Pub Date : 2025-12-18DOI: 10.1038/s41588-025-02408-7
Georgios Kanellos, Chiara Giacomelli, Alexander Raven, Nikola Vlahov, Hu Jin, Pauline Herviou, Sudhir B. Malla, Nadia Nasreddin, Patricia P. Centeno, Constantinos Alexandrou, Kathryn Gilroy, Rachel L. Baird, Kathryn Pennel, June Munro, Joseph A. Waldron, Holly Hall, Leah Officer-Jones, Sheila Bryson, Douglas Strathdee, Sergio Lilla, Sara Zanivan, Vivienne Morrison, Colin Nixon, Rachel A. Ridgway, Crispin Miller, John R. P. Knight, Andrew D. Campbell, Philip D. Dunne, John Le Quesne, Joanne Edwards, Peter J. Park, Martin Bushell, Owen J. Sansom
Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5’-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers. Npm1 promotes tumor formation via attenuating the integrated stress response and p53 activation in mouse WNT-driven intestinal and liver tumorigenesis.
{"title":"Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation","authors":"Georgios Kanellos, Chiara Giacomelli, Alexander Raven, Nikola Vlahov, Hu Jin, Pauline Herviou, Sudhir B. Malla, Nadia Nasreddin, Patricia P. Centeno, Constantinos Alexandrou, Kathryn Gilroy, Rachel L. Baird, Kathryn Pennel, June Munro, Joseph A. Waldron, Holly Hall, Leah Officer-Jones, Sheila Bryson, Douglas Strathdee, Sergio Lilla, Sara Zanivan, Vivienne Morrison, Colin Nixon, Rachel A. Ridgway, Crispin Miller, John R. P. Knight, Andrew D. Campbell, Philip D. Dunne, John Le Quesne, Joanne Edwards, Peter J. Park, Martin Bushell, Owen J. Sansom","doi":"10.1038/s41588-025-02408-7","DOIUrl":"10.1038/s41588-025-02408-7","url":null,"abstract":"Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5’-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers. Npm1 promotes tumor formation via attenuating the integrated stress response and p53 activation in mouse WNT-driven intestinal and liver tumorigenesis.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"100-115"},"PeriodicalIF":29.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02408-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770712","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 : 2025-12-17DOI: 10.1038/s41588-025-02445-2
Kevin T. Mintz
In 1990, I was diagnosed with cerebral palsy. Like many in the community, my parents were told explicitly that the condition has no genetic roots. Now, as research suggests that up to 30% of cases have genetic etiologies, robust community engagement is needed to ensure that the perspectives of the community shape the future of genetic research into cerebral palsy.
{"title":"My call for community-engaged genetic research into cerebral palsy","authors":"Kevin T. Mintz","doi":"10.1038/s41588-025-02445-2","DOIUrl":"10.1038/s41588-025-02445-2","url":null,"abstract":"In 1990, I was diagnosed with cerebral palsy. Like many in the community, my parents were told explicitly that the condition has no genetic roots. Now, as research suggests that up to 30% of cases have genetic etiologies, robust community engagement is needed to ensure that the perspectives of the community shape the future of genetic research into cerebral palsy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"1-1"},"PeriodicalIF":29.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770713","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}
Enhancer-promoter (E-P) interactions regulate transcription during cell fate determination. However, the regulatory mechanisms underlying E-P interactions have remained elusive. Here we present a chromatin-interaction-based proteomic approach, LoopID, to profile proteins (termed the looposome) at certain E-P anchors. We find that histone demethylase JMJD2, a key looposome component, can regulate E-P interactions and the looposome in a catalytic-independent manner through formation of biomolecular condensates. Furthermore, we introduce a system to engineer E-P interactions by assembling JMJD2 condensates at certain genomic loci, enabling construction of cell-type-specific E-P interactions to promote cellular reprogramming into pluripotent or two-cell-like cells. Our findings reveal a noncanonical function of a histone demethylase in regulation of chromatin organization and provide a strategy to regulate cell fate transitions through E-P interactions.
