Nature genetics最新文献

{"title":"A genetic map of human metabolism across the allele frequency spectrum.","authors":"Martijn Zoodsma,Carl Beuchel,Summaira Yasmeen,Leonhard Kohleick,Aakash Nepal,Mine Koprulu,Florian Kronenberg,Manuel Mayr,Alice Williamson,Maik Pietzner,Claudia Langenberg","doi":"10.1038/s41588-025-02355-3","DOIUrl":"https://doi.org/10.1038/s41588-025-02355-3","url":null,"abstract":"Genetic studies of human metabolism have been limited in scale and allelic breadth. Here we provide a data-driven map of the genetic regulation of circulating small molecules and lipoprotein characteristics (249 traits) measured using proton nuclear magnetic resonance spectroscopy across the allele frequency spectrum in ~450,000 individuals. Trans-ancestral meta-analyses identify 29,824 locus-metabolite associations mapping to 753 regions with effects largely consistent between men and women and large ancestral groups represented in UK Biobank. We observe and classify extreme genetic pleiotropy, identify regulators of lipid metabolism, and assign effector genes at >100 loci through rare-to-common allelic series. We propose roles for genes less established in metabolic control (for example, SIDT2), genes characterized by phenotypic heterogeneity (for example, APOA1) and genes with specific disease relevance (for example, VEGFA). Our study demonstrates the value of broad, large-scale metabolomic phenotyping to identify and characterize regulators of human metabolism.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"28 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215838","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":"Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer.","authors":"Jie Luo,Zhixiang Chen,Yuanyuan Qiao,Jean Ching-Yi Tien,Eleanor Young,Rahul Mannan,Somnath Mahapatra,Rupam Bhattacharyya,Lanbo Xiao,Tongchen He,Sanjana Eyunni,Yuping Zhang,Yang Zheng,Fengyun Su,Xuhong Cao,Rui Wang,Yunhui Cheng,Rithvik Seri,James George,Miriam Shahine,Stephanie J Miner,Matthew G Rees,Melissa M Ronan,Jennifer A Roth,Ulka Vaishampayan,Mi Wang,Shaomeng Wang,Abhijit Parolia,Arul M Chinnaiyan","doi":"10.1038/s41588-025-02336-6","DOIUrl":"https://doi.org/10.1038/s41588-025-02336-6","url":null,"abstract":"Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CREB-binding protein (CBP) are key cofactors that activate enhancers through histone acetylation. Here we identify p300/CBP-mediated multisite histone H2B N-terminal acetylation (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ETS transcription factor ERG transcriptional activity, and their dual degradation eliminates H2BNTac and histone H3 lysine 27 acetylation at hyperactive enhancers, leading to stronger suppression of oncogenic transcription than targeting either paralog or bromodomain alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists and showed no evident toxicity. These findings position H2BNTac as an epigenetic marker of enhancer addiction and establish dual p300/CBP degradation as a promising therapeutic strategy for enhancer-driven cancers.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"111 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215839","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":"Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.","authors":"Wangjie Liu,Wouter Saelens,Pernille Rainer,Marjan Biočanin,Vincent Gardeux,Antoni Jakub Gralak,Guido van Mierlo,Angelika Gebhart,Julie Russeil,Tingdang Liu,Wanze Chen,Bart Deplancke","doi":"10.1038/s41588-025-02343-7","DOIUrl":"https://doi.org/10.1038/s41588-025-02343-7","url":null,"abstract":"Reprogramming often yields heterogeneous cell fates, yet the underlying mechanisms remain poorly understood. To address this, we developed single-cell transcription factor sequencing (scTF-seq), a single-cell technique that induces barcoded, doxycycline-inducible TF overexpression and quantifies TF dose-dependent transcriptomic changes. Applied to mouse embryonic multipotent stromal cells, scTF-seq generated a gain-of-function atlas for 384 mouse TFs, identifying key regulators of lineage specification, cell cycle control and their interplay. Leveraging single-cell resolution, we uncovered how TF dose shapes reprogramming heterogeneity, revealing both dose-dependent and stochastic cell state transitions. We classified TFs into low-capacity and high-capacity groups, with the latter further subdivided by dose sensitivity. Combinatorial scTF-seq demonstrated that TF interactions can