Pub Date : 2025-10-31DOI: 10.1038/s41556-025-01789-5
Shan Lu, Sitao Zhang, Spencer Oung, Jolene K. Diedrich, Peng Han, Olatz Arnold-Garcia, Takuya Ohkubo, Olubankole Aladesuyi Arogundade, Sonia Vazquez-Sanchez, Ke Zhang, John Ravits, John R. Yates III, Don W. Cleveland
In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion. Lu et al. show that, under proteotoxic stress, TDP-43 inclusions of skein-like morphology are guided by the chaperone HSP70 and its nucleotide exchange factor BAG3 to induce TDP-43 co-aggregation with F-actin-bound actin-binding proteins.
{"title":"TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins","authors":"Shan Lu, Sitao Zhang, Spencer Oung, Jolene K. Diedrich, Peng Han, Olatz Arnold-Garcia, Takuya Ohkubo, Olubankole Aladesuyi Arogundade, Sonia Vazquez-Sanchez, Ke Zhang, John Ravits, John R. Yates III, Don W. Cleveland","doi":"10.1038/s41556-025-01789-5","DOIUrl":"10.1038/s41556-025-01789-5","url":null,"abstract":"In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion. Lu et al. show that, under proteotoxic stress, TDP-43 inclusions of skein-like morphology are guided by the chaperone HSP70 and its nucleotide exchange factor BAG3 to induce TDP-43 co-aggregation with F-actin-bound actin-binding proteins.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1925-1937"},"PeriodicalIF":19.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404894","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}
Pub Date : 2025-10-31DOI: 10.1038/s41556-025-01799-3
Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe
The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine–GCN2–SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer. Li et al. uncover a connection between metabolic cues and mitochondrial protein degradation, showing that specifically leucine stabilizes outer mitochondrial membrane proteins by inhibiting ubiquitylation and promoting mitochondrial respiration.
{"title":"Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration","authors":"Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe","doi":"10.1038/s41556-025-01799-3","DOIUrl":"10.1038/s41556-025-01799-3","url":null,"abstract":"The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine–GCN2–SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer. Li et al. uncover a connection between metabolic cues and mitochondrial protein degradation, showing that specifically leucine stabilizes outer mitochondrial membrane proteins by inhibiting ubiquitylation and promoting mitochondrial respiration.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1889-1901"},"PeriodicalIF":19.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01799-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404895","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}
Pub Date : 2025-10-29DOI: 10.1038/s41556-025-01790-y
Mike Lange, Michele Wölk, Vivian Wen Li, Cody E. Doubravsky, Joseph M. Hendricks, Shunji Kato, Yurika Otoki, Benjamin Styler, Sean L. Johnson, Cynthia A. Harris, Kiyotaka Nakagawa, Isabel F. Snodgrass, Dohee Kim, John W. Newman, Maria Fedorova, James A. Olzmann
Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here we identify LD-localized ferroptosis suppressor protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, inducing polyunsaturated fatty acid-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality-control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the build-up of oxidized lipids and induction of ferroptosis. Lange et al. identify a lipid droplet quality control pathway in which FSP1 safeguards stored neutral lipids from lipid peroxidation, thereby preventing the induction of ferroptosis.
{"title":"FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis","authors":"Mike Lange, Michele Wölk, Vivian Wen Li, Cody E. Doubravsky, Joseph M. Hendricks, Shunji Kato, Yurika Otoki, Benjamin Styler, Sean L. Johnson, Cynthia A. Harris, Kiyotaka Nakagawa, Isabel F. Snodgrass, Dohee Kim, John W. Newman, Maria Fedorova, James A. Olzmann","doi":"10.1038/s41556-025-01790-y","DOIUrl":"10.1038/s41556-025-01790-y","url":null,"abstract":"Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here we identify LD-localized ferroptosis suppressor protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, inducing polyunsaturated fatty acid-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality-control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the build-up of oxidized lipids and induction of ferroptosis. Lange et al. identify a lipid droplet quality control pathway in which FSP1 safeguards stored neutral lipids from lipid peroxidation, thereby preventing the induction of ferroptosis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1902-1913"},"PeriodicalIF":19.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01790-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381937","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}
International efforts have yielded extensive single-cell time-series atlas datasets, such as those on mouse embryogenesis, providing a reference for mapping disease models across biomedical research. However, effectively using such data for temporal analysis of individual datasets is challenging due to the intricate nature of cell states and the tight coupling between time stamps and experimental batches. Here we introduce TemporalVAE, a deep generative model in a dual-objective setting that infers the biological time of each cell from a compressed latent space, even in a zero-shot setting. With a mouse development atlas, we demonstrated its scalability with millions of cells, accuracy in atlas-based cell staging across platforms and interpretability by identifying temporally sensitive genes with in silico perturbation. TemporalVAE effectively stages cells during human peri-implantation under both in vivo and in vitro conditions, and supports cross-primate comparisons among human, cynomolgus and marmoset embryos, highlighting its potential for broad biomedical applications. Liu et al. present TemporalVAE, a method for integrating single-cell time course data. The model proposes a workflow to determine the biological timing of samples and its temporally sensitive genes, enabling single-cell developmental stage inference.
{"title":"TemporalVAE: atlas-assisted temporal mapping of time-series single-cell transcriptomes during embryogenesis","authors":"Yijun Liu, Fangxin Cai, Melania Barile, Yi Chang, Dandan Cao, Yuanhua Huang","doi":"10.1038/s41556-025-01787-7","DOIUrl":"10.1038/s41556-025-01787-7","url":null,"abstract":"International efforts have yielded extensive single-cell time-series atlas datasets, such as those on mouse embryogenesis, providing a reference for mapping disease models across biomedical research. However, effectively using such data for temporal analysis of individual datasets is challenging due to the intricate nature of cell states and the tight coupling between time stamps and experimental batches. Here we introduce TemporalVAE, a deep generative model in a dual-objective setting that infers the biological time of each cell from a compressed latent space, even in a zero-shot setting. With a mouse development atlas, we demonstrated its scalability with millions of cells, accuracy in atlas-based cell staging across platforms and interpretability by identifying temporally sensitive genes with in silico perturbation. TemporalVAE effectively stages cells during human peri-implantation under both in vivo and in vitro conditions, and supports cross-primate comparisons among human, cynomolgus and marmoset embryos, highlighting its potential for broad biomedical applications. Liu et al. present TemporalVAE, a method for integrating single-cell time course data. The model proposes a workflow to determine the biological timing of samples and its temporally sensitive genes, enabling single-cell developmental stage inference.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1982-1992"},"PeriodicalIF":19.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381135","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}
Pseudouridine (Ψ) is one of the most abundant RNA modifications in human cells, introduced post-transcriptionally by pseudouridine synthases (PUS). Despite its prevalence, the biological functions of Ψ remain poorly understood, largely due to the limited knowledge linking specific PUS enzymes to their targets. Here, to address this gap, we systematically knocked out or knocked down nine stand-alone PUS in HCT116 cells and mapped their Ψ profiles using 2-bromoacrylamide-assisted cyclization sequencing. Through this approach, we uncovered previously unknown targets of several PUS enzymes, including RPUSD1, RPUSD2, PUS3, PUSL1 and PUS7L. In addition, we revealed that TRUB1 and PUS10 function redundantly to catalyse the highly conserved Ψ55 modification in cytosolic tRNAs. Intriguingly, we found that RPUSD3 and TRUB2 do not exhibit noticeable enzymatic activities in human cells. By integrating these findings with earlier results for TRUB1, PUS7 and PUS1, we constructed a comprehensive map of stand-alone PUS-dependent Ψ modifications across human tRNAs. Using this map, we further demonstrated that different PUS enzymes introduce Ψ modifications at distinct stages of pre-tRNA processing. Xu, Kong, Li, Pisignano and colleagues provide a map of pseudouridine sites in human noncoding RNA. Using a systematic knockout approach, they associate each pseudouridine site with the activity of a specific pseudouridine synthase.