{"title":"JMJD2 regulates enhancer-promoter interactions via biomolecular condensate formation.","authors":"Shaoshuai Jiang,Xinyi Liu,Zhuheng Zhang,Mingzhu Yang,Xing Zhu,Lin Ma,Longying Zhao,Xiaoru Ling,Ziqiang Zhou,Ziqiang Wu,Jiale Qu,Haochen Li,Jiawei Liang,Zhiheng Deng,Qi Tian,Xiaona Huang,Xianglin Huang,Jin Tan,Jun Sun,Jia Wang,Diana Guallar,Partha Pratim Das,Luca Pinello,Liang Wang,Hongfu Wu,Dong-Feng Huang,Jichang Wang,Hancheng Lin,Jin Bai,Lili Fan,Wei Chi,Xue Xiao,Junjun Ding","doi":"10.1038/s41588-025-02415-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02415-8","url":null,"abstract":"Enhancer-promoter (E-P) interactions regulate transcription during cell fate determination. However, the regulatory mechanisms underlying E-P interactions have remained elusive. Here we present a chromatin-interaction-based proteomic approach, LoopID, to profile proteins (termed the looposome) at certain E-P anchors. We find that histone demethylase JMJD2, a key looposome component, can regulate E-P interactions and the looposome in a catalytic-independent manner through formation of biomolecular condensates. Furthermore, we introduce a system to engineer E-P interactions by assembling JMJD2 condensates at certain genomic loci, enabling construction of cell-type-specific E-P interactions to promote cellular reprogramming into pluripotent or two-cell-like cells. Our findings reveal a noncanonical function of a histone demethylase in regulation of chromatin organization and provide a strategy to regulate cell fate transitions through E-P interactions.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"1 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765286","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 : 2025-12-16DOI: 10.1038/s41588-025-02477-8
Takeo Narita, Sinan Kilic, Yoshiki Higashijima, Natalie M. Scherer, Georgios Pappas, Elina Maskey, Chunaram Choudhary
{"title":"Author Correction: Disentangling the architectural and non-architectural functions of CTCF and cohesin in gene regulation","authors":"Takeo Narita, Sinan Kilic, Yoshiki Higashijima, Natalie M. Scherer, Georgios Pappas, Elina Maskey, Chunaram Choudhary","doi":"10.1038/s41588-025-02477-8","DOIUrl":"10.1038/s41588-025-02477-8","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"230-230"},"PeriodicalIF":29.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02477-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768676","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}
Chalkiness and seed vigor are major agronomic traits affecting rice grain quality and productivity, respectively. Little is known about the intrinsic relationship and the regulatory mechanisms of these two traits. Here we identified a chalkiness locus qPGWC-8, which encodes trehalose-6-phosphate synthase 8 (OsTPS8) that suppresses trehalose-6-phosphate (Tre6P) biosynthesis by interacting with and inhibiting OsTPS1. A natural promoter variation in OsTPS8 confers differential transcriptional regulation by OsbHLH001. Elevated expression of OsTPS8 reduces Tre6P levels and activates the expression of OsMYBS1 and α-amylase genes, thus promoting starch degradation, chalkiness formation and seed vigor elevation. Two major haplotypes, OsTPS8ASO and OsTPS8IR24, were defined by this functional promoter variation, with OsTPS8IR24 preferentially selected during the domestication of indica rice. Collectively, our findings establish an OsbHLH001-OsTPS8-Tre6P-α-amylase signaling cascade that has a dual role in regulating grain chalkiness and seed vigor, which reveals a molecular link between the appearance quality and seed vigor of rice. Natural variation in the promoter of OsTPS8 contributes to differences in grain chalkiness and seed vigor between indica and japonica rice subspecies by altering trehalose-6-phosphate biosynthesis and α-amylase levels.
