{"title":"Early infiltration of ischemia-conditioned Tregs attenuates BBB damage via suppressing neutrophil extracellular traps in ischemic stroke.","authors":"Huaming Li, Xiaotao Zhang, Jianan Lu, Lingxiao Lu, Jiarui Chen, An Ping, Yimin Lu, Ziyang Jin, Shenjie Tang, Rui Wang, Yichen Gu, Junjie Wang, Zhouhan Xu, Qia Zhang, Weimin Luan, Xuejiao Dai, Jianmin Zhang, Ligen Shi","doi":"10.1016/j.celrep.2026.118102","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118102","url":null,"abstract":"<p><p>Regulatory T cells (Tregs) modulate myeloid cells but are absent early after ischemic stroke when neutrophil infiltration peaks. Whether promoting their early infiltration into the brain as an introduced niche could modulate the cerebral immune micromilieu remains unknown. Here, we show that splenic Tregs at day 5 post-MCAO (ischemia-conditioned Tregs, ICTregs) exhibit enhanced adhesion. Transferred ICTregs infiltrate the infarcted area early, alter brain cellular composition, reduce neutrophil extracellular traps (NETs) and preserve blood-brain barrier (BBB) integrity during the acute phase. Mechanistically, integrin α4 anchors ICTregs to cerebral venous endothelium, and ICTreg Annexin A1 interacts with neutrophil Dectin-1 to suppress NETs. The transcription factor Ikzf2 is critical for ICTreg induction, and modulating Ikzf2 enables Sham Tregs to acquire early brain-homing capacity. These findings offer valuable insights into the neuroprotective function of ICTregs in the early stage of ischemic stroke and identify engineered-Tregs target for optimizing the brain-immune ecosystem for neural protection.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118102"},"PeriodicalIF":7.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163654","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}
Cell reportsPub Date : 2026-10-09DOI: 10.1016/j.celrep.2026.118025
Nikita Gryzunov, Dmitry Penzar, Vasilii Kamenets, Valery Vyaltsev, Ivan Kozin, Irina A Eliseeva, Vladimir Nozdrin, Ilya E Vorontsov, Sergey Bushuev, Vadim Strekalovskikh, Arsenii Zinkevich, Gregory Andrews, Matwej Bedarew, Ido Blass, Dmitry Frolov, Iuliia Lariushina, Jill Moore, Yaron Orenstein, German Roev, Danil Salimov, Noam Shimshoviz, Ido Tziony, Zhiping Weng, Philipp Bucher, Bart Deplancke, Oriol Fornes, Jan Grau, Ivo Grosse, Arttu Jolma, Fedor A Kolpakov, Vsevolod J Makeev, Timothy R Hughes, Ivan V Kulakovskiy
{"title":"Inferring binding specificities of human transcription factors with the wisdom of crowds.","authors":"Nikita Gryzunov, Dmitry Penzar, Vasilii Kamenets, Valery Vyaltsev, Ivan Kozin, Irina A Eliseeva, Vladimir Nozdrin, Ilya E Vorontsov, Sergey Bushuev, Vadim Strekalovskikh, Arsenii Zinkevich, Gregory Andrews, Matwej Bedarew, Ido Blass, Dmitry Frolov, Iuliia Lariushina, Jill Moore, Yaron Orenstein, German Roev, Danil Salimov, Noam Shimshoviz, Ido Tziony, Zhiping Weng, Philipp Bucher, Bart Deplancke, Oriol Fornes, Jan Grau, Ivo Grosse, Arttu Jolma, Fedor A Kolpakov, Vsevolod J Makeev, Timothy R Hughes, Ivan V Kulakovskiy","doi":"10.1016/j.celrep.2026.118025","DOIUrl":"10.1016/j.celrep.2026.118025","url":null,"abstract":"<p><p>DNA motif discovery and, particularly, computational modeling of transcription factor binding motifs, has been a mecca of algorithmic bioinformatics for several decades. Here, we report the results of the largest open community challenge in Inferring BInding Specificities (IBIS), where participants all over the world were invited to construct binding specificity models from multi-assay experimental data for poorly studied human transcription factors. The submissions were rigorously tested against a rich held-out dataset. Benchmarking demonstrated a consistent advantage of properly designed deep learning models over traditional positional weight matrices and other machine learning methods. Yet, the positional weight matrices displayed a surprisingly strong performance out of the box, being only slightly behind the best deep learning models. A post-challenge assessment of a selection of other deep learning methods further solidified this finding. IBIS highlights the power of benchmarking in finding adequate DNA motif representations, emphasizes the pros and cons of various machine learning methods applied to DNA motif modeling, and establishes a rich dataset, benchmarking protocols, and computational framework for a fair cross-platform evaluation of future models of transcription factor binding motifs in DNA sequences.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118025"},"PeriodicalIF":7.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147696","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}
