Nature geneticsPub Date : 2025-05-14DOI: 10.1038/s41588-025-02214-1
Wei Li
{"title":"Complete genomes of six ape species","authors":"Wei Li","doi":"10.1038/s41588-025-02214-1","DOIUrl":"10.1038/s41588-025-02214-1","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 5","pages":"1061-1061"},"PeriodicalIF":31.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950581","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}
Nature geneticsPub Date : 2025-05-13DOI: 10.1038/s41588-025-02189-z
Nora I. Strom, Zachary F. Gerring, Marco Galimberti, Dongmei Yu, Matthew W. Halvorsen, Abdel Abdellaoui, Cristina Rodriguez-Fontenla, Julia M. Sealock, Tim Bigdeli, Jonathan R. Coleman, Behrang Mahjani, Jackson G. Thorp, Katharina Bey, Christie L. Burton, Jurjen J. Luykx, Gwyneth Zai, Silvia Alemany, Christine Andre, Kathleen D. Askland, Julia Bäckman, Nerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O. Joseph Bienvenu, Donald Black, Michael H. Bloch, Sigrid Børte, Rosa Bosch, Michael Breen, Brian P. Brennan, Helena Brentani, Joseph D. Buxbaum, Jonas Bybjerg-Grauholm, Enda M. Byrne, Judit Cabana-Dominguez, Beatriz Camarena, Adrian Camarena, Carolina Cappi, Angel Carracedo, Miguel Casas, Maria Cristina Cavallini, Valentina Ciullo, Edwin H. Cook, Jesse Crosby, Bernadette A. Cullen, Elles J. De Schipper, Richard Delorme, Srdjan Djurovic, Jason A. Elias, Xavier Estivill, Martha J. Falkenstein, Bengt T. Fundin, Lauryn Garner, Christina Gironda, Fernando S. Goes, Marco A. Grados, Jakob Grove, Wei Guo, Jan Haavik, Kristen Hagen, Kelly Harrington, Alexandra Havdahl, Kira D. Höffler, Ana G. Hounie, Donald Hucks, Christina Hultman, Magdalena Janecka, Eric Jenike, Elinor K. Karlsson, Kara Kelley, Julia Klawohn, Janice E. Krasnow, Kristi Krebs, Christoph Lange, Nuria Lanzagorta, Daniel Levey, Kerstin Lindblad-Toh, Fabio Macciardi, Brion Maher, Brittany Mathes, Evonne McArthur, Nathaniel McGregor, Nicole C. McLaughlin, Sandra Meier, Euripedes C. Miguel, Maureen Mulhern, Paul S. Nestadt, Erika L. Nurmi, Kevin S. O’Connell, Lisa Osiecki, Olga Therese Ousdal, Teemu Palviainen, Nancy L. Pedersen, Fabrizio Piras, Federica Piras, Sriramya Potluri, Raquel Rabionet, Alfredo Ramirez, Scott Rauch, Abraham Reichenberg, Mark A. Riddle, Stephan Ripke, Maria C. Rosário, Aline S. Sampaio, Miriam A. Schiele, Anne Heidi Skogholt, Laura G. Sloofman, Jan Smit, María Soler Artigas, Laurent F. Thomas, Eric Tifft, Homero Vallada, Nathanial van Kirk, Jeremy Veenstra-VanderWeele, Nienke N. Vulink, Christopher P. Walker, Ying Wang, Jens R. Wendland, Bendik S. Winsvold, Yin Yao, Hang Zhou, Arpana Agrawal, Pino Alonso, Götz Berberich, Kathleen K. Bucholz, Cynthia M. Bulik, Danielle Cath, Damiaan Denys, Valsamma Eapen, Howard Edenberg, Peter Falkai, Thomas V. Fernandez, Abby J. Fyer, J. M. Gaziano, Dan A. Geller, Hans J. Grabe, Benjamin D. Greenberg, Gregory L. Hanna, Ian B. Hickie, David M. Hougaard, Norbert Kathmann, James Kennedy, Dongbing Lai, Mikael Landén, Stéphanie Le Hellard, Marion Leboyer, Christine Lochner, James T. McCracken, Sarah E. Medland, Preben B. Mortensen, Benjamin M. Neale, Humberto Nicolini, Merete Nordentoft, Michele Pato, Carlos Pato, David L. Pauls, John Piacentini, Christopher Pittenger, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Steven A. Rasmussen, Margaret A. Richter, David R. Rosenberg, Stephan Ruhrmann, Jack F. Samuels, Sven Sandin, Paul Sandor, Gianfranco Spalletta, Dan J. Stein, S. Evelyn Stewart, Eric A. Storch, Barbara E. Stranger, Maurizio Turiel, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Susanne Walitza, Kristian Hveem, Bjarne K. Hansen, Christian Rück, Nicholas G. Martin, Lili Milani, Ole Mors, Ted Reichborn-Kjennerud, Marta Ribasés, Gerd Kvale, David Mataix-Cols, Katharina Domschke, Edna Grünblatt, Michael Wagner, John-Anker Zwart, Gerome Breen, Gerald Nestadt, Jaakko Kaprio, Paul D. Arnold, Dorothy E. Grice, James A. Knowles, Helga Ask, Karin J. Verweij, Lea K. Davis, Dirk J. Smit, James J. Crowley, Jeremiah M. Scharf, Murray B. Stein, Joel Gelernter, Carol A. Mathews, Eske M. Derks, Manuel Mattheisen
{"title":"Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder","authors":"Nora I. Strom, Zachary F. Gerring, Marco Galimberti, Dongmei Yu, Matthew W. Halvorsen, Abdel Abdellaoui, Cristina Rodriguez-Fontenla, Julia M. Sealock, Tim Bigdeli, Jonathan R. Coleman, Behrang Mahjani, Jackson G. Thorp, Katharina Bey, Christie L. Burton, Jurjen J. Luykx, Gwyneth Zai, Silvia Alemany, Christine Andre, Kathleen D. Askland, Julia Bäckman, Nerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O. Joseph Bienvenu, Donald Black, Michael H. Bloch, Sigrid Børte, Rosa Bosch, Michael Breen, Brian P. Brennan, Helena Brentani, Joseph D. Buxbaum, Jonas Bybjerg-Grauholm, Enda M. Byrne, Judit Cabana-Dominguez, Beatriz Camarena, Adrian Camarena, Carolina Cappi, Angel Carracedo, Miguel Casas, Maria Cristina Cavallini, Valentina Ciullo, Edwin H. Cook, Jesse Crosby, Bernadette A. Cullen, Elles J. De Schipper, Richard Delorme, Srdjan Djurovic, Jason A. Elias, Xavier Estivill, Martha J. Falkenstein, Bengt T. Fundin, Lauryn Garner, Christina Gironda, Fernando S. Goes, Marco A. Grados, Jakob Grove, Wei Guo, Jan Haavik, Kristen Hagen, Kelly Harrington, Alexandra Havdahl, Kira D. Höffler, Ana G. Hounie, Donald Hucks, Christina Hultman, Magdalena Janecka, Eric Jenike, Elinor K. Karlsson, Kara Kelley, Julia Klawohn, Janice E. Krasnow, Kristi Krebs, Christoph Lange, Nuria Lanzagorta, Daniel Levey, Kerstin Lindblad-Toh, Fabio Macciardi, Brion Maher, Brittany Mathes, Evonne McArthur, Nathaniel McGregor, Nicole C. McLaughlin, Sandra Meier, Euripedes C. Miguel, Maureen Mulhern, Paul S. Nestadt, Erika L. Nurmi, Kevin S. O’Connell, Lisa Osiecki, Olga Therese Ousdal, Teemu Palviainen, Nancy L. Pedersen, Fabrizio Piras, Federica Piras, Sriramya Potluri, Raquel Rabionet, Alfredo Ramirez, Scott Rauch, Abraham Reichenberg, Mark A. Riddle, Stephan Ripke, Maria C. Rosário, Aline S. Sampaio, Miriam A. Schiele, Anne Heidi Skogholt, Laura G. Sloofman, Jan Smit, María Soler Artigas, Laurent F. Thomas, Eric Tifft, Homero Vallada, Nathanial van Kirk, Jeremy Veenstra-VanderWeele, Nienke N. Vulink, Christopher P. Walker, Ying Wang, Jens R. Wendland, Bendik S. Winsvold, Yin Yao, Hang Zhou, Arpana Agrawal, Pino Alonso, Götz Berberich, Kathleen K. Bucholz, Cynthia M. Bulik, Danielle Cath, Damiaan Denys, Valsamma Eapen, Howard Edenberg, Peter Falkai, Thomas V. Fernandez, Abby J. Fyer, J. M. Gaziano, Dan A. Geller, Hans J. Grabe, Benjamin D. Greenberg, Gregory L. Hanna, Ian B. Hickie, David M. Hougaard, Norbert Kathmann, James Kennedy, Dongbing Lai, Mikael Landén, Stéphanie Le Hellard, Marion Leboyer, Christine Lochner, James T. McCracken, Sarah E. Medland, Preben B. Mortensen, Benjamin M. Neale, Humberto Nicolini, Merete Nordentoft, Michele Pato, Carlos Pato, David L. Pauls, John Piacentini, Christopher Pittenger, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Steven