2-regulated transcriptome is largely non-overlapping with the LC3B-mediated degradation pathway, highlighting the unique and non-redundant role of PAN2 in maternal mRNA clearance. Our study establishes maternal PAN2 as a critical regulator of poly(A) tail homeostasis, ensuring timely maternal mRNA clearance and proper ZGA, highlighting the stage-specific and tail-composition-dependent functions of the deadenylase cascade during the maternal-to-zygotic transition. These findings offer new perspectives on post-transcriptional regulatory mechanisms in early mammalian embryogenesis.
    Keywords:  Deadenylation; Maternal mRNA decay; Oocyte-to-embryo transition; Poly(A) tail dynamics; RNA homeostasis; Zygotic genome activation (ZGA)
    DOI:  https://doi.org/10.1016/j.scib.2026.08.051
  22. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  23. Nat Med. 2026 Sep 01.
    Isthmin-2 is a first-trimester predictor of preeclampsia and fetal growth restriction.
    IMPACT Consortium
      Preeclampsia and fetal growth restriction (FGR) are major causes of global morbidity and mortality. Both conditions are associated with impaired invasion of the uterus by extravillous trophoblast (EVT). We performed proteomics in maternal serum obtained at ~12 weeks of gestational age in a prospective pregnancy cohort (Pregnancy Outcome Prediction Study). Here we show that low maternal serum isthmin-2 (ISM2) was the strongest protein signal (out of 2,904) in the first trimester of pregnancy for preeclampsia or FGR. We validated the association in two independent cohorts (Pregnancy Outcome Prediction Study 2 and Improving Maternal Pregnancy And Child ouTcomes study). ISM2 protein and mRNA are almost exclusively produced in the placenta, and, within the placenta, ISM2 mRNA is highly enriched in EVT. Knocking down ISM2 in cultured human trophoblast stem cells profoundly inhibited EVT invasion. Conversely, expressing ISM2 in a cell line lacking endogenous ISM2 (HEK293 cells) promoted migration. We conclude that ISM2 may be causally involved in the early pathophysiology of failed trophoblast invasion and that the protein and its associated pathways are potential targets for the prediction and prevention of preeclampsia and FGR.
    DOI:  https://doi.org/10.1038/s41591-026-04573-6
  24. Mol Cell. 2026 Aug 31. pii: S1097-2765(26)00555-1. [Epub ahead of print]
    Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state.
    Amoldeep S Kainth, Pallavi Sirjoosingh, Michael S Werner, Ankit Gupta, Akiko Koide, Shohei Koide, Alexander J Ruthenburg.
      Chromatin-modifying complexes are critical in gene regulation, yet their proposed interactions with RNA remain poorly understood. Counter to prior models of specific recruitment, we find that WDR5, an essential subunit of the MLL1/KMT2A histone methyltransferase complex, binds RNA promiscuously. Using a stringent approach, we demonstrate that WDR5 directly engages a diverse pool of cellular RNAs, dictated primarily by RNA abundance rather than specific motifs. Equilibrium binding assays show that RNA length, rather than sequence, governs high affinity. WDR5 binds to RNA through multiple surfaces, some of which overlap with MLL1 complex subunit interfaces. Strikingly, we find that RNA binding disrupts the MLL1 complex by competitively displacing WDR5 from these critical protein-protein interactions, leading to a marked inhibition of MLL1 catalytic activity. Further experiments in human cell lines suggest that this disassembly mechanism may operate to homeostatically downregulate MLL1 complex activity, thereby integrating transcriptional activity with chromatin state.
    Keywords:  H3K4me3; KMT2A (MLL1); MLL; PAR-CRAC; RNA-binding protein; WDR5; chromatin; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.008
  25. Sci Adv. 2026 Sep 04. 12(36): eaeg3201
    Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.
    Yongjia Duan, Ye Lu, Sanjoy Paul, Johannes Betz, Léa P Wilhelm, Annan S I Cook, Xuefeng Ren, Elias Adriaenssens, Sascha Martens, Ian G Ganley, Gerhard Hummer, James H Hurley.
      The human Unc51-like kinase 1 (ULK1) autophagy-initiating complex consists of ULK1, FIP200, and the Hop/Rev7/Mad2 (HORMA) domain heterodimer ATG13:ATG101. Phosphatidylinositol 3-phosphate (PI3P) is essential to recruit ULK1 complex (ULK1C) to membranes for ULK1, but ULK1C subunits do not contain PI3P-binding domains. Here, we show that the ATG13:ATG101 dimer forms a complex with the PI3P-binding protein WD40 interacting with phosphoinositide protein 3 (WIPI3), as well as WIPI2. Bound to WIPI2 and WIPI3, ATG13:ATG101 inserts its Trp-Phe (WF) finger into the membrane. Molecular dynamics simulations show that WIPIs and the WF finger cooperatively stabilize the complex on membranes. Biochemical reconstitution and cell-based assays show that WIPI3:ATG13 engagement promotes ATG16L1 phosphorylation, autophagy, and mitophagy. A kinase domain (KD)-proximal Pro-Val-Pro (PVP) motif in the ULK1 intrinsically disordered region docks onto the ATG13:ATG101 HORMA dimer brings the ULK1 KD close to the membrane. The PVP motif is essential for in vitro ULK1 phosphorylation of ATG16L1 and important for autophagy and mitophagy. These data establish a stepwise pathway for recruitment of the ULK1 KD to the vicinity of the membrane surface.
    DOI:  https://doi.org/10.1126/sciadv.aeg3201
  26. Sci Immunol. 2026 Sep 04. 11(123): eaea1426
    Adaptive motility enables neutrophils to rapidly navigate confined capillaries.
    Mathieu Deygas, Mathilde Bernard, Pierre Nivoit, Henry De Belly, Alexandre Deslys, Theresa Jakuszeit, Damien Cuvelier, Moira Garcia-Gomez, Lucie Barbier, Li Wang, Mathieu Maurin, Emmanuel Tejerina, Oumaima Baaziz, Emmanuel Terriac, Rafaele Attia, Anna Kniazeva, Serge Garbay, Marina Ortega-Zapero, Angela Saez, Raquel Gomez-Bris, Pilar Gonzalo, Jose M Gonzalez-Granado, Vicente Andrés, Orion D Weiner, Ana-Maria Lennon-Duménil, Guillaume Duménil, Matthieu Piel, Pablo Vargas.
      To reach inflamed tissues, neutrophils must traverse capillaries as narrow as 2 micrometers. However, how they do so without compromising blood flow or capillary function has remained unclear. By combining intravital live-cell imaging with biomimetic microdevices, we show that neutrophils maintain migration speed in capillaries across increasing levels of confinement. This behavior was not shared by other leukocytes and was independent of nuclear properties. Instead, confinement rapidly engaged Rho-dependent actomyosin contractility at the cell rear, thereby offsetting the increased mechanical resistance imposed by confinement. Disrupting this adaptive response caused neutrophil jamming and eventual occlusion of confined capillary-like networks. These findings identify a neutrophil-intrinsic mechanism that couples capillary confinement to rapid migratory adaptation, helping preserve vascular patency and potentially limiting tissue dysfunction during inflammation.
    DOI:  https://doi.org/10.1126/sciimmunol.aea1426
  27. Nucleic Acids Res. 2026 Aug 24. pii: gkag850. [Epub ahead of print]54(16):
    Bridging-driven condensation by eukaryotic SMC complexes is a conserved feature of genome organization.
    Jae-Won Jang, Torahiko L Higashi, Minzhe Tang, Changyeop Kim, Yoshimi Kinoshita, Hajin Myeong, Joonyoung Lee, Tomoko Nishiyama, Won-Ki Cho, Frank Uhlmann, Cees Dekker, Je-Kyung Ryu.
      The Structural Maintenance of Chromosome (SMC) protein family plays a central role in higher-order genome organization through ATP-dependent DNA loop extrusion by cohesin and condensin and other processes. Whether these activities fully account for the complexity of chromosome architecture remains unknown. Here, we uncover a conserved ATP-independent mechanism of chromatin condensation by SMC complexes, occurring via biomolecular condensation. Using single-molecule fluorescence imaging, we show that a variety of SMCs form dynamic DNA-bound condensates that exhibit key features of biomolecular condensates, including droplet coalescence, fluorescence recovery after photobleaching, and rapid exchange with free SMC complexes. Atomic force microscopy analysis of human cohesin-DNA assemblies reveals DNA-length-dependent clustering, providing evidence for bridging-driven condensation. Analyses of in vivo super-resolution imaging and high-throughput chromosome conformation capture (Hi-C) data indicate that these condensates form chromatin-associated clusters with multi-loop structures. Together, our results establish that SMC complexes employ ATP-independent phase condensation as well as ATP-dependent activities to shape genome architecture. This work reveals a broadly conserved principle of chromosomal organization across eukaryotes.
    DOI:  https://doi.org/10.1093/nar/gkag850
  28. Nat Commun. 2026 08 03. pii: 9338. [Epub ahead of print]17(1):
    Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
    Helin Hocaoglu, Shenlu Qin, Leah Eller, Farhan Abu, Benjamin Ohlstein, Lei Wang, Matthew H Sieber.
      Maternal metabolic stress is a major determinant of progeny health and disease susceptibility, yet the mechanisms linking germline metabolism to lifelong changes in tissue physiology remain poorly defined. Here, we show that maternal metabolic stress alters the cellular composition of the progeny intestinal epithelium through a conserved metabolic pathway. Germline metabolic dysfunction depletes NAD⁺ in mature oocytes, reprogramming progeny redox metabolism and impairing the methionine cycle. This metabolic shift reduces protein levels of the Notch ligand Delta, disrupting intestinal stem cell niche signaling and altering progeny intestinal physiology. Across insect and mammalian models, our findings reveal that maternal metabolic health has conserved effects on progeny metabolism and intestinal function. Together, this work identifies heritable redox-metabolic changes as a mechanistic link between maternal metabolic stress, stem cell regulation, and intestinal disease susceptibility.
    DOI:  https://doi.org/10.1038/s41467-026-76249-1
  29. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)00976-9. [Epub ahead of print]45(9): 117898
    An integrated landscape of mRNA and protein isoforms.
    Amir Kedan, Henrik Zauber, Meng-Ran Wang, Suyeon Kim, Qionghua Zhu, Liang Fang, Kathryn S Lilley, Wei Chen, Matthias Selbach.
      Alternative splicing and proteolytic processing expand proteome diversity by generating distinct protein isoforms from a single gene. However, the relationship between transcript isoforms and protein products remains poorly understood because of limitations in current proteomic workflows. Here, we combined full-length mRNA sequencing with protein fractionation and quantitative mass spectrometry to generate an integrated landscape of mRNA and protein isoforms in human RPE-1 cells. To overcome the ambiguity of bottom-up proteomics, we developed IsoFrac, a computational pipeline that resolves protein isoforms from molecular-weight-resolved peptide migration profiles. Using this approach, we identified ∼45,000 full-length transcripts, ∼32,000 open reading frames (ORFs), and ∼14,000 protein isoform candidates. Comparative analyses revealed widespread translation of alternative transcripts and identified shorter protein variants, likely arising from proteolytic processing and/or alternative translation, as a major and underappreciated source of proteome complexity. Our results establish a scalable framework for isoform-resolved proteogenomics and provide a resource for studying protein isoform diversity.
    Keywords:  CP: genomics; CP: molecular biology; alternative splicing; alternative translation; bottom-up proteomics; long-read sequencing; peptide correlation profiling; protein isoforms; proteogenomics; proteolytic processing; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117898
  30. Nat Commun. 2026 Jul 30. pii: 9473. [Epub ahead of print]17(1):
    A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation.
    Antoine N Dessus, Yohei Ohashi, Maxime Bourguet, Tomos E Morgan, Anastasia Nunez, Maria Manifava, Nicholas T Ktistakis, Roger L Williams.
      In mammalian cells, autophagosomes can reach diameters of over 1000 nm within 30 min after triggering starvation, but how such substantial amounts of membranes can be synthesized remains elusive. The phagophore initiation needs the lipid kinase PIK3C3-Complex 1 (PtdIns3K-C1), which produces phosphatidylinositol-3-phosphate (PtdIns3P). PtdIns3P recruits WIPI2 that facilitates lipidation of mammalian ATG8 (mATG8) family proteins on phagophores. Here we show that recombinant membrane-coupled GABARAP binds to and potently activates PtdIns3K-C1. By a combination of cryo-electron microscopy, structural mass spectrometry, activity assays and mutagenesis, we show that GABARAP activates PtdIns3K-C1 through two binding sites. We propose that once GABARAP is indirectly recruited by PtdIns3P generated by basal activity of PtdIns3K-C1, a positive feedback loop is formed where PtdIns3K-C1 interacts with GABARAP and becomes activated to produce more PtdIns3P, thereby further stimulating GABARAP lipidation. This mechanism would be central for autophagosome biogenesis, where enlarged membranes need to be rapidly synthesized.
    DOI:  https://doi.org/10.1038/s41467-026-76135-w
  31. Sci Adv. 2026 Sep 04. 12(36): eaef8132
    Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
    Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel.
      Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef8132
  32. Sci Adv. 2026 Sep 04. 12(36): eaef2333
    Hijacking pre-tRNA enables LTR-retrotransposon-initiated constitutive heterochromatin formation.
    Yazi Deng, Yu Liang, Yi Ni Luo, Luoqi Ma, Wei Wu, Wei Wu, Lu Wang.
      Pericentric heterochromatin serves as a fundamental component of eukaryotic chromosomes, endowing specialized genomic architecture with broad functional consequences. Although it is universally marked by H3K9me3 modification, the underlying pericentric DNA sequences diverge substantially across species. Here, by leveraging a transposition reporter system combined with a genome-wide RNA interference (RNAi) screen, we identified a specialized mechanism for recruiting SUV39H methyltransferase to initiate pericentric heterochromatin formation. This pathway depends on a highly ordered complex comprising the Puf68, pre-transfer RNAs (tRNAs), and the primer binding site (PBS). Puf68 binds with high affinity to poly-U tracts in pre-tRNA 3' trailer, forming a Puf68/pre-tRNA complex that subsequently base-pairs with the PBS of nascent long terminal repeat (LTR)-retrotransposons. Through direct interaction, Puf68 recruits Su(var)3-9 to these regions, catalyzing H3K9 trimethylation. Notably, Puf68 is sufficient to initiate de novo heterochromatin assembly both at pericentric and ectopically integrated LTR-retrotransposon regions. Our findings not only uncover a previously unrecognized mechanism of heterochromatin initiation but also resolve a long-standing question of how hosts harness nascent LTR-retrotransposon transcripts.
    DOI:  https://doi.org/10.1126/sciadv.aef2333
  33. Nat Cell Biol. 2026 Sep 02.
    Multi-stromal organoid co-culture modelling reveals epithelial-fibroblast heterogeneity in pancreatic cancer and pancreatitis.
    Wenlong Li, Muntadher Jihad, Eloise G Lloyd, Marta Zaccaria, Gianluca Mucciolo, Gideon Nsubuga, Alwin Koonan-Lonappan, Joaquín Araos Henríquez, Priscilla S W Cheng, Sneha Harish, Sally Mills, Paul M Johnson, Weike Luo, Alejandro Alonso Montero, Rebecca Brais, Alex Deamer, Ania M Piskorz, Julia Jones, Jodi L Miller, Bristi Basu, Paul D W Kirk, Mireia Vallespinos, Giulia Biffi.
      Interactions between epithelial cells and fibroblasts influence disease progression and treatment response in pancreatic ductal adenocarcinoma (PDAC). While the diversity of fibroblasts in PDAC is increasingly recognized, it remains unclear how these cells differ from fibroblasts found in pancreatic inflammation. Chronic pancreatitis is a stroma-rich inflammatory disease and a risk factor for PDAC, making it a useful setting to study how epithelial cells and fibroblasts change during disease. Here we compare fibroblast diversity and epithelial-stromal interactions in pancreatitis and PDAC using human samples, mouse models and mouse pancreatitis-derived epithelial organoids. We also developed pancreatitis and PDAC organoid co-cultures containing pancreatic stellate cells, fibroblasts and mesothelial cells. Combining in vitro and in vivo models better reflected human disease than mouse models alone. Overall, our findings reveal distinct epithelial and fibroblast features in pancreatitis and PDAC and provide models to identify disease-specific markers and therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1038/s41556-026-02057-w
  34. Nat Commun. 2026 08 03. pii: 9320. [Epub ahead of print]17(1):
    Unbiased screen of human transcriptome reveals an unexpected role of 3'UTRs in translation initiation.
    Yun Yang, Xiaojuan Fan, Yanwen Ye, Zhenzhen Zhang, Chuyun Chen, Sebastian E J Ludwig, Sirui Zhang, Qianyun Lu, Cindy L Will, Henning Urlaub, Jing Sun, Reinhard Lührmann, Zefeng Wang.
      Although most eukaryotic mRNAs require a 5'-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we develop a circRNA-based system and unbiasedly identify more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3'UTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5'UTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5'UTR structures and facilitate ribosome scanning. Functionally, we show that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5'UTR structure and a new 3'-CiTI in response to hypoxia. Consistently, deletion of 3'-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3'UTR actively participate in the translation initiation.
    DOI:  https://doi.org/10.1038/s41467-026-75574-9
  35. Cell Stem Cell. 2026 Sep 03. pii: S1934-5909(26)00305-X. [Epub ahead of print]
    Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases.
    Zhengmin Wang, Chengzhi Han, Yiming Huang, Yuyuan Fu, Kaijie Hu, Zheyong Huang, Weiying Meng, Qiyao Chen, Leilei Wu, Qiaozi Wang, Jinyan Zhang, Hao Luo, Yifan Wang, Lulu Zuo, Yingqi Li, Yiwen Tan, Qin Zhou, Shaoshuai Mao, Wenbo Peng, Juan Meng, Maoxiang Chen, Zhiyang Tian, Shuwei Chen, Zihan Hu, Lu Zhao, Yihan Shen, Shanshan Chen, Zhixin Shen, Lijuan Mo, Jinfeng Gao, Qiyu Li, Shiteng Cai, Jianhuang Xue, Yanan Song, Yidi Sun, Junbo Ge, Changyang Zhou.
      Epigenetic regulation may underlie asymmetric allelic expression of many genes during development and disease pathogenesis. Allele-specific epigenetic modification could provide an efficient therapy for dominant genetic diseases due to heterozygous mutations. We developed an allele-specific epigenetic editing method ("Epi-Allele") for silencing pathogenic alleles and found surprisingly elevated expression of the non-targeted alleles, leaving total gene expression unchanged. Genome-wide screening revealed that such compensated allelic expression represents a common phenomenon, suggesting that the Epi-Allele approach could avoid the haploinsufficiency induced by current allele-specific silencing therapies. This notion was validated by allele-specific epigenetic remodeling of Myh6 and MYH7 genes in ameliorating cardiac phenotypes in a hypertrophic cardiomyopathy (HCM) mouse model and HCM patient iPSC-derived cardiomyocytes, respectively. Thus, Epi-Allele offers an allele-specific haploinsufficiency-free therapeutic approach for treating dominant genetic diseases.
    Keywords:  DNA methylation; allele-specific therapy; chromatin remodeling; compensatory allele expression; dominant genetic diseases; epigenetic editing; haploinsufficiency; hypertrophic cardiomyopathy; transcription factors
    DOI:  https://doi.org/10.1016/j.stem.2026.08.004
  36. Cell Syst. 2026 Sep 02. pii: S2405-4712(26)00199-7. [Epub ahead of print] 101717
    Genome-wide chromatin recording resolves dynamic cell state changes.
    Yodai Takei, Jordan A Lay, James M Linton, Duncan M Chadly, Yoshiki Ochiai, Ron Hadas, Andrew A Perez, Mario R Blanco, Paola Laurino, Mitchell Guttman, Michael B Elowitz.
      Understanding how the chromatin state of a cell influences its future behavior is a major challenge throughout biology. However, most chromatin profiling methods are limited to endpoint assays. Here, we present LagTag, a method for recovery of earlier and endpoint chromatin states in the same mammalian cells. In this approach, transient activity of bacterial adenine methyltransferase fusions records the DNA-binding profiles of chromatin-associated proteins of interest at earlier time points. Subsequent tagmentation and sequencing recover the earlier chromatin profile from adenine methylation profiles, alongside endpoint profiles of endogenous chromatin-associated proteins. We verified that LagTag profiles aligned with those from established methods in mouse and human cells. We then applied LagTag to record and recover dynamic chromatin state transitions during mouse embryonic stem cell differentiation, capturing transcriptional signatures from pre- and post-differentiation time points within the same cell population. LagTag thus provides a foundation for temporally resolved chromatin profiling. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  chromatin organization; chromatin recording; gene regulation; genomics; synthetic biology
    DOI:  https://doi.org/10.1016/j.cels.2026.101717
  37. Nat Neurosci. 2026 Aug 31.
    Spatial mapping of RNA turnover kinetics in the mouse brain.
    Qi Qiu, Hongjie Zhang, Zijie Xia, William Gao, Julia I Leu, Dongming Liang, Ying Li, Fan Li, Yijing Su, Emily Feierman, Erin Van Horn, Guo-Li Ming, Erica Korb, Hongjun Song, Zhaolan Zhou, Hao Wu.
      Gene regulation requires coordinated control of RNA synthesis and degradation, yet measuring RNA turnover across intact tissues remains challenging. Here we present spatial NT-seq, a method that combines transgenesis-free metabolic RNA labeling with in situ chemical recoding on spatial transcriptomics platforms to co-map newly synthesized and pre-existing RNAs. Applying spatial NT-seq to the mouse brain reveals pronounced regional heterogeneity in RNA turnover and identifies the dentate gyrus as a spatial hotspot marked by coordinated upregulation of basal RNA synthesis and decay. Moreover, spatial NT-seq uncovers rapid, brain region-specific transcriptional and post-transcriptional responses to electroconvulsive stimulation, a clinically relevant treatment for refractory depression. Finally, we leverage computational modeling to identify sequence features and post-transcriptional regulators that shape transcriptome-wide mRNA stability across spatial and cellular contexts in the mouse brain. Together, this integrated 'in vivo timescope' framework provides a spatially resolved view of RNA turnover kinetics and reveals the regulatory architecture of RNA stability in vivo.
    DOI:  https://doi.org/10.1038/s41593-026-02420-y
  38. Nat Rev Mol Cell Biol. 2026 Sep 04.
    The molecular basis of transcription initiation by RNA polymerase II.
    Xizi Chen, Yanhui Xu.
      Transcription initiation in eukaryotes is a major regulatory checkpoint for ensuring that genes are precisely activated. Although the basic components of the transcription machinery were identified decades ago, recent breakthroughs in high-resolution cryo-electron microscopy have transformed our understanding of how these massive complexes function as dynamic assemblies rather than as static entities. In this Review, we focus on transcription by RNA polymerase II (Pol II) and discuss the integrated roles of the universal promoter scaffold factor TFIID, the transcription co-activator Mediator and the epigenetic status of the +1 nucleosome. We first discuss the structural basis of TFIID-mediated recognition of the core promoter and the modular assembly of the pre-initiation complex and pre-initiation complex-Mediator, which involves phosphorylation of the Pol II C-terminal domain. We then discuss how the chromatin environment regulates selection of the transcription start site and transcription directionality, before turning to the progression from transcription initiation to elongation, including promoter opening and promoter escape. Finally, we discuss transcription initiation as a programmed process, in which inhibitory factors are released and regulatory factors are progressively exchanged through competition for binding surfaces.
    DOI:  https://doi.org/10.1038/s41580-026-01019-2
  39. Nat Commun. 2026 08 01. pii: 9306. [Epub ahead of print]17(1):
    CALIPERS: Cell cycle-aware live imaging for phenotyping experiments and regeneration studies.
    Moises Di Sante, Melissa Pezzotti, Julius Zimmermann, Alessandro Enrico, Joran Deschamps, Elisa Balmas, Silvia Becca, Eloisa Torchia, Giulia Ballio, Samantha Solito, Martina Sarchi, Alessandro Reali, Alessandro Bertero, Florian Jug, Francesco S Pasqualini.
      Cell-cycle progression is a major source of variability in live-cell phenotyping, yet imaging workflows still lack a general way to account for it alongside structural and functional readouts. Here we show CALIPERS (Cell-cycle-Aware Live-cell Imaging for Phenotyping Experiments and Regeneration Studies), an integrated framework that pairs a spectrally redesigned FUCCI reporter with continuous cell-cycle inference and flexible delivery strategies in human cells and stem-cell models. In epithelial cells, CALIPERS simultaneously images actin, tubulin, or calcium dynamics, phase-locks migration and proliferation, triggers mitosis-aware smart microscopy, and recovers fast calcium signals. In induced pluripotent stem-cell workflows, lentiviral and safe-harbor versions span pluripotent, lineage-restricted, and cardiac models. In cardiac organoids, CALIPERS tracks cell-cycle exit, tissue compaction, and calcium onset, and distinguishes productive proliferation from multinucleation and endoreplication. By making cell-cycle state an explicit, measurable variable, CALIPERS helps triage candidate regenerative interventions across diverse live-imaging assays.
    DOI:  https://doi.org/10.1038/s41467-026-76144-9
  40. Sci Adv. 2026 Sep 04. 12(36): eaef9406
    Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo.
    Ruizhao Wang, Jian Jiang, Zhuoyuan Li, Tianning Liu, Yangdong Wang, Mingqi Xie, Kiryl D Piatkevich.
      Recording and real-time imaging of promoter activities are critical for deciphering signaling cross-talk, but technologies for simultaneously capturing multiple transient events in living cells are lacking. Here, we design fluorescent protein-based ticker tapes (FPTT) for multiplexed, scalable, longitudinal recording of single-cell physiological activities by integrating multispectral monomeric fluorescent proteins with self-assembling protein fibers. FPTT logged dose-dependent, reversible endogenous cFos transcriptional histories in hippocampal neurons at 3-hour resolution over 8 days. We engineered FPTT variants for human nuclear factor κB (NF-κB), Janus kinase/signal transducer and activator of transcription 3 (STAT3), mechanistic target of rapamycin (mTOR), nuclear factor of activated T cells (NFAT), and adenosine 3',5'-monophosphate (cAMP) signaling. This expanded toolset enabled quantification of cFos and NF-κB cross-talk in neurons, tracking of STAT3/cAMP dynamics during mouse liver injury, discovery of unexpected NFAT/STAT3 cross-talk, and characterization of cell cycle-dependent oscillating mTOR dynamics. Last, we achieved simultaneous analysis of four major pathways during T cell activation. FPTT provides a versatile platform to investigate transcriptional histories and signaling interplay, with broad applications in developmental biology and disease modeling.
    DOI:  https://doi.org/10.1126/sciadv.aef9406
  41. Mol Cell. 2026 Sep 03. pii: S1097-2765(26)00550-2. [Epub ahead of print]86(17): 3411-3430.e14
    Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability.
    Wisam Zaatra, George Philippos, Petr Smirnov, Shira Milo, Jan Otoničar, Michelle Chan, Michal Harel, Frauke Devens, Tchelet Goldberg, Alexandra Eliassaf, Karen Grimes, Michal Irony-Tur Sinai, Gianluca Sigismondo, Kathrin Laue, Uri Ben-David, Tamar Geiger, Jan O Korbel, Jeroen Krijgsveld, Ori Shalev, Batsheva Kerem, Aurélie Ernst.