Cell reportsPub Date : 2026-10-08DOI: 10.1016/j.celrep.2026.118110
Chenxu Zhu, Sylvie Manuse, Quentin Perrier, Subhasree Venkatasubramaniyan, Houssam Akherraz, Norbert Lodej, Cathy I Ramos, Meiling Zhang, Christophe Grangeasse, Agnieszka Razim, François Leulier, Renata C Matos
{"title":"Host-triggered prophage induction drives Lactiplantibacillus plantarum symbiosis through bacterial lysis.","authors":"Chenxu Zhu, Sylvie Manuse, Quentin Perrier, Subhasree Venkatasubramaniyan, Houssam Akherraz, Norbert Lodej, Cathy I Ramos, Meiling Zhang, Christophe Grangeasse, Agnieszka Razim, François Leulier, Renata C Matos","doi":"10.1016/j.celrep.2026.118110","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118110","url":null,"abstract":"<p><p>The release of bacterial bioactive molecules across the gut barrier is a crucial yet poorly understood step in host-microbe communication. Here, we identify a phage-driven mechanism associated with this process in the beneficial symbiont Lactiplantibacillus plantarum NC8 (Lp<sup>NC8</sup>). We show that a stress-responsive prophage, pp2, undergoes activation and triggers holin-lysin-mediated bacterial lysis, leading to the production of infectious phage particles and increased extracellular recovery of bacterial vesicles carrying lipoteichoic acids. In a model of nutritional symbiosis, pp2-dependent lysis is required for Lp<sup>NC8</sup> to promote juvenile growth in undernourished Drosophila melanogaster. Disruption of prophage-mediated lysis impairs vesicle recovery and host growth promotion. Furthermore, we demonstrate that the copper cell region of the Drosophila midgut acts as a physiological trigger of prophage induction. Together, our findings link host intestinal physiology to prophage activity and bacterial lysis, revealing phage-driven lysis as a mechanism contributing to beneficial bacterial-host interactions during nutritional stress.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118110"},"PeriodicalIF":7.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135042","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}
Cell reportsPub Date : 2026-10-08DOI: 10.1016/j.celrep.2026.118108
Chuan Jiang, Wenwen Zhu, Per Alström, Yanchun Xu, Yang Zhou, Jiazheng Jin, Nassoro Mohamed, Yue Ma, Suying Bai, Yang Liu, Bo Li
{"title":"Introgression catalyzing plumage evolution and speciation in an Asian songbird complex.","authors":"Chuan Jiang, Wenwen Zhu, Per Alström, Yanchun Xu, Yang Zhou, Jiazheng Jin, Nassoro Mohamed, Yue Ma, Suying Bai, Yang Liu, Bo Li","doi":"10.1016/j.celrep.2026.118108","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118108","url":null,"abstract":"<p><p>Hybridization and introgression can promote speciation and phenotypic diversity. We investigated genomic divergence between two closely related Asian songbirds, Naumann's Thrush (Turdus naumanni, Nau) and Dusky Thrush (T. eunomus, Eun), and their evolutionary relationship with the geographically adjacent Red-throated Thrush (T. ruficollis, Ruf). Utilizing a de novo chromosome-level genome and whole-genome resequencing data from 66 individuals, we characterized differentiation and introgression among the three species. Genomic divergence between Nau and Eun was restricted to a few genomic islands that overlap with regions introgressed into Nau from Ruf. Notably, these regions harbor three melanin-related genes under strong selection in Nau (ASIP, OCA2, and HERC2), which may account for the plumage similarity between Nau and Ruf. These findings suggest that the morphological and genetic divergence between Nau and Eun may have been driven by adaptive introgression of melanin-related genes from Ruf into Nau. This study reveals how introgression can generate rapid genomic and phenotypic divergence, indicating a potentially ubiquitous yet overlooked speciation mechanism.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118108"},"PeriodicalIF":7.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135045","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}
