Nature Cell Biology最新文献

{"title":"Cracking glioblastoma core regulatory codes","authors":"Yonglong Dang, Yuk Kit Lor, Gonçalo Castelo-Branco","doi":"10.1038/s41556-025-01780-0","DOIUrl":"10.1038/s41556-025-01780-0","url":null,"abstract":"Glioblastoma (GBM) heterogeneity might arise because of the activation of various gene core regulatory circuitries (CRCs). A new study highlights the central role of HOXB3 in GBM CRCs and how peptide-mediated perturbation of HOXB3-related CRCs in GBM holds potential as treatment for a subset of patients.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1600-1602"},"PeriodicalIF":19.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200369","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":"Defining heterogeneity in core regulatory circuitry reveals HOXB3 condensation as a potential target in glioblastoma","authors":"Chuanxia Zhang, Yijing He, Xiudan Zhan, Jiaming Yu, Shao Xu, Qinkai Zhang, Ru Qiu, Xinyue Wang, Zhuoxing Gao, Meng Huang, Wenyong Long, Qing Liu, Wei Zhao","doi":"10.1038/s41556-025-01758-y","DOIUrl":"10.1038/s41556-025-01758-y","url":null,"abstract":"Glioblastoma (GBM) exhibits marked heterogeneity, yet therapeutic strategies effectively targeting this variability remain inadequately developed. Here we employed single-cell CUT&Tag analysis to investigate H3K27ac modifications, uncovering pronounced heterogeneity within the core regulatory circuitry (CRC) of GBM. Notably, we observed heterogeneous condensation states of CRC factors, particularly HOXB3, which are shaped by its intrinsically disordered regions and interactions with RUNX1, driving the phenotypic manifestations. Leveraging these findings, we synthesized the peptide P621-R9, which effectively disrupted HOXB3 condensation, altered chromatin structure and reduced transcription at super-enhancer-associated oncogenic sites in GBM cells exhibiting HOXB3 condensation. Treatment with P621-R9 selectively diminished tumourigenic potential in GBM patient-derived xenograft models characterized by HOXB3 condensates, but showed no efficacy in the models lacking these condensates. These results highlight the critical role of CRC condensation in GBM heterogeneity and suggest that peptide-based targeting of distinct GBM subpopulations could represent an avenue for therapeutic exploration. Zhang et al. delineate the heterogeneity of core regulatory circuitry in glioblastoma and identify HOXB3 condensation as a vulnerability that may be targeted with a therapeutic peptide in mouse models.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1848-1862"},"PeriodicalIF":19.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194794","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":"Phase-separated NDF-FACT condensates facilitate transcription elongation on chromatin.","authors":"Ziwei Li,Francesca Burgos-Bravo,Kevin Xu,Chen Li,Kelvin Y Kwan,Alexander B Tong,Zelin Shan,Huan Wang,Motoki Takaku,Joey Li,Zheng Shi,Dmitry Lyumkis,Carlos Bustamante,Jia Fei","doi":"10.1038/s41556-025-01778-8","DOIUrl":"https://doi.org/10.1038/s41556-025-01778-8","url":null,"abstract":"How the facilitates chromatin transcription (FACT) complex enables RNA polymerase II to overcome chromatin barriers in cells remains poorly understood-especially given the limited direct interactions of FACT with polymerases, DNA or nucleosomes. Here we demonstrate that phase separation, mediated by nucleosome destabilizing factor (NDF), is a key mechanism enabling the function of FACT during transcription elongation. Through biochemical and single-molecule assays, we found that NDF-FACT condensates create specialized biochemical environments that enhance transcription efficiency approximately 20-fold compared with FACT alone. These dynamic condensates form on transcribing RNA polymerase II and travel along chromatin, where they promote efficient nucleosome disassembly at barriers while retaining histones on DNA to preserve chromatin integrity. In human stem cells, disruption of these condensates leads to genome-wide transcriptional defects and chromatin instability, mirroring the effects of FACT depletion. By showing that phase separation enhances FACT function during transcription elongation, our study reveals a key mechanism that preserves chromatin integrity and transcriptional homeostasis in human stem cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"32 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194795","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":"ER shaping closes the gap in wound healing","authors":"Craig Blackstone","doi":"10.1038/s41556-025-01779-7","DOIUrl":"10.1038/s41556-025-01779-7","url":null,"abstract":"During wound healing, epithelial gaps trigger curvature-dependent ER remodelling. Tubules form at convex cell edges and promote lamellipodial crawling, whereas ER sheets at concave edges support purse-string contractions. Cytoskeletal forces drive this reorganization and position the ER as a key mechanotransducer in tissue repair.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1592-1593"},"PeriodicalIF":19.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194796","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":"Forcing cell fate","authors":"Roberto Mayor","doi":"10.1038/s41556-025-01775-x","DOIUrl":"10.1038/s41556-025-01775-x","url":null,"abstract":"The transition of a pluripotent stem cell into a differentiated lineage is one of the most complex yet precisely orchestrated events in developmental biology. A study now reveals that mechanical and osmotic forces, long considered background players in guiding this transition, are essential regulators of chromatin accessibility and cell fate decisions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1594-1595"},"PeriodicalIF":19.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192192","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":"Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells","authors":"Kaitlin P. McCreery, Aki Stubb, Rebecca Stephens, Nadezda A. Fursova, Andrew Cook, Kai Kruse, Anja Michelbach, Leah C. Biggs, Adib Keikhosravi, Sonja Nykänen, Roosa Pulkkanen, Christel Hydén-Granskog, Jizhong Zou, Jan-Wilm Lackmann, Carien M. Niessen, Sanna Vuoristo, Yekaterina A. Miroshnikova, Sara A. Wickström","doi":"10.1038/s41556-025-01767-x","DOIUrl":"10.1038/s41556-025-01767-x","url":null,"abstract":"Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although signalling circuits and gene regulatory networks that regulate pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological changes and mechanical deformations to control state transitions remains a fundamental open question. Here we focus on two distinct models of pluripotency, preimplantation inner cell mass cells of human embryos and primed pluripotent stem cells, to discover that cell fate transitions associate with rapid, compaction-triggered changes in nuclear shape and volume. These phenotypical changes and the associated active deformation of the nuclear envelope arise from growth factor signalling-controlled changes in cytoskeletal confinement and chromatin mechanics. The resulting osmotic stress state triggers global transcriptional repression, macromolecular crowding and remodelling of nuclear condensates that prime chromatin for a cell fate transition by attenuating repression of differentiation genes. However, while this mechano-osmotic chromatin priming has the potential to accelerate fate transitions and differentiation, sustained biochemical signals are required for robust induction of specific lineages. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signalling and chromatin state to control cell fate transition dynamics. McCreery, Stubb et al. show that mechano-osmotic changes in the nucleus induce general transcriptional repression and prime chromatin for cell fate transitions by relieving repression of specific differentiation genes.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1757-1770"},"PeriodicalIF":19.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01767-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192268","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}

