Nature geneticsPub Date : 2025-06-02DOI: 10.1038/s41588-025-02197-z
Zheqi Li, Guillermo Peluffo, Laura E. Stevens, Xintao Qiu, Marco Seehawer, Amatullah Tawawalla, Xiao-Yun Huang, Shawn B. Egri, Shaunak Raval, Maeve McFadden, Clive S. D’Santos, Eva Papachristou, Natalie L. Kingston, Jun Nishida, Kyle E. Evans, Ji-Heui Seo, Kendell Clement, Daniel Temko, Muhammad Ekram, Rong Li, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Anton Simeonov, Stephen C. Kales, Ganesha Rai, Madhu Lal-Nag, David J. Maloney, Ajit Jadhav, Franziska Michor, Alex Meissner, Justin M. Balko, Jason S. Carroll, Matthew L. Freedman, Jacob D. Jaffe, Malvina Papanastasiou, Henry W. Long, Kornelia Polyak
{"title":"KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage","authors":"Zheqi Li, Guillermo Peluffo, Laura E. Stevens, Xintao Qiu, Marco Seehawer, Amatullah Tawawalla, Xiao-Yun Huang, Shawn B. Egri, Shaunak Raval, Maeve McFadden, Clive S. D’Santos, Eva Papachristou, Natalie L. Kingston, Jun Nishida, Kyle E. Evans, Ji-Heui Seo, Kendell Clement, Daniel Temko, Muhammad Ekram, Rong Li, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Anton Simeonov, Stephen C. Kales, Ganesha Rai, Madhu Lal-Nag, David J. Maloney, Ajit Jadhav, Franziska Michor, Alex Meissner, Justin M. Balko, Jason S. Carroll, Matthew L. Freedman, Jacob D. Jaffe, Malvina Papanastasiou, Henry W. Long, Kornelia Polyak","doi":"10.1038/s41588-025-02197-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02197-z","url":null,"abstract":"<p>Basal breast cancer is a subtype with a poor prognosis in need of more effective therapeutic approaches. Here we describe a unique role for the KDM4C histone lysine demethylase in <i>KDM4C</i>-amplified basal breast cancers, where KDM4C inhibition reshapes chromatin and transcriptomic landscapes without substantial alterations of its canonical substrates, trimethylated histone H3 lysine 9 (H3K9me3) and lysine 36 (H3K36me3). Rather, KDM4C loss causes proteolytic cleavage of histone H3 mediated by cathepsin L (CTSL), resulting in decreased glutamate–cysteine ligase expression and increased reactive oxygen species. CTSL is recruited to the chromatin by the grainyhead-like 2 (GRHL2) transcription factor that is methylated at lysine 453 following KDM4C inhibition, triggering CTSL histone clipping activity. Deletion of CTSL rescued KDM4-loss-mediated tumor suppression. Our study reveals a function for KDM4C that connects cellular redox regulation and chromatin remodeling.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"51 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193046","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 : 2025-06-02DOI: 10.1038/s41588-025-02198-y
Camille L. G. Lambert, Guido van Mierlo, Johannes J. Bues, Orane J. Guillaume-Gentil, Bart Deplancke
{"title":"Engineering next-generation microfluidic technologies for single-cell phenomics","authors":"Camille L. G. Lambert, Guido van Mierlo, Johannes J. Bues, Orane J. Guillaume-Gentil, Bart Deplancke","doi":"10.1038/s41588-025-02198-y","DOIUrl":"https://doi.org/10.1038/s41588-025-02198-y","url":null,"abstract":"<p>The completion of the Human Genome Project catalyzed the development of ‘omics’ technologies, enabling the detailed exploration of biological systems at an unprecedented molecular scale. Microfluidics has transformed the omics toolbox by facilitating large-scale, high-throughput and highly accurate measurements of DNA and RNA, driving the transition from bulk to single-cell analyses. This transition has ushered in a new era, moving beyond a gene- and protein-centric perspective toward a holistic understanding of cellular phenotypes. This emerging ‘single-cell phenomics era’ integrates diverse omics datasets with spatial, morphological and temporal phenotypes to provide a comprehensive perspective on cellular function. This Review highlights how microfluidics addressed key challenges in the transition to single-cell omics and explores how lessons learned from these efforts will propel the single-cell phenomics revolution. Furthermore, we discuss emerging opportunities in which integrative single-cell phenomics could serve as a foundation for transformative discoveries in biology.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"5 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193048","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":"Towards trustworthiness of precision medicine research for people with disabilities","authors":"Alejandra Aguirre, Sandra Soo-Jin Lee, Shawneequa Callier, Paul Spicer, Maya Sabatello","doi":"10.1038/s41588-025-02195-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02195-1","url":null,"abstract":"People with disabilities are under-represented in general (non-disability-specific) precision medicine research (PMR), limiting access to its benefits. We examine key reasons for this, focusing on the role of (dis)trust, and identify areas for further inquiry to guide researchers and enhance PMR’s trustworthiness for people with disabilities.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"62 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193067","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 : 2025-06-02DOI: 10.1038/s41588-025-02205-2
David Gremmelspacher, Johannes Gawron, Barbara M. Szczerba, Katharina Jahn, Francesc Castro-Giner, Jack Kuipers, Jochen Singer, Francesco Marass, Ana Gvozdenovic, Selina Budinjas, Heike Pueschel, Cyrill A. Rentsch, Alfred Zippelius, Viola Heinzelmann-Schwarz, Christian Kurzeder, Walter Paul Weber, Christoph Rochlitz, Marcus Vetter, Niko Beerenwinkel, Nicola Aceto
{"title":"Phylogenetic inference reveals clonal heterogeneity in circulating tumor cell clusters","authors":"David Gremmelspacher, Johannes Gawron, Barbara M. Szczerba, Katharina Jahn, Francesc Castro-Giner, Jack Kuipers, Jochen Singer, Francesco Marass, Ana Gvozdenovic, Selina Budinjas, Heike Pueschel, Cyrill A. Rentsch, Alfred Zippelius, Viola Heinzelmann-Schwarz, Christian Kurzeder, Walter Paul Weber, Christoph Rochlitz, Marcus Vetter, Niko Beerenwinkel, Nicola Aceto","doi":"10.1038/s41588-025-02205-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02205-2","url":null,"abstract":"<p>Circulating tumor cell (CTC) clusters are highly efficient metastatic seeds in various cancers. Yet, their genetic heterogeneity and clonal architecture is poorly characterized. Using whole-exome sequencing coupled with phylogenetic inference from CTC clusters of patients with breast and prostate cancer, as well as mouse cancer models alongside barcode-mediated clonal tracking in vivo, we demonstrate oligoclonal composition of individual CTC clusters. These results improve our understanding of metastasis-relevant clonal dynamics.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"41 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193120","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 : 2025-06-02DOI: 10.1038/s41588-025-02204-3
Karena Zhao, Joris Vos, Stanley Lam, Lillian A. Boe, Daniel Muldoon, Catherine Y. Han, Cristina Valero, Mark Lee, Conall Fitzgerald, Andrew S. Lee, Manu Prasad, Swati Jain, Xinzhu Deng, Timothy A. Chan, Michael F. Berger, Chaitanya Bandlamudi, Xi Kathy Zhou, Luc G. T. Morris
{"title":"Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination","authors":"Karena Zhao, Joris Vos, Stanley Lam, Lillian A. Boe, Daniel Muldoon, Catherine Y. Han, Cristina Valero, Mark Lee, Conall Fitzgerald, Andrew S. Lee, Manu Prasad, Swati Jain, Xinzhu Deng, Timothy A. Chan, Michael F. Berger, Chaitanya Bandlamudi, Xi Kathy Zhou, Luc G. T. Morris","doi":"10.1038/s41588-025-02204-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02204-3","url":null,"abstract":"<p>To understand genetic evolution in cancer during metastasis, we analyzed genomic profiles of 3,732 cancer patients in whom several tumor sites were longitudinally biopsied. During distant metastasis, tumors were observed to accumulate copy number alterations (CNAs) to a much greater degree than mutations. In particular, the development of whole genome duplication was a common event during metastasis, emerging de novo in 28% of patients. Loss of 9p (including <i>CDKN2A</i>) developed during metastasis in 11% of patients. To a lesser degree, mutations and allelic loss in human leukocyte antigen class I and other genes associated with antigen presentation also emerged. Increasing CNA, but not increasing mutational load, was associated with immune evasion in patients treated with immunotherapy. Taken together, these data suggest that CNA, rather than mutational accumulation, is enriched during cancer metastasis, perhaps due to a more favorable balance of enhanced cellular fitness versus immunogenicity.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"3 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193047","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 : 2025-05-30DOI: 10.1038/s41588-025-02199-x
{"title":"A simple genomic score to predict progression of multiple myeloma","authors":"","doi":"10.1038/s41588-025-02199-x","DOIUrl":"https://doi.org/10.1038/s41588-025-02199-x","url":null,"abstract":"The ‘multiple myeloma-like’ genomic score identifies somatic mutations that are more commonly found in active forms of multiple myeloma. In patients with a precursor stage of multiple myeloma, this score helps in predicting who is at a higher risk of progressing to an active form of cancer and may benefit from early therapeutic interventions.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"5 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176599","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 : 2025-05-29DOI: 10.1038/s41588-025-02210-5