{"title":"Natural variation in OsTPS8 confers differential regulation of chalkiness and seed vigor in indica and japonica rice","authors":"Xiaoli Chen, Yulong Ren, Hui Dong, Xiaokang Jiang, Xiaoming Zheng, Erchao Duan, Xuan Teng, Yunlong Wang, Chuanwei Gu, Rongbo Chen, Qingkai Wang, Yongfei Wang, Yipeng Zhang, Rushuang Zhang, Yunpeng Zhang, Wenjie Zhao, Yu Zhang, Xue Yang, Lei Zhou, Chao Li, Tiaofeng Shan, Yiqun Bao, Yunlu Tian, Xi Liu, Shijia Liu, Tao Guo, Mingjiang Chen, Haiyang Wang, Yihua Wang, Jianmin Wan","doi":"10.1038/s41588-025-02429-2","DOIUrl":"10.1038/s41588-025-02429-2","url":null,"abstract":"Chalkiness and seed vigor are major agronomic traits affecting rice grain quality and productivity, respectively. Little is known about the intrinsic relationship and the regulatory mechanisms of these two traits. Here we identified a chalkiness locus qPGWC-8, which encodes trehalose-6-phosphate synthase 8 (OsTPS8) that suppresses trehalose-6-phosphate (Tre6P) biosynthesis by interacting with and inhibiting OsTPS1. A natural promoter variation in OsTPS8 confers differential transcriptional regulation by OsbHLH001. Elevated expression of OsTPS8 reduces Tre6P levels and activates the expression of OsMYBS1 and α-amylase genes, thus promoting starch degradation, chalkiness formation and seed vigor elevation. Two major haplotypes, OsTPS8ASO and OsTPS8IR24, were defined by this functional promoter variation, with OsTPS8IR24 preferentially selected during the domestication of indica rice. Collectively, our findings establish an OsbHLH001-OsTPS8-Tre6P-α-amylase signaling cascade that has a dual role in regulating grain chalkiness and seed vigor, which reveals a molecular link between the appearance quality and seed vigor of rice. Natural variation in the promoter of OsTPS8 contributes to differences in grain chalkiness and seed vigor between indica and japonica rice subspecies by altering trehalose-6-phosphate biosynthesis and α-amylase levels.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"206-217"},"PeriodicalIF":29.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02429-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759749","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 : 2025-12-12DOI: 10.1038/s41588-025-02471-0
Avantika Gupta, Andrea Gazzo, Pier Selenica, Anton Safonov, Fresia Pareja, Edaise M. da Silva, David N. Brown, Hong Shao, Yingjie Zhu, Juber Patel, Juan Blanco-Heredia, Bojana Stefanovska, Michael A. Carpenter, Yanjun Chen, Isabella Vegas, Xin Pei, Denise Frosina, Achim A. Jungbluth, Marc Ladanyi, Giuseppe Curigliano, Britta Weigelt, Nadeem Riaz, Simon N. Powell, Pedram Razavi, Reuben S. Harris, Jorge S. Reis-Filho, Antonio Marra, Sarat Chandarlapaty
{"title":"Publisher Correction: APOBEC3 mutagenesis drives therapy resistance in breast cancer","authors":"Avantika Gupta, Andrea Gazzo, Pier Selenica, Anton Safonov, Fresia Pareja, Edaise M. da Silva, David N. Brown, Hong Shao, Yingjie Zhu, Juber Patel, Juan Blanco-Heredia, Bojana Stefanovska, Michael A. Carpenter, Yanjun Chen, Isabella Vegas, Xin Pei, Denise Frosina, Achim A. Jungbluth, Marc Ladanyi, Giuseppe Curigliano, Britta Weigelt, Nadeem Riaz, Simon N. Powell, Pedram Razavi, Reuben S. Harris, Jorge S. Reis-Filho, Antonio Marra, Sarat Chandarlapaty","doi":"10.1038/s41588-025-02471-0","DOIUrl":"10.1038/s41588-025-02471-0","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"232-232"},"PeriodicalIF":29.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02471-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732585","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}
A complete telomere-to-telomere (T2T) genome is essential for advancing pig genomic research. Here we assembled a pig T2T gap-free genome T2T-pig1.0 (2.63 Gb) for a boar in Wuzhishan, China, covering all 20 chromosomes. T2T-pig1.0 with an accuracy of >99.999% uncovers 194.42 Mb of previously unresolved regions (PURs), and 1,189 new genes are added to the current reference genome Sscrofa11.1. We annotated 111 protein-coding genes with 11 male-specific conserved orthologous genes on chromosome Y (43.25 Mb). Pig-specific centromeric satellite repeat units are revealed. Centromeric regions of all telocentric chromosomes harbor a unique structure, ‘telomere-SAT1B-(mSAT)ₙ-SAT3-q_arm’, and a few young long terminal repeats. With the addition of 339,092 single-nucleotide polymorphisms in PURs, the population structure is updated with cross-continental introgression, and a selective sweep analysis reveals 280 new regions and 133 new genes potentially associated with body stature. GALNT13, with strong selection signals, has a role in inhibiting porcine chondrocyte proliferation while promoting chondrocyte differentiation. A telomere-to-telomere gap-free pig genome assembly (T2T-pig1.0) for a Wuzhishan boar highlights Y chromosome structure and genomic regions potentially associated with body stature.