{"title":"A comprehensive tRNA pseudouridine map uncovers targets dependent on human stand-alone pseudouridine synthases","authors":"Haiqi Xu, Linzhen Kong, Mengjie Li, Giuseppina Pisignano, Jingfei Cheng, Feng Feng, Parinaz Mehdipour, Chun-Xiao Song","doi":"10.1038/s41556-025-01803-w","DOIUrl":"10.1038/s41556-025-01803-w","url":null,"abstract":"Pseudouridine (Ψ) is one of the most abundant RNA modifications in human cells, introduced post-transcriptionally by pseudouridine synthases (PUS). Despite its prevalence, the biological functions of Ψ remain poorly understood, largely due to the limited knowledge linking specific PUS enzymes to their targets. Here, to address this gap, we systematically knocked out or knocked down nine stand-alone PUS in HCT116 cells and mapped their Ψ profiles using 2-bromoacrylamide-assisted cyclization sequencing. Through this approach, we uncovered previously unknown targets of several PUS enzymes, including RPUSD1, RPUSD2, PUS3, PUSL1 and PUS7L. In addition, we revealed that TRUB1 and PUS10 function redundantly to catalyse the highly conserved Ψ55 modification in cytosolic tRNAs. Intriguingly, we found that RPUSD3 and TRUB2 do not exhibit noticeable enzymatic activities in human cells. By integrating these findings with earlier results for TRUB1, PUS7 and PUS1, we constructed a comprehensive map of stand-alone PUS-dependent Ψ modifications across human tRNAs. Using this map, we further demonstrated that different PUS enzymes introduce Ψ modifications at distinct stages of pre-tRNA processing. Xu, Kong, Li, Pisignano and colleagues provide a map of pseudouridine sites in human noncoding RNA. Using a systematic knockout approach, they associate each pseudouridine site with the activity of a specific pseudouridine synthase.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2186-2197"},"PeriodicalIF":19.1,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01803-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357637","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}
Pub Date : 2025-10-23DOI: 10.1038/s41556-025-01797-5
Needhi Bhalla, JoAnn Trejo, Mary Munson
Programmes that support diversity, equity and inclusion (DEI) in science are under attack in the USA. Data indicate that diversity in the scientific workforce increases creativity and success in tackling challenging problems. Loss of promising talent supported by these programmes will substantially weaken our research capacity, limit innovation and substantially reduce discoveries important for driving scientific advancements.
{"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":"10.1038/s41556-025-01797-5","url":null,"abstract":"Programmes that support diversity, equity and inclusion (DEI) in science are under attack in the USA. Data indicate that diversity in the scientific workforce increases creativity and success in tackling challenging problems. Loss of promising talent supported by these programmes will substantially weaken our research capacity, limit innovation and substantially reduce discoveries important for driving scientific advancements.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1881-1883"},"PeriodicalIF":19.1,"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}
Pub Date : 2025-10-21DOI: 10.1038/s41556-025-01788-6
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
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. Kraft, Murphy, Jones et al. identify extrachromosomal DNA (ecDNA)-interacting elements (EIEs) enriched for transposable elements within ecDNA in colorectal cancer cells. They show that EIE 14 integrated within ecDNA acts as an enhancer to promote cancer fitness.
{"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":"10.1038/s41556-025-01788-6","url":null,"abstract":"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. Kraft, Murphy, Jones et al. identify extrachromosomal DNA (ecDNA)-interacting elements (EIEs) enriched for transposable elements within ecDNA in colorectal cancer cells. They show that EIE 14 integrated within ecDNA acts as an enhancer to promote cancer fitness.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1914-1924"},"PeriodicalIF":19.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01788-6.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1038/s41556-025-01786-8
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
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. Watt, Dauber, Szkop and colleagues find that H3K4me3 remodels 5′UTR selection in hypoxia and that this process is independent of HIF-1 transcriptional mechanisms.
{"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":"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. Watt, Dauber, Szkop and colleagues find that H3K4me3 remodels 5′UTR selection in hypoxia and that this process is independent of HIF-1 transcriptional mechanisms.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1965-1981"},"PeriodicalIF":19.1,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01786-8.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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. The authors identify a chemical cocktail to generate totipotent-like cells, which they then use to build an embryo model. This model captures a developmental spectrum from early embryogenesis to post-implantation events.
{"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":"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. The authors identify a chemical cocktail to generate totipotent-like cells, which they then use to build an embryo model. This model captures a developmental spectrum from early embryogenesis to post-implantation events.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1993-2006"},"PeriodicalIF":19.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01793-9.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1038/s41556-025-01771-1
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
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.
{"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}
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