Maria C. Costanzo, Laura W. Harris, Yue Ji, Aoife McMahon, Noël P. Burtt, Jason Flannick
{"title":"Realizing the promise of genome-wide association studies for effector gene prediction","authors":"Maria C. Costanzo, Laura W. Harris, Yue Ji, Aoife McMahon, Noël P. Burtt, Jason Flannick","doi":"10.1038/s41588-025-02210-5","DOIUrl":"https://doi.org/10.1038/s41588-025-02210-5","url":null,"abstract":"<p>Genome-wide association studies (GWAS) identify regions of the genome in which genetic variation is associated with the risk of complex diseases, such as diabetes, or the magnitude of traits, such as blood pressure. Determining which ‘effector genes’ mediate the effects of GWAS associations is essential to using GWAS to understand disease mechanisms and develop new therapies. In recent years, GWAS authors have increasingly included effector gene predictions as part of their study results. However, the research community has not yet converged on standards for generating or reporting these predictions. In this Perspective, we illustrate the diversity of the evidence types used to support effector gene predictions and argue for future initiatives to increase their accessibility and usefulness.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"147 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165315","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 : 2025-05-29DOI: 10.1038/s41588-025-02209-y
Adam Jackson, Nishi Thaker, Alexander Blakes, Gillian Rice, Sam Griffiths-Jones, Meena Balasubramanian, Jennifer Campbell, Nora Shannon, Jungmin Choi, Juhyeon Hong, David Hunt, Anna de Burca, Soo Yeon Kim, Taekeun Kim, Seungbok Lee, Melody Redman, Rocio Rius, Cas Simons, Tiong Yang Tan, Jamie Ellingford, Raymond T. O’Keefe, Jong Hee Chae, Siddharth Banka
{"title":"Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes","authors":"Adam Jackson, Nishi Thaker, Alexander Blakes, Gillian Rice, Sam Griffiths-Jones, Meena Balasubramanian, Jennifer Campbell, Nora Shannon, Jungmin Choi, Juhyeon Hong, David Hunt, Anna de Burca, Soo Yeon Kim, Taekeun Kim, Seungbok Lee, Melody Redman, Rocio Rius, Cas Simons, Tiong Yang Tan, Jamie Ellingford, Raymond T. O’Keefe, Jong Hee Chae, Siddharth Banka","doi":"10.1038/s41588-025-02209-y","DOIUrl":"https://doi.org/10.1038/s41588-025-02209-y","url":null,"abstract":"<p>R-loops are DNA–RNA hybrid structures that may promote mutagenesis. However, their contribution to human Mendelian disorders is unexplored. Here we show excess de novo variants in genomic regions that form R-loops (henceforth, ‘R-loop regions’) and demonstrate enrichment of R-loop region variants (RRVs) in ribozyme, snoRNA and snRNA genes, specifically in rare disease cohorts. Using this insight, we report neurodevelopmental disorders (NDDs) caused by rare variants in two major spliceosomal RNA encoding genes, <i>RNU2-2</i> and <i>RNU5B-1</i>. These, along with the recently described <i>RNU4-2</i>-related ReNU syndrome, provide a genetic explanation for a substantial proportion of individuals with NDDs.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"138 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165359","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 : 2025-05-28DOI: 10.1038/s41588-025-02211-4
Zhiyuan Chen, Mohamed Nadhir Djekidel, Yi Zhang
{"title":"Author Correction: Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos","authors":"Zhiyuan Chen, Mohamed Nadhir Djekidel, Yi Zhang","doi":"10.1038/s41588-025-02211-4","DOIUrl":"https://doi.org/10.1038/s41588-025-02211-4","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153384","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 : 2025-05-27DOI: 10.1038/s41588-025-02194-2
Alex de Mendoza
{"title":"Genome synteny reveals hidden enhancer conservation","authors":"Alex de Mendoza","doi":"10.1038/s41588-025-02194-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02194-2","url":null,"abstract":"Enhancer sequences evolve rapidly, which has led to the prevailing view that most are not functionally conserved across species. A study now challenges this assumption by leveraging interspecies point projection — a method that uses genome synteny to uncover hidden enhancer conservation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"49 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145595","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}