{"title":"Telomere-to-telomere genome assembly of a male pig provides insight into population structure and selection for body stature","authors":"Ya-Biao Luo, Ning Huang, Cheng-Wan Zha, Li-Xian Yang, Peng-Xiang Xue, Qiao Xu, Xiao-Yang Yang, Long-Miao Zhang, Yu-Bei Wang, Zhe Chao, Rui-Ping Sun, Feng Wang, Shan-Gang Jia, Mei-Ying Fang","doi":"10.1038/s41588-025-02433-6","DOIUrl":"10.1038/s41588-025-02433-6","url":null,"abstract":"A complete telomere-to-telomere (T2T) genome is essential for advancing pig genomic research. Here we assembled a pig T2T gap-free genome T2T-pig1.0 (2.63 Gb) for a boar in Wuzhishan, China, covering all 20 chromosomes. T2T-pig1.0 with an accuracy of >99.999% uncovers 194.42 Mb of previously unresolved regions (PURs), and 1,189 new genes are added to the current reference genome Sscrofa11.1. We annotated 111 protein-coding genes with 11 male-specific conserved orthologous genes on chromosome Y (43.25 Mb). Pig-specific centromeric satellite repeat units are revealed. Centromeric regions of all telocentric chromosomes harbor a unique structure, ‘telomere-SAT1B-(mSAT)ₙ-SAT3-q_arm’, and a few young long terminal repeats. With the addition of 339,092 single-nucleotide polymorphisms in PURs, the population structure is updated with cross-continental introgression, and a selective sweep analysis reveals 280 new regions and 133 new genes potentially associated with body stature. GALNT13, with strong selection signals, has a role in inhibiting porcine chondrocyte proliferation while promoting chondrocyte differentiation. A telomere-to-telomere gap-free pig genome assembly (T2T-pig1.0) for a Wuzhishan boar highlights Y chromosome structure and genomic regions potentially associated with body stature.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"195-205"},"PeriodicalIF":29.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732589","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 : 2025-12-11DOI: 10.1038/s41588-025-02419-4
Melanie Schoof, Tuyu Zheng, Martin Sill, Roland Imle, Alessia Cais, Lea Altendorf, Alicia Fürst, Nina Hofmann, Kati Ernst, Dominik Vonficht, Kenneth Chun-Ho Chan, Tim Holland-Letz, Andreas Postlmayr, Ryo Shiraishi, Wanchen Wang, Alaide Morcavallo, Michael Spohn, Carolin Göbel, Judith Niesen, Levke-Sophie Peter, Franck Bourdeaut, Zhi-Yan Han, Yanxin Pei, Najiba Murad, Fredrik J. Swartling, Jessica Taylor, Monika Yadav, Garrett R. Gibson, Richard J. Gilbertson, Matthias Dottermusch, Rajanya Roy, Kornelius Kerl, Rainer Glass, Jiying Cheng, Martin A. Horstmann, Gerrit Wolters-Eisfeld, Haotian Zhao, Dominik Sturm, Viveka Nand Yadav, Louis Chesler, Simon Haas, William A. Weiss, Paul A. Northcott, Lena M. Kutscher, Ana Guerreiro Stucklin, Olivier Ayrault, Julia E. Neumann, Daisuke Kawauchi, David T. W. Jones, Kristian Pajtler, Ana Banito, Stefan M. Pfister, Ulrich Schüller, Marc Zuckermann
Copy number alterations (CNAs) are hallmarks of cancer, yet investigation of their oncogenic role has been hindered by technical limitations and missing model systems. Here we generated a genome-wide DNA methylation and CNA atlas of 106 genetic mouse models across 31 pediatric tumor types, including 18 new models for pediatric glioma. We demonstrated their epigenetic resemblance to human disease counterparts and identified entity-specific patterns of immune infiltration. We discovered that mouse tumors harbor highly recurrent CNA signatures that occur distinctly based on the tumor subgroup and driving oncogene and showed that these CNAs share syntenic regions with the matching human tumor types, thereby revealing a conserved but previously underappreciated role in subgroup-specific tumorigenesis that can be analyzed using the presented models. Our study provides insights into globally available mouse models for pediatric solid cancers and enables access to functional CNA interrogation, with the potential to unlock new translational targets in pediatric cancers. DNA methylation and copy number variant analyses across a large number of genetic mouse models of pediatric brain tumors reveal subtype-specific molecular alterations shared with the corresponding human diseases.