shift from synergistic to antagonistic depending on the relative dose. Altogether, scTF-seq enables the dissection of TF function, dose and cell fate control, providing a high-resolution framework to understand and predict reprogramming outcomes, advancing gene regulation research and the design of cell engineering strategies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"78 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215837","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":"Limited overlap between genetic effects on disease susceptibility and disease survival.","authors":"Zhiyu Yang, Fanny-Dhelia Pajuste, Kristina Zguro, Yipeng Cheng, Danielle E Kurant, Andrea Eoli, Julian Wanner, Bradley Jermy, Joel Rämö, Stavroula Kanoni, David A van Heel, Caroline Hayward, Riccardo E Marioni, Daniel L McCartney, Alessandra Renieri, Simone Furini, Reedik Mägi, Alexander Gusev, Petros Drineas, Peristera Paschou, Henrike Heyne, Samuli Ripatti, Nina Mars, Andrea Ganna","doi":"10.1038/s41588-025-02342-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02342-8","url":null,"abstract":"<p><p>Understanding disease progression is of high biological and clinical interest. Unlike disease susceptibility, whose genetic basis has been abundantly studied, less is known about the genetics of disease progression and its overlap with disease susceptibility. Considering nine common diseases (n_cases ranging from 11,980 to 124,682) across seven biobanks, we systematically compared genetic architectures of susceptibility and progression, defined as disease-specific mortality. We identified only one locus substantially associated with disease-specific mortality and showed that, at a similar sample size, more genome-wide significant loci can be identified in a genome-wide association study of disease susceptibility. Variants substantially affecting disease susceptibility were weakly or not associated with disease-specific mortality. Moreover, susceptibility polygenic scores (PGSs) were weak predictors of disease-specific mortality, while a PGS for general lifespan was substantially associated with disease-specific mortality for seven of nine diseases. We explored alternative definitions of disease progression and found that genetic signals for macrovascular complications in type 2 diabetes overlap with similar phenotypes in the general population; however, these effects are attenuated. Overall, our findings indicate limited similarity in genetic effects between disease susceptibility and disease-specific mortality, suggesting that larger sample sizes, different measures of progression, or the integration of related phenotypes from the general population is needed to identify the genetic underpinnings of disease progression.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200415","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":"Dipping into the function of DNA methylation at centromeres.","authors":"Sylvia Erhardt","doi":"10.1038/s41588-025-02334-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02334-8","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"116 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189054","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":"Genetic perturbations link autoimmune risk variants to T cell function.","authors":"","doi":"10.1038/s41588-025-02302-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02302-2","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"20 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189426","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":"Publisher Correction: Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes.","authors":"Camiel M van der Laan, Hill F Ip, Marijn Schipper, Jouke-Jan Hottenga, Beate St Pourcain, Tetyana Zayats, René Pool, Eva M L Krapohl, Isabell Brikell, María Soler Artigas, Judit Cabana-Domínguez, Natalia Llonga, Ilja M Nolte, Koen Bolhuis, Teemu Palviainen, Hadi Zafarmand, Scott Gordon, Fazil Aliev, S Alexandra Burt, Carol A Wang, Gretchen Saunders, Ville Karhunen, Daniel E Adkins, Richard Border, Roseann E Peterson, Joseph A Prinz, Elisabeth Thiering, Natàlia Vilor-Tejedor, Tarunveer S Ahluwalia, Andrea Allegrini, Kaili Rimfeld, Qi Chen, Yi Lu, Joanna Martin, Rosa Bosch, Josep Antoni Ramos-Quiroga, Alexander Neumann, Judith Ensink, Katrina L Grasby, José J Morosoli, Xiaoran Tong, Shelby Marrington, James G Scott, Andrey A Shabalin, Robin Corley, Luke M Evans, Karen Sugden, Silvia Alemany, Lærke Sass, Rