{"title":"Scaling back DEI programmes and the loss of scientific talent.","authors":"Needhi Bhalla,JoAnn Trejo,Mary Munson","doi":"10.1038/s41556-025-01797-5","DOIUrl":"https://doi.org/10.1038/s41556-025-01797-5","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"13 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katerina Kraft, Sedona E Murphy, Matthew G Jones, Quanming Shi, Aarohi Bhargava-Shah, Christy Luong, King L Hung, Britney J He, Rui Li, Seung Kuk Park, Michael T Montgomery, Natasha E Weiser, Yanbo Wang, Jens Luebeck, Vineet Bafna, Jef D Boeke, Paul S Mischel, Alistair N Boettiger, Howard Y Chang
{"title":"Enhancer activation from transposable elements in extrachromosomal DNA.","authors":"Katerina Kraft, Sedona E Murphy, Matthew G Jones, Quanming Shi, Aarohi Bhargava-Shah, Christy Luong, King L Hung, Britney J He, Rui Li, Seung Kuk Park, Michael T Montgomery, Natasha E Weiser, Yanbo Wang, Jens Luebeck, Vineet Bafna, Jef D Boeke, Paul S Mischel, Alistair N Boettiger, Howard Y Chang","doi":"10.1038/s41556-025-01788-6","DOIUrl":"https://doi.org/10.1038/s41556-025-01788-6","url":null,"abstract":"<p><p>Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoural heterogeneity in aggressive cancers. While transposable element reactivation is common in cancer, its role on ecDNA remains unexplored. Here we map the 3D architecture of MYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements-genomic loci enriched for transposable elements that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified with MYC, which functions only in the ecDNA-amplified context. Using CRISPR-CATCH, CRISPR interference and reporter assays, we confirm its presence on ecDNA, enhancer activity and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumour evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":" ","pages":""},"PeriodicalIF":19.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathleen Watt,Bianca Dauber,Krzysztof J Szkop,Laura Lee,Predrag Jovanovic,Shan Chen,Ranveer Palia,Julia A Vassalakis,Tyler T Cooper,David Papadopoli,Laìa Masvidal,Michael Jewer,Kristofferson Tandoc,Hannah Plummer,Gilles A Lajoie,Ivan Topisirovic,Ola Larsson,Lynne-Marie Postovit
{"title":"Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.","authors":"Kathleen Watt,Bianca Dauber,Krzysztof J Szkop,Laura Lee,Predrag Jovanovic,Shan Chen,Ranveer Palia,Julia A Vassalakis,Tyler T Cooper,David Papadopoli,Laìa Masvidal,Michael Jewer,Kristofferson Tandoc,Hannah Plummer,Gilles A Lajoie,Ivan Topisirovic,Ola Larsson,Lynne-Marie Postovit","doi":"10.1038/s41556-025-01786-8","DOIUrl":"https://doi.org/10.1038/s41556-025-01786-8","url":null,"abstract":"Adaptation to cellular stresses entails an incompletely understood coordination of transcriptional and post-transcriptional gene expression programs. Here, by quantifying hypoxia-dependent transcriptomes, epigenomes and translatomes in T47D breast cancer cells and H9 human embryonic stem cells, we show pervasive changes in transcription start site (TSS) selection associated with nucleosome repositioning and alterations in H3K4me3 distribution. Notably, hypoxia-associated TSS switching was induced or reversed via pharmacological modulation of H3K4me3 in the absence of hypoxia, defining a role for H3K4me3 in TSS selection independent of HIF1-transcriptional programs. By remodelling 5'UTRs, TSS switching selectively alters protein synthesis, including enhanced translation of messenger RNAs encoding pyruvate dehydrogenase kinase 1, which is essential for metabolic adaptation to hypoxia. These results demonstrate a previously unappreciated mechanism of translational regulation during hypoxia driven by epigenetic reprogramming of the 5'UTRome.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"66 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A continuous totipotent-like cell-based embryo model recapitulates mouse embryogenesis from zygotic genome activation to gastrulation.","authors":"Yixuan Ren,Xuyang Wang,Haiyin Liu,Yaxing Xu,Ruoqi Cheng,Shengnan Ren,Zining Li,Yunfei Huo,Bo Li,Jingyang Guan,Cheng Li,Hongkui Deng,Jun Xu","doi":"10.1038/s41556-025-01793-9","DOIUrl":"https://doi.org/10.1038/s41556-025-01793-9","url":null,"abstract":"The development of stem-cell-derived models of mammalian embryogenesis has provided invaluable tools for investigating embryo development. However, constructing embryo models that can continuously recapitulate the developmental trajectory, from zygotic genome activation to gastrulation, remains challenging. Here we report the development of a chemical cocktail to induce totipotent-like cells with robust proliferative ability and leverage these cells to establish a stepwise protocol for generating a continuous embryo model. This model sequentially mimics mouse embryogenesis from embryonic day 1.5 to 7.5. It recapitulates key developmental milestones, including zygotic genome activation in 2-cell embryos, the diversification of embryonic and extraembryonic lineages from 4-cell to 64-cell stages, the formation of blastocysts and the subsequent development into post-implantation egg cylinders. Notably, these structures undergo gastrulation, as indicated by the formation of a primitive streak-like structure and the subsequent emergence of several early organogenesis hallmarks. Our study opens avenues for modelling mammalian embryogenesis in vitro.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"37 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rabia R. Khawaja, Ernesto Griego, Kristen Lindenau, Asma Salek, Jessica Gambardella, Aurora Scrivo, Hannah R. Monday, Mathieu Bourdenx, Jesús Madero-Pérez, Zohaib N. Khan, Bhakti Chavda, Ronald Cutler, Sarah Graff, Simone Sidoli, Gaetano Santulli, Laura Santambrogio, Inmaculada Tasset, Susmita Kaushik, Li Gan, Pablo E. Castillo, Ana Maria Cuervo
{"title":"Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome","authors":"Rabia R. Khawaja, Ernesto Griego, Kristen Lindenau, Asma Salek, Jessica Gambardella, Aurora Scrivo, Hannah R. Monday, Mathieu Bourdenx, Jesús Madero-Pérez, Zohaib N. Khan, Bhakti Chavda, Ronald Cutler, Sarah Graff, Simone Sidoli, Gaetano Santulli, Laura Santambrogio, Inmaculada Tasset, Susmita Kaushik, Li Gan, Pablo E. Castillo, Ana Maria Cuervo","doi":"10.1038/s41556-025-01771-1","DOIUrl":"10.1038/s41556-025-01771-1","url":null,"abstract":"Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer’s disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline. Khawaja et al. show sex-specific differences in neuronal-activity regulation by chaperone-mediated autophagy and that loss of chaperone-mediated autophagy leads to defective neuronal physiology and increased seizure susceptibility, linking chaperone-mediated autophagy to neuronal excitability.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1688-1707"},"PeriodicalIF":19.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Muhammad Aminu,Bo Zhu,Natalie Vokes,Hong Chen,Lingzhi Hong,Jianrong Li,Junya Fujimoto,Mehdi Chaib,Yuqiu Yang,Bo Wang,Alissa Poteete,Monique B Nilsson,Xiuning Le,Tina Cascone,David Jaffray,Nicholas Navin,Tao Wang,Lauren A Byers,Don L Gibbons,John Heymach,Ken Chen,Chao Cheng,Jianjun Zhang,Jia Wu
{"title":"CoCo-ST detects global and local biological structures in spatial transcriptomics datasets.","authors":"Muhammad Aminu,Bo Zhu,Natalie Vokes,Hong Chen,Lingzhi Hong,Jianrong Li,Junya Fujimoto,Mehdi Chaib,Yuqiu Yang,Bo Wang,Alissa Poteete,Monique B Nilsson,Xiuning Le,Tina Cascone,David Jaffray,Nicholas Navin,Tao Wang,Lauren A Byers,Don L Gibbons,John Heymach,Ken Chen,Chao Cheng,Jianjun Zhang,Jia Wu","doi":"10.1038/s41556-025-01781-z","DOIUrl":"https://doi.org/10.1038/s41556-025-01781-z","url":null,"abstract":"Spatial domain detection methods often focus on high-variance structures, such as tumour-adjacent regions with sharp gene expression changes, while missing low-variance structures with subtle gene expression shifts, like those between adjacent normal and early adenoma regions. Here, to address this, we introduce 'compare and contrast spatial transcriptomics' (CoCo-ST), a graph contrastive feature representation framework. By comparing a target sample with a background sample, CoCo-ST detects both high-variance, broadly shared structures and low-variance, tissue-specific features. It offers technical advantages, including multisample integration, batch-effect correction and scalability across technologies from spot-level Visium data to single-cell Xenium Prime 5K and subcellular Visium HD data. We benchmarked CoCo-ST against ten state-of-the-art spatial-domain-detection algorithms using mouse lung precancerous samples, demonstrating its superior ability to identify low-variance spatial structures overlooked by other methods. CoCo-ST also effectively distinguishes cell clusters and niche structures in Visium HD and Xenium Prime 5K data. CoCo-ST is accessible at GitHub ( https://github.com/WuLabMDA/CoCo-ST ).","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"94 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mai Nguyen, Jack J. Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J. Milnerwood, Sidong Huang, Michel Desjardins, Heidi M. McBride
{"title":"MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death","authors":"Mai Nguyen, Jack J. Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J. Milnerwood, Sidong Huang, Michel Desjardins, Heidi M. McBride","doi":"10.1038/s41556-025-01774-y","DOIUrl":"10.1038/s41556-025-01774-y","url":null,"abstract":"Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson’s disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria–lysosome pathway at the nexus of immune signalling and cell death. Nguyen, Collier et al. find a mitochondria–lysosome inflammatory pathway regulated by the SUMO E3 ligase MAPL, which promotes vesicular mtDNA transport to lysosomes and subsequent gasdermin-dependent lysosomal permeabilization to activate pyroptosis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1708-1724"},"PeriodicalIF":19.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01774-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Boran Li, Dongheng Zhou, Xinyi Wang, Xiao Jiang, Yongjuan Sang, Youjing Dai, Yu Yao, Yi Zhang, Chen Chen, Shulin Li, Wang Ni, Quan Zhou, Aifu Lin, Xinyang Hu, Liang Ge, Zhiying Wu, Pinglong Xu, Dante Neculai, Wei Liu, Qiming Sun
{"title":"Cholesterol sensing by the SCAP–FAM134B complex regulates ER-phagy and STING innate immunity","authors":"Boran Li, Dongheng Zhou, Xinyi Wang, Xiao Jiang, Yongjuan Sang, Youjing Dai, Yu Yao, Yi Zhang, Chen Chen, Shulin Li, Wang Ni, Quan Zhou, Aifu Lin, Xinyang Hu, Liang Ge, Zhiying Wu, Pinglong Xu, Dante Neculai, Wei Liu, Qiming Sun","doi":"10.1038/s41556-025-01766-y","DOIUrl":"10.1038/s41556-025-01766-y","url":null,"abstract":"The endoplasmic reticulum (ER) is central to cholesterol biosynthesis and trafficking, yet paradoxically maintains low cholesterol levels, enabling it to sense fluctuations that impact various signalling pathways. However, the role of ER cholesterol in cellular signalling remains unclear. Here we show that the ER-phagy receptor FAM134B interacts directly with both cholesterol and SCAP, a key regulator of cholesterol biosynthesis. When ER cholesterol is high, FAM134B and SCAP are sequestered by cholesterol-tightened interactions, halting ER-phagy, STING activation and cholesterol synthesis. Under low cholesterol conditions, FAM134B dissociates from SCAP, allowing SCAP to activate SREBP2 and upregulate cholesterol synthesis, while FAM134B either facilitates ER-phagy through oligomerization or aids STING trafficking to activate innate immune responses. These findings reveal that the SCAP–FAM134B complex senses ER cholesterol levels, regulating both ER-phagy and immune signalling, with implications for diseases linked to cholesterol imbalance. The authors show that the endoplasmic reticulum-phagy receptor FAM134B interacts with SCAP to regulate cholesterol biosynthesis, sequestering SCAP when endoplasmic reticulum cholesterol is high but dissociating upon low cholesterol levels, allowing SCAP to activate cholesterol synthesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1739-1756"},"PeriodicalIF":19.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Navigating cell state transitions with deep learning","authors":"","doi":"10.1038/s41556-025-01759-x","DOIUrl":"10.1038/s41556-025-01759-x","url":null,"abstract":"We present CellNavi, a deep learning framework that predicts driver genes that orchestrate cellular transitions by modelling cell states on a biologically meaningful manifold. We demonstrated how CellNavi predictions of driver genes have potential applications in advancing cell therapy, uncovering key factors that drive cellular diseases, and identifying crucial genes involved in drug responses.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1607-1608"},"PeriodicalIF":19.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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