{"title":"Investigation of a global mouse methylome atlas reveals subtype-specific copy number alterations in pediatric cancer models","authors":"Melanie Schoof, Tuyu Zheng, Martin Sill, Roland Imle, Alessia Cais, Lea Altendorf, Alicia Fürst, Nina Hofmann, Kati Ernst, Dominik Vonficht, Kenneth Chun-Ho Chan, Tim Holland-Letz, Andreas Postlmayr, Ryo Shiraishi, Wanchen Wang, Alaide Morcavallo, Michael Spohn, Carolin Göbel, Judith Niesen, Levke-Sophie Peter, Franck Bourdeaut, Zhi-Yan Han, Yanxin Pei, Najiba Murad, Fredrik J. Swartling, Jessica Taylor, Monika Yadav, Garrett R. Gibson, Richard J. Gilbertson, Matthias Dottermusch, Rajanya Roy, Kornelius Kerl, Rainer Glass, Jiying Cheng, Martin A. Horstmann, Gerrit Wolters-Eisfeld, Haotian Zhao, Dominik Sturm, Viveka Nand Yadav, Louis Chesler, Simon Haas, William A. Weiss, Paul A. Northcott, Lena M. Kutscher, Ana Guerreiro Stucklin, Olivier Ayrault, Julia E. Neumann, Daisuke Kawauchi, David T. W. Jones, Kristian Pajtler, Ana Banito, Stefan M. Pfister, Ulrich Schüller, Marc Zuckermann","doi":"10.1038/s41588-025-02419-4","DOIUrl":"10.1038/s41588-025-02419-4","url":null,"abstract":"Copy number alterations (CNAs) are hallmarks of cancer, yet investigation of their oncogenic role has been hindered by technical limitations and missing model systems. Here we generated a genome-wide DNA methylation and CNA atlas of 106 genetic mouse models across 31 pediatric tumor types, including 18 new models for pediatric glioma. We demonstrated their epigenetic resemblance to human disease counterparts and identified entity-specific patterns of immune infiltration. We discovered that mouse tumors harbor highly recurrent CNA signatures that occur distinctly based on the tumor subgroup and driving oncogene and showed that these CNAs share syntenic regions with the matching human tumor types, thereby revealing a conserved but previously underappreciated role in subgroup-specific tumorigenesis that can be analyzed using the presented models. Our study provides insights into globally available mouse models for pediatric solid cancers and enables access to functional CNA interrogation, with the potential to unlock new translational targets in pediatric cancers. DNA methylation and copy number variant analyses across a large number of genetic mouse models of pediatric brain tumors reveal subtype-specific molecular alterations shared with the corresponding human diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"143-156"},"PeriodicalIF":29.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02419-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718541","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 : 2025-12-10DOI: 10.1038/s41588-025-02447-0
Yann Joly, Yunhe Xue, Jessica Huang, Diya Uberoi
Amid growing geopolitical tension and scientific advances, fragmented and reactive governance policies could increase the risks of dual-use genomics, undermining international collaboration and data security. This Comment calls on the international genomics community to meet to establish robust, harmonized standards to safeguard genomic data.
{"title":"A call for a global cyberbiosecurity framework in genomics","authors":"Yann Joly, Yunhe Xue, Jessica Huang, Diya Uberoi","doi":"10.1038/s41588-025-02447-0","DOIUrl":"10.1038/s41588-025-02447-0","url":null,"abstract":"Amid growing geopolitical tension and scientific advances, fragmented and reactive governance policies could increase the risks of dual-use genomics, undermining international collaboration and data security. This Comment calls on the international genomics community to meet to establish robust, harmonized standards to safeguard genomic data.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"9-12"},"PeriodicalIF":29.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717914","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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