Cell reportsPub Date : 2026-10-07DOI: 10.1016/j.celrep.2026.118100
Stephanie Vargas Aguilar, Matthieu Dos Santos, Wei Tan, Efrain Sanchez-Ortiz, Kenian Chen, Hui Li, Lin Xu, Ning Liu, Eric N Olson
{"title":"A developmentally restricted γδ T cell-IL-17A axis supports mouse heart regeneration.","authors":"Stephanie Vargas Aguilar, Matthieu Dos Santos, Wei Tan, Efrain Sanchez-Ortiz, Kenian Chen, Hui Li, Lin Xu, Ning Liu, Eric N Olson","doi":"10.1016/j.celrep.2026.118100","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118100","url":null,"abstract":"<p><p>Mammalian heart regeneration is restricted to a brief postnatal period during which neonatal-specific mechanisms, including a tightly regulated immune response, enable tissue repair. Here, we show that cardiac injury during the regenerative window induces the accumulation of a distinct γδ T cell population that is absent from older, non-regenerative hearts. Following injury, these cells serve as a rapid source of IL-17A, which shapes the timing and composition of the neonatal immune response. Genetic ablation of γδ T cells or disruption of IL-17 signaling limits heart regeneration and results in dysregulated immune cell infiltration and impaired cardiac function. Mechanistically, our data suggest that γδ T cell-derived IL-17A acts on myeloid cells to initiate a rapid, self-limited inflammatory response that facilitates apoptotic cell clearance and limits sustained inflammation. Our study identifies a developmentally restricted immune axis that supports heart regeneration and advances our understanding of how neonatal-specific immune circuits shape tissue repair.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118100"},"PeriodicalIF":7.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126697","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}
Cell reportsPub Date : 2026-10-07DOI: 10.1016/j.celrep.2026.118101
Andrew J Fritz, Haley Greenyer, Louis Dillac, Priyanka Chavarkar, Akshay Neeli, Rahim Ullah, Miles Malik, Deli Hong, Rabail Toor, Emory Pacht, Abigail G Person, Georgiy Zotkin, Sadie Korzec, Cong Gao, Alquassem Abuorquob, Janine Warren, Jackson Del Porto, Jonah Perelman, Martin Montecino, Jane B Lian, Andre Van Wijnen, Jessica Heath, Prachi Ghule, Seth Frietze, Zaidi Sayyed, Kristy Stengel, Scott Hiebert, Kathleen Reed, Thomas Misteli, Jonathan A Gordon, Janet L Stein, Gary S Stein
{"title":"Acute degron-mediated RUNX1 loss reprograms enhancer activity associated with epithelial destabilization and initiation of cancer hallmarks.","authors":"Andrew J Fritz, Haley Greenyer, Louis Dillac, Priyanka Chavarkar, Akshay Neeli, Rahim Ullah, Miles Malik, Deli Hong, Rabail Toor, Emory Pacht, Abigail G Person, Georgiy Zotkin, Sadie Korzec, Cong Gao, Alquassem Abuorquob, Janine Warren, Jackson Del Porto, Jonah Perelman, Martin Montecino, Jane B Lian, Andre Van Wijnen, Jessica Heath, Prachi Ghule, Seth Frietze, Zaidi Sayyed, Kristy Stengel, Scott Hiebert, Kathleen Reed, Thomas Misteli, Jonathan A Gordon, Janet L Stein, Gary S Stein","doi":"10.1016/j.celrep.2026.118101","DOIUrl":"10.1016/j.celrep.2026.118101","url":null,"abstract":"<p><p>RUNX1 coordinates phenotypic gene expression, and its suppression or perturbations are associated with breast tumor initiation and progression. Mechanisms governing the dual roles of RUNX1 in sustaining the mammary epithelial phenotype while suppressing initiation of cancer-compromised gene expression are unclear. Degron-mediated acute, selective, and complete RUNX1 ablation in human mammary epithelial cells reveals promoter and distal enhancer-driven expression of a gene cohort. RUNX1 ablation rapidly and selectively decreases chromatin accessibility and H3K27ac at RUNX1-bound enhancers but not promoters. While differentially initiated and expressed genes contacted by RUNX1-bound enhancers are enriched in epithelial maintenance and stemness pathways, genes with RUNX1-promoter occupancy support DNA damage responsiveness. Modified cell morphology, metabolic control, breast cancer stemness, plasticity, anchorage-independent survival, chemoresistance, and perturbed DNA damage reactivity are observed upon RUNX1 ablation. These findings define RUNX1 as a tumor suppressor maintaining epithelial cell state, preserving enhancer activity to prevent gene expression associated with cancer hallmarks.