Pub Date : 2025-12-10DOI: 10.1038/s41556-025-01847-y
Daryl J. V. David
{"title":"Zippering against the beat","authors":"Daryl J. V. David","doi":"10.1038/s41556-025-01847-y","DOIUrl":"10.1038/s41556-025-01847-y","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2040-2040"},"PeriodicalIF":19.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723786","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 : 2025-12-10DOI: 10.1038/s41556-025-01843-2
Our study showed that lineage-determining transcription factors, such as EBF1 in B cell lymphoma and TCF1 in T cell leukaemia, shape 3D genome architecture by constraining cohesin movement. Cohesin in turn positions enhancers at the spatial centres of oncogenic loci and enables multi-enhancer regulation of key oncogenes. Together, these findings identify a unifying mechanism that links transcription factor activity, chromatin topology and oncogene control.
{"title":"Lineage-determining transcription factors EBF1 and TCF1 shape chromatin fibre folding","authors":"","doi":"10.1038/s41556-025-01843-2","DOIUrl":"10.1038/s41556-025-01843-2","url":null,"abstract":"Our study showed that lineage-determining transcription factors, such as EBF1 in B cell lymphoma and TCF1 in T cell leukaemia, shape 3D genome architecture by constraining cohesin movement. Cohesin in turn positions enhancers at the spatial centres of oncogenic loci and enables multi-enhancer regulation of key oncogenes. Together, these findings identify a unifying mechanism that links transcription factor activity, chromatin topology and oncogene control.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"11-12"},"PeriodicalIF":19.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718003","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 : 2025-12-09DOI: 10.1038/s41556-025-01820-9
Zhouyang Shen, Zaza Gelashvili, Philipp Niethammer
Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca²⁺-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN– or cPLA2–INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER–nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger. Shen, Gelashvili and Niethammer developed an inner nuclear membrane tension sensor and demonstrated that ER–nuclear membrane contiguity acts as a mechanical buffer.
{"title":"Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction","authors":"Zhouyang Shen, Zaza Gelashvili, Philipp Niethammer","doi":"10.1038/s41556-025-01820-9","DOIUrl":"10.1038/s41556-025-01820-9","url":null,"abstract":"Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca²⁺-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN– or cPLA2–INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER–nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger. Shen, Gelashvili and Niethammer developed an inner nuclear membrane tension sensor and demonstrated that ER–nuclear membrane contiguity acts as a mechanical buffer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"125-134"},"PeriodicalIF":19.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01820-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705138","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 : 2025-12-05DOI: 10.1038/s41556-025-01824-5
Ruth R. Cheng, Rebecca L. Bradford
For a century, the American Type Culture Collection (ATCC) has been an essential resource for biologists, fuelling discoveries in areas from cancer to infectious diseases. In this Comment, we outline ATCC’s key role in setting global standards and championing innovation and quality in biological research.
{"title":"A foundation for tomorrow’s discoveries in cell biology","authors":"Ruth R. Cheng, Rebecca L. Bradford","doi":"10.1038/s41556-025-01824-5","DOIUrl":"10.1038/s41556-025-01824-5","url":null,"abstract":"For a century, the American Type Culture Collection (ATCC) has been an essential resource for biologists, fuelling discoveries in areas from cancer to infectious diseases. In this Comment, we outline ATCC’s key role in setting global standards and championing innovation and quality in biological research.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2033-2035"},"PeriodicalIF":19.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680115","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 : 2025-12-03DOI: 10.1038/s41556-025-01831-6
Irene Zorzan, Elena Carbognin, Andrea Lauria, Valentina Proserpio, Davide Benvegnù, Federica Bertelli, Susana De Juambelz Urías, Caterina Dalrio, Giorgia Panebianco, Rebecca Scarfò, Eleonora Pensabene, Mattia Arboit, Irene Paolucci, Andrea Drusin, Dario Bizzotto, Monika Sledziowska, Paola Braghetta, Andrea Ditadi, Gianluca Amadei, Salvatore Oliviero, Graziano Martello
Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN—a distinct TGFβ family ligand—induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity. The authors optimize an in vitro human epiblast model, which they utilize to show that early TGFβ family inhibition prevents epithelial identity, whereas it is dispensable after epithelium formation. These phenomena are conserved in mice.
{"title":"A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development","authors":"Irene Zorzan, Elena Carbognin, Andrea Lauria, Valentina Proserpio, Davide Benvegnù, Federica Bertelli, Susana De Juambelz Urías, Caterina Dalrio, Giorgia Panebianco, Rebecca Scarfò, Eleonora Pensabene, Mattia Arboit, Irene Paolucci, Andrea Drusin, Dario Bizzotto, Monika Sledziowska, Paola Braghetta, Andrea Ditadi, Gianluca Amadei, Salvatore Oliviero, Graziano Martello","doi":"10.1038/s41556-025-01831-6","DOIUrl":"10.1038/s41556-025-01831-6","url":null,"abstract":"Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN—a distinct TGFβ family ligand—induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity. The authors optimize an in vitro human epiblast model, which they utilize to show that early TGFβ family inhibition prevents epithelial identity, whereas it is dispensable after epithelium formation. These phenomena are conserved in mice.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"49-65"},"PeriodicalIF":19.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664069","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 : 2025-12-02DOI: 10.1038/s41556-025-01812-9
Toshiya Kozai, Javier Fernandez-Martinez, Larisa E. Kapinos, Paola Gallardo, Trevor van Eeuwen, Martin Saladin, Roi Eliasian, Adam Mazur, Wenzhu Zhang, Jeremy Tempkin, Radhakrishnan Panatala, Maria Delgado-Izquierdo, Raul Escribano-Marin, Qingzhou Feng, Chenxiang Lin, Andrej Sali, Brian T. Chait, Barak Raveh, Liesbeth M. Veenhoff, Michael P. Rout, Roderick Y. H. Lim
Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies. Kozai, Fernandez-Martinez et al. use high-speed atomic force microscopy to study the permeability barrier of yeast nuclear pore complexes. They show that karyopherins remodel a central plug that shapes barrier dynamics and disorder within the pore.