      p53 plays a central role in the DNA damage response, inducing repair, cell-cycle arrest or apoptosis. Its loss is associated with replication stress and genomic instability. While several underlying mechanisms were suggested, the primary triggers of catastrophic genomic events like chromothripsis, a known driver of tumorigenesis linked with p53 loss, are still unclear. Using p53-depleted epithelial cells and fibroblasts, as well as patient-derived fibroblasts with germline p53 variants that spontaneously undergo chromothripsis, we found that p53 loss causes hypertranscription and increased nucleotide consumption. The resulting nucleotide shortage induces replication stress, causing telomere dysfunction, micronuclei formation, and chromothripsis. These effects were rescued by nucleoside supplementation or normalization of transcription levels, demonstrating a causal link between transcriptional activity, nucleotide availability, and genome stability. Emerging chromothriptic clones displayed restored DNA replication, telomere stabilization, and extrachromosomal DNA, suggesting key features that support clonal selection. We identify nucleotide pool homeostasis as a critical p53 function that suppresses replication stress, prevents chromothripsis, and protects against early tumorigenesis.
    Keywords:  cancer; chromothripsis; genomic instability; hypertranscription; nucleotide insufficiency; p53 deficiency; replication stress
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.003
  42. Cell. 2026 Sep 03. pii: S0092-8674(26)00928-1. [Epub ahead of print]189(18): 5488-5503
    The regulatory logic linking inflammation and fibrosis.
    Michael Alexanian, Deepak Srivastava.
      Whether tissue injury resolves or progresses to chronic scarring is determined by regulatory choices that remain only partially understood. In this review, we propose that immune cells and fibroblasts function as dynamic interpreters of intercellular cues, integrating these signals through chromatin-regulated gene circuits that govern cell state and fate. Drawing on insights from cardiac biology and from settings where tissues regenerate or resolve injury without scarring, we outline a molecular framework in which immune-stromal crosstalk and gene regulatory networks dictate the choice between recovery and chronic fibrosis across organs, including the heart, lung, liver, and kidney. Reframing fibrosis as a reversible state shaped by disrupted regulatory logic opens therapeutic avenues that move beyond suppressing fibrotic outputs toward rewiring the regulatory programs that sustain them.
    DOI:  https://doi.org/10.1016/j.cell.2026.08.001
  43. Nature. 2026 Sep 02.
    Rewiring the ribosome to translate proteins encoded in its own RNA.
    Kasra Alizadeh, Dorota Klepacki, Nora Vázquez-Laslop, Alexander S Mankin.
      Cellular protein synthesis relies on random encounters between ribosomes and mRNAs, limiting optimization of the translation machinery for production of a single protein-a key need in biotechnology. One potential solution is integrating the protein-coding sequence into the ribosome itself, thereby committing the ribosome to synthesis of a single polypeptide. The feasibility of such integration could also address a long-standing challenge in RNA world models: explaining how early protein synthesis could function reliably despite the scarcity and poor organization of its components1. Whether a ribosome can translate its own ribosomal RNA (rRNA) has remained unclear. Here we show that bacterial ribosomes can synthesize proteins encoded within their own RNA. We engineered a chimeric messenger-ribosomal RNA (mrRNA) by appending a protein-coding sequence to 16S rRNA. The hybrid mrRNA assembles into a small ribosomal subunit that binds to the large subunit to form Ribo-M, a ribosome capable of translating mrRNA-encoded proteins. Translation is abolished by mutations or antibiotics that impair the function of the small subunit, demonstrating that mrRNA translation is carried out in cis by ribosomes assembled on the chimeric mrRNA. Incorporating mrRNA into a ribosome with tethered subunits yielded Ribo-TM, in which encoding, decoding and peptide synthesis are united within a single RNA scaffold. These findings establish the mechanistic feasibility of a ribosome translating its own rRNA in vivo and in vitro, offering a versatile platform for orthogonal protein production and insights into the origin of translation.
    DOI:  https://doi.org/10.1038/s41586-026-10962-1
  44. PLoS Genet. 2026 Sep;22(9): e1012279
    Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions.
    Carolyn Sangokoya, Isabella R Rosso, Rana Ghandehari-Alavijeh, Robert Blelloch.
      Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3'untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation.
    DOI:  https://doi.org/10.1371/journal.pgen.1012279
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