{"title":"Remote control of AMPK via extracellular adenosine controls tissue growth","authors":"Yao Zhang, Katrin Strassburger, Aurelio A. Teleman","doi":"10.1038/s41556-025-01764-0","DOIUrl":"10.1038/s41556-025-01764-0","url":null,"abstract":"Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a regulator of cellular catabolism that is activated by AMP. As AMP accumulates in cells with low ATP, AMPK is considered a stress-activated kinase. While studying organ growth during Drosophila development, we find that AMPK can also be activated by a signalling metabolite not related to stress. Specifically, we find that two physiological inputs known to regulate organ growth rates (ecdysone (a steroid hormone) and dietary protein) modulate expression of adenosine deaminase in the intestine. This, in turn, alters circulating adenosine levels. Circulating adenosine acts as a signalling molecule by entering cells, becoming phosphorylated to AMP and activating AMPK to inhibit organ growth. Thus, AMPK activity is regulated developmentally, and AMPK activity in one tissue can be remote controlled by another tissue via circulating adenosine. Notably, this mechanism accounts for half the effect of dietary protein on tissue growth rates in Drosophila. Zhang et al. demonstrate that AMPK can be activated by signalling metabolite, adenosine, under non-stress conditions during Drosophila development. The intestine regulates adenosine levels, thus, remotely controlling wing disc AMPK activation and growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1827-1837"},"PeriodicalIF":19.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01764-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153443","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}

{"title":"AMPK signalling integrated in growth control","authors":"Sebastian Rumpf, Neeraja Sanal","doi":"10.1038/s41556-025-01777-9","DOIUrl":"10.1038/s41556-025-01777-9","url":null,"abstract":"The AMP-dependent protein kinase AMPK is thought to be activated only when cellular energy levels are low. However, a study now finds that intracellular AMP is generated from extracellular adenosine in an intricate growth signalling cascade, explaining how AMPK can be regulated by extracellular cues.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1598-1599"},"PeriodicalIF":19.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153444","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":"ERCC6L2–CtIP condensation tunes end resection","authors":"Rongwei Zhao, Huaiying Zhang","doi":"10.1038/s41556-025-01772-0","DOIUrl":"10.1038/s41556-025-01772-0","url":null,"abstract":"ATM inhibitors (ATMi) cause cell death by enabling CtIP to induce excessive DNA resection. A study now shows that ERCC6L2 regulates resection by forming condensates with CtIP to prevent its degradation. Loss of ERCC6L2 decreases sensitivity to ATMi, which suggests that ERCC6L2 deficiency can be a biomarker for ATMi resistance.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1596-1597"},"PeriodicalIF":19.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176644","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":"Membrane receptors cluster phosphatidylserine to activate LC3-associated phagocytosis","authors":"Emilio Boada-Romero, Clifford S. Guy, Gustavo Palacios, Luigi Mari, Suresh Poudel, Zhenrui Li, Piyush Sharma, Douglas R. Green","doi":"10.1038/s41556-025-01749-z","DOIUrl":"10.1038/s41556-025-01749-z","url":null,"abstract":"LC3-associated phagocytosis (LAP) represents a non-canonical function of autophagy proteins in which ATG8-family proteins (LC3 and GABARAP proteins) are lipidated onto single-membrane phagosomes as particles are engulfed by phagocytic cells. LAP plays roles in innate immunity, inflammation and anticancer responses, and is initiated following phagocytosis of particles that stimulate Toll-like receptors (TLR) and Fc receptors as well as following engulfment of dying cells. However, how this molecular process is initiated remains elusive. Here we report that receptors that engage LAP enrich phosphatidylserine (PS) in the phagosome membrane via membrane-proximal domains that are necessary and sufficient for LAP to proceed. Subsequently, PS recruits the Rubicon-containing PI3-kinase complex to initiate the enzymatic cascade leading to LAP. Manipulation of plasma membrane PS content, PS binding by Rubicon or the PS-clustering domains of receptors prevents LAP and delays phagosome maturation. Therefore, the initiation of LAP represents a novel mechanism of PS-mediated signal transduction following ligation of surface receptors. Here the authors show that LC3-associated phagocytosis is initiated by various receptors, which enrich phosphatidylserine in the membrane domains proximal to the phagosome, recruiting Rubicon to the membrane for phagosome maturation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1676-1687"},"PeriodicalIF":19.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01749-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117057","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}