A. Rasmussen, Margaret A. Richter, David R. Rosenberg, Stephan Ruhrmann, Jack F. Samuels, Sven Sandin, Paul Sandor, Gianfranco Spalletta, Dan J. Stein, S. Evelyn Stewart, Eric A. Storch, Barbara E. Stranger, Maurizio Turiel, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Susanne Walitza, Kristian Hveem, Bjarne K. Hansen, Christian Rück, Nicholas G. Martin, Lili Milani, Ole Mors, Ted Reichborn-Kjennerud, Marta Ribasés, Gerd Kvale, David Mataix-Cols, Katharina Domschke, Edna Grünblatt, Michael Wagner, John-Anker Zwart, Gerome Breen, Gerald Nestadt, Jaakko Kaprio, Paul D. Arnold, Dorothy E. Grice, James A. Knowles, Helga Ask, Karin J. Verweij, Lea K. Davis, Dirk J. Smit, James J. Crowley, Jeremiah M. Scharf, Murray B. Stein, Joel Gelernter, Carol A. Mathews, Eske M. Derks, Manuel Mattheisen","doi":"10.1038/s41588-025-02189-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02189-z","url":null,"abstract":"<p>Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including <i>WDR6</i>, <i>DALRD3</i> and <i>CTNND1</i> and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D<sub>1</sub> and D<sub>2</sub> type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"7 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940096","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}
Nature geneticsPub Date : 2025-05-12DOI: 10.1038/s41588-025-02182-6
Quan Xu, Lennard Halle, Soroor Hediyeh-zadeh, Merel Kuijs, Rya Riedweg, Umut Kilik, Timothy Recaldin, Qianhui Yu, Isabell Rall, Tristan Frum, Lukas Adam, Shrey Parikh, Raphael Kfuri-Rubens, Manuel Gander, Dominik Klein, Fabiola Curion, Zhisong He, Jonas Simon Fleck, Koen Oost, Maurice Kahnwald, Silvia Barbiero, Olga Mitrofanova, Grzegorz Jerzy Maciag, Kim B. Jensen, Matthias Lutolf, Prisca Liberali, Jason R. Spence, Nikolche Gjorevski, Joep Beumer, Barbara Treutlein, Fabian J. Theis, J. Gray Camp
{"title":"An integrated transcriptomic cell atlas of human endoderm-derived organoids","authors":"Quan Xu, Lennard Halle, Soroor Hediyeh-zadeh, Merel Kuijs, Rya Riedweg, Umut Kilik, Timothy Recaldin, Qianhui Yu, Isabell Rall, Tristan Frum, Lukas Adam, Shrey Parikh, Raphael Kfuri-Rubens, Manuel Gander, Dominik Klein, Fabiola Curion, Zhisong He, Jonas Simon Fleck, Koen Oost, Maurice Kahnwald, Silvia Barbiero, Olga Mitrofanova, Grzegorz Jerzy Maciag, Kim B. Jensen, Matthias Lutolf, Prisca Liberali, Jason R. Spence, Nikolche Gjorevski, Joep Beumer, Barbara Treutlein, Fabian J. Theis, J. Gray Camp","doi":"10.1038/s41588-025-02182-6","DOIUrl":"10.1038/s41588-025-02182-6","url":null,"abstract":"Human pluripotent stem cells and tissue-resident fetal and adult stem cells can generate epithelial tissues of endodermal origin in vitro that recapitulate aspects of developing and adult human physiology. Here, we integrate single-cell transcriptomes from 218 samples covering organoids and other models of diverse endoderm-derived tissues to establish an initial version of a human endoderm-derived organoid cell atlas. The integration includes nearly one million cells across diverse conditions, data sources and protocols. We compare cell types and states between organoid models and harmonize cell annotations through mapping to primary tissue counterparts. Focusing on the intestine and lung, we provide examples of mapping data from new protocols and show how the atlas can be used as a diverse cohort to assess perturbations and disease models. The human endoderm-derived organoid cell atlas makes diverse datasets centrally available and will be valuable to assess fidelity, characterize perturbed and diseased states, and streamline protocol development. The human endoderm-derived organoid cell atlas (HEOCA) presents an integrative analysis of single-cell transcriptomes across different conditions, sources and protocols. It compares cell types and states between models, and harmonizes cell annotations through mapping to primary tissues.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 5","pages":"1201-1212"},"PeriodicalIF":31.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02182-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933234","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}
Nature geneticsPub Date : 2025-05-12DOI: 10.1038/s41588-025-02188-0
Kathryn E. Yost, Yanding Zhao, King L. Hung, Kaiyuan Zhu, Duo Xu, M. Ryan Corces, Shadi Shams, Bryan H. Louie, Shahab Sarmashghi, Laksshman Sundaram, Jens Luebeck, Stanley Clarke, Ashley S. Doane, Jeffrey M. Granja, Hani Choudhry, Marcin Imieliński, Andrew D. Cherniack, Ekta Khurana, Vineet Bafna, Ina Felau, Jean C. Zenklusen, Peter W. Laird, Christina Curtis, Cancer Genome Atlas Analysis Network, William J. Greenleaf, Howard Y. Chang
{"title":"Three-dimensional genome landscape of primary human cancers","authors":"Kathryn E. Yost, Yanding Zhao, King L. Hung, Kaiyuan Zhu, Duo Xu, M. Ryan Corces, Shadi Shams, Bryan H. Louie, Shahab Sarmashghi, Laksshman Sundaram, Jens Luebeck, Stanley Clarke, Ashley S. Doane, Jeffrey M. Granja, Hani Choudhry, Marcin Imieliński, Andrew D. Cherniack, Ekta Khurana, Vineet Bafna, Ina Felau, Jean C. Zenklusen, Peter W. Laird, Christina Curtis, Cancer Genome Atlas Analysis Network, William J. Greenleaf, Howard Y. Chang","doi":"10.1038/s41588-025-02188-0","DOIUrl":"10.1038/s41588-025-02188-0","url":null,"abstract":"Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas. We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape. Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms. These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy. This study characterizes the three-dimensional (3D) genome architecture of 15 primary human cancer types from The Cancer Genome Atlas. The analyses identify different archetypes of enhancer usage and enhancer rewiring events due to different classes of mutations and structural variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 5","pages":"1189-1200"},"PeriodicalIF":31.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02188-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933221","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}
Nature geneticsPub Date : 2025-05-09DOI: 10.1038/s41588-025-02168-4
Avishay Spitzer, Kevin C. Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-belaid, Noam Galili Darnell, Alissa C. Greenwald, Lillian Bussema, Young Taek Oh, Frederick S. Varn, Fulvio D’Angelo, Simon Gritsch, Kevin J. Anderson, Simona Migliozzi, L. Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P. Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M. Ashley, Stephen T. Keir, Keith L. Ligon, Jason T. Huse, W. K. Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G. W. Verhaak, Itay Tirosh, Mario L. Suvà