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118101"},"PeriodicalIF":7.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126719","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}
Cell reportsPub Date : 2026-10-07DOI: 10.1016/j.celrep.2026.118104
Hyun Ju Lee, Jung Hwa Ko, Jin Suk Ryu, Joo Youn Oh
{"title":"HIF-1α-driven lactate from mesenchymal stem/stromal cells reprograms monocyte metabolism and suppresses autoimmune uveoretinitis.","authors":"Hyun Ju Lee, Jung Hwa Ko, Jin Suk Ryu, Joo Youn Oh","doi":"10.1016/j.celrep.2026.118104","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118104","url":null,"abstract":"<p><p>Metabolic reprogramming of immune cells is emerging as a therapeutic strategy for autoimmune diseases. Here, we identify mesenchymal stem/stromal cell (MSC)-derived lactate as a signaling metabolite that reprograms monocyte metabolism and differentiation. GM-CSF enhanced glycolytic activity in bone marrow cells and expanded pro-inflammatory monocytes, whereas pharmacologic inhibition of glycolysis with 2-deoxy-D-glucose reversed these effects. MSC coculture suppressed glycolytic activation and redirected monocyte differentiation toward an immunosuppressive phenotype. MSCs produced lactate in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, and blocking lactate production through oxamate treatment or HIF1A knockdown attenuated the effects of MSCs on differentiating monocytes, whereas exogenous lactate recapitulated them. In experimental autoimmune uveoretinitis, intravenous administration of MSCs ameliorated the disease, but oxamate-pretreated or HIF1A-knockdown MSCs exhibited reduced efficacy. The HIF-1α-lactate axis may therefore represent a targetable pathway for optimizing MSC-based therapies and for developing lactate-centered interventions in autoimmune diseases.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118104"},"PeriodicalIF":7.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126687","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}
Cell reportsPub Date : 2026-10-07DOI: 10.1016/j.celrep.2026.118105
Paul E Schavemaker, Kaitlyn S Tam, Michael Lynch
{"title":"Quantifying the energetic costs and growth benefits of phagocytosis.","authors":"Paul E Schavemaker, Kaitlyn S Tam, Michael Lynch","doi":"10.1016/j.celrep.2026.118105","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118105","url":null,"abstract":"<p><p>Phagocytosis, the ingestion of cells by other cells, is ubiquitous among eukaryotic life. It is utilized for food uptake and in the immune response in many species. The origin of phagocytosis and its role in the evolution of endomembranes and the eukaryotic cell remains obscure. Drawing on a wealth of empirical data, we integrate prey capture, engulfment, and internal and external digestion into a mathematical model that quantifies the cellular performance of a primitive phagocytoser relative to a non-phagocytosing ancestor. The primitive phagocytoser can outperform the ancestor in a range of situations. The rate of engulfment delineates when phagocytosis is advantageous, providing clear benchmarks for interpreting the importance of results in genetic knockout studies and mechanical models. The phagocytoser even outperforms the ancestor when food vacuoles cannot be recycled. The model suggests plausible waypoints for the evolution of phagocytosis and the eukaryotic endomembrane system.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118105"},"PeriodicalIF":7.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126780","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}
Cell reportsPub Date : 2026-10-07DOI: 10.1016/j.celrep.2026.118082
Safder S Ganaie, Farheen Fatma, Zhengzheng Hu, Marco Grodzki, Rachael E Rush, Jennifer Clees, Griffin Brown, Olivia Barreca, Xiaoxia Cui, Byoung-Kyu Cho, Young Ah Goo, Amy L Hartman, Daisy W Leung, Gaya K Amarasinghe
{"title":"SNX17 facilitates entry and infection of Rift Valley fever virus and related bunyaviruses.","authors":"Safder S Ganaie, Farheen Fatma, Zhengzheng Hu, Marco Grodzki, Rachael E Rush, Jennifer Clees, Griffin Brown, Olivia Barreca, Xiaoxia Cui, Byoung-Kyu Cho, Young Ah Goo, Amy L Hartman, Daisy W Leung, Gaya K Amarasinghe","doi":"10.1016/j.celrep.2026.118082","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118082","url":null,"abstract":"<p><p>Bunyaviruses are a group of multisegmented, negative-sense RNA viruses. Rift Valley fever virus (RVFV) is a representative member that can cause sporadic human outbreaks. We previously identified low-density lipoprotein receptor-related protein 1 (LRP1) as a host entry factor for RVFV and several bunyaviruses. This screen also identified additional factors as proviral host proteins, including sorting nexin 17 (SNX17). Here, we describe efforts to characterize SNX17 in bunyaviral infection. Our findings reveal that the removal of SNX17 results in a substantial reduction of RVFV infection in SNX17 knockout (KO) cells. Further analysis revealed that SNX17 removal resulted in a reduction but not complete elimination of LRP1 expression. Importantly, SNX17 interacts with full-length RVFV Gc and, upon infection by RVFV, co-migrates with RVFV to late endosomes. In addition to RVFV, several other bunyaviruses also appear to be dependent on SNX17 for infection, suggesting a potential broader role for SNX17 in bunyaviral entry.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118082"},"PeriodicalIF":7.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134990","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}
Cell reportsPub Date : 2026-10-07DOI: 10.1016/j.celrep.2026.118111
Robin H Oh, Kevin C L Cheng, Evgenija Serafimova, Ellen Langille, Miguel Ángel Pérez-Castro, Christopher Lowden, Jocelyn Nurtanto, Julien Dessapt, Iosifina Fotiadou, Shahan Haider, Jacob Berman, Ricky Tsai, Ahmad Malik, Liis Uusküla-Reimand, Sampath K Loganathan, Khalid N Al-Zahrani, Jüri Reimand, Daniel Schramek
{"title":"Functional identification of non-coding regulatory regions that drive breast and skin carcinogenesis.","authors":"Robin H Oh, Kevin C L Cheng, Evgenija Serafimova, Ellen Langille, Miguel Ángel Pérez-Castro, Christopher Lowden, Jocelyn Nurtanto, Julien Dessapt, Iosifina Fotiadou, Shahan Haider, Jacob Berman, Ricky Tsai, Ahmad Malik, Liis Uusküla-Reimand, Sampath K Loganathan, Khalid N Al-Zahrani, Jüri Reimand, Daniel Schramek","doi":"10.1016/j.celrep.2026.118111","DOIUrl":"https://doi.org/10.1016/j.celrep.2026.118111","url":null,"abstract":"<p><p>Whole-genome sequencing has revealed hundreds of cancer driver mutations in protein-coding genes, while our knowledge of how non-coding mutations contribute to tumorigenesis remains limited. Here, we develop and perform large-scale functional screens to identify non-coding regulatory elements whose mutations drive cancer development in non-transformed human breast epithelial cells and mouse models of breast and skin cancer. We identify 12 frequently mutated regulatory elements associated with 16 genes as candidate cancer drivers. Mechanistically, we characterize two elements associated with the microRNA MIR21 and the tumor suppressor gene, ZFP36L2. Mutating these regulatory elements dysregulates the expression of MIR21 and ZFP36L2, thereby leading to oncogenic transformation. We identify ZFP36L2 as a p53 target gene and find that mutating the p53-binding motif in the ZFP36L2 promoter is sufficient to drive tumorigenesis. Conceptually, our data indicate that cancer driver mutations in non-coding regulatory elements are much more prevalent and potent than initially assumed.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118111"},"PeriodicalIF":7.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134946","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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