{"title":"Karyopherins remodel the dynamic organization of the nuclear pore complex transport barrier","authors":"Toshiya Kozai, Javier Fernandez-Martinez, Larisa E. Kapinos, Paola Gallardo, Trevor van Eeuwen, Martin Saladin, Roi Eliasian, Adam Mazur, Wenzhu Zhang, Jeremy Tempkin, Radhakrishnan Panatala, Maria Delgado-Izquierdo, Raul Escribano-Marin, Qingzhou Feng, Chenxiang Lin, Andrej Sali, Brian T. Chait, Barak Raveh, Liesbeth M. Veenhoff, Michael P. Rout, Roderick Y. H. Lim","doi":"10.1038/s41556-025-01812-9","DOIUrl":"10.1038/s41556-025-01812-9","url":null,"abstract":"Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies. Kozai, Fernandez-Martinez et al. use high-speed atomic force microscopy to study the permeability barrier of yeast nuclear pore complexes. They show that karyopherins remodel a central plug that shapes barrier dynamics and disorder within the pore.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2089-2101"},"PeriodicalIF":19.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01812-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656996","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 : 2025-12-02DOI: 10.1038/s41556-025-01757-z
Robert J. Torphy, Yuliya Pylayeva-Gupta
Targeting oncogenic KRAS holds great promise but is often limited by rapid adaptive resistance. A study now shows that RASH3D19 is regulated by microRNAs and promotes resistance to RAS inhibition by enhancing EGFR dimerization. Targeting RASH3D19 improves sensitivity to RAS inhibitors in preclinical settings.
{"title":"Deciphering KRAS inhibitor resistance","authors":"Robert J. Torphy, Yuliya Pylayeva-Gupta","doi":"10.1038/s41556-025-01757-z","DOIUrl":"10.1038/s41556-025-01757-z","url":null,"abstract":"Targeting oncogenic KRAS holds great promise but is often limited by rapid adaptive resistance. A study now shows that RASH3D19 is regulated by microRNAs and promotes resistance to RAS inhibition by enhancing EGFR dimerization. Targeting RASH3D19 improves sensitivity to RAS inhibitors in preclinical settings.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"8-10"},"PeriodicalIF":19.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661589","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 : 2025-12-02DOI: 10.1038/s41556-025-01827-2
Yeqiao Zhou, Atishay Jay, Noah Burget, Tobias Friedrich, Sora Yoon, Jessica Alsing, Guy Nir, Rudolf Grosschedl, Golnaz Vahedi, Robert B. Faryabi
Multiple enhancers, often separated by vast genomic distances, regulate key genes. However, how the folding of individual chromatin fibres enables cell-type-restricted multi-enhancer regulation remains unclear. Here, using acute protein degradation and time-resolved chromatin conformation capture in mantle cell lymphoma, we found that the B cell-lineage-determining factor EBF1 organizes multiple enhancers around sparsely distributed genes essential for B cell identity and oncogenesis. Time-resolved sub-diffraction optical tracing of more than 100,000 chromatin fibres further revealed diverse topological conformations that facilitate multi-enhancer interactions. Mechanistically, we discovered that enhancer positioning at local topological centres is required for promoter engagement, with EBF1 acting as a permeable barrier to loop-extruding cohesin at enhancers. Extending these findings to T cell leukaemia, we show that lineage-determining transcription factors such as EBF1 and TCF1 radially position enhancers within gene loci to enable multi-enhancer regulation of key oncogenes at the single-allele level. Zhou, Jay et al. report that in mantle cell lymphoma and T cell leukaemia, lineage-determining transcription factors share a mechanism to regulate how multiple enhancers control oncogene expression through topological conformation and interaction.
{"title":"Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation","authors":"Yeqiao Zhou, Atishay Jay, Noah Burget, Tobias Friedrich, Sora Yoon, Jessica Alsing, Guy Nir, Rudolf Grosschedl, Golnaz Vahedi, Robert B. Faryabi","doi":"10.1038/s41556-025-01827-2","DOIUrl":"10.1038/s41556-025-01827-2","url":null,"abstract":"Multiple enhancers, often separated by vast genomic distances, regulate key genes. However, how the folding of individual chromatin fibres enables cell-type-restricted multi-enhancer regulation remains unclear. Here, using acute protein degradation and time-resolved chromatin conformation capture in mantle cell lymphoma, we found that the B cell-lineage-determining factor EBF1 organizes multiple enhancers around sparsely distributed genes essential for B cell identity and oncogenesis. Time-resolved sub-diffraction optical tracing of more than 100,000 chromatin fibres further revealed diverse topological conformations that facilitate multi-enhancer interactions. Mechanistically, we discovered that enhancer positioning at local topological centres is required for promoter engagement, with EBF1 acting as a permeable barrier to loop-extruding cohesin at enhancers. Extending these findings to T cell leukaemia, we show that lineage-determining transcription factors such as EBF1 and TCF1 radially position enhancers within gene loci to enable multi-enhancer regulation of key oncogenes at the single-allele level. Zhou, Jay et al. report that in mantle cell lymphoma and T cell leukaemia, lineage-determining transcription factors share a mechanism to regulate how multiple enhancers control oncogene expression through topological conformation and interaction.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"149-165"},"PeriodicalIF":19.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661596","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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