{"title":"Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics","authors":"Avishay Spitzer, Kevin C. Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-belaid, Noam Galili Darnell, Alissa C. Greenwald, Lillian Bussema, Young Taek Oh, Frederick S. Varn, Fulvio D’Angelo, Simon Gritsch, Kevin J. Anderson, Simona Migliozzi, L. Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P. Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M. Ashley, Stephen T. Keir, Keith L. Ligon, Jason T. Huse, W. K. Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G. W. Verhaak, Itay Tirosh, Mario L. Suvà","doi":"10.1038/s41588-025-02168-4","DOIUrl":"10.1038/s41588-025-02168-4","url":null,"abstract":"The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM’s diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them. Comparison of paired primary and recurrent glioblastomas at the single-cell transcriptomic level describes molecular and cellular trajectories associated with tumor recurrence, highlighting extensive heterogeneity and microenvironmental co-evolution.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 5","pages":"1168-1178"},"PeriodicalIF":31.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02168-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926911","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}
Nature geneticsPub Date : 2025-05-09DOI: 10.1038/s41588-025-02167-5
Masashi Nomura, Avishay Spitzer, Kevin C. Johnson, Luciano Garofano, Djamel Nehar-belaid, Noam Galili Darnell, Alissa C. Greenwald, Lillian Bussema, Young Taek Oh, Frederick S. Varn, Fulvio D’Angelo, Simon Gritsch, Kevin J. Anderson, Simona Migliozzi, L. Nicolas Gonzalez Castro, Tamrin ChowdhFury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P. Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M. Ashley, Stephen T. Keir, Keith L. Ligon, Jason T. Huse, W. K. Alfred Yung, Anna Lasorella, Roel G. W. Verhaak, Antonio Iavarone, Mario L. Suvà, Itay Tirosh
{"title":"The multilayered transcriptional architecture of glioblastoma ecosystems","authors":"Masashi Nomura, Avishay Spitzer, Kevin C. Johnson, Luciano Garofano, Djamel Nehar-belaid, Noam Galili Darnell, Alissa C. Greenwald, Lillian Bussema, Young Taek Oh, Frederick S. Varn, Fulvio D’Angelo, Simon Gritsch, Kevin J. Anderson, Simona Migliozzi, L. Nicolas Gonzalez Castro, Tamrin ChowdhFury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P. Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M. Ashley, Stephen T. Keir, Keith L. Ligon, Jason T. Huse, W. K. Alfred Yung, Anna Lasorella, Roel G. W. Verhaak, Antonio Iavarone, Mario L. Suvà, Itay Tirosh","doi":"10.1038/s41588-025-02167-5","DOIUrl":"10.1038/s41588-025-02167-5","url":null,"abstract":"In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression programs. These three layers of heterogeneity are interrelated and partially associated with specific genetic aberrations, thereby defining three stereotypic GBM ecosystems. This work provides an unparalleled view of the multilayered transcriptional architecture of GBM. How this architecture evolves during disease progression is addressed in the companion manuscript by Spitzer et al. Integrated single-cell transcriptomic and genetic characterization of 121 adult glioblastomas identifies heterogeneity at cell type, cell state and baseline expression program levels associated with specific mutations that form three stereotypical ecosystems.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 5","pages":"1155-1167"},"PeriodicalIF":31.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02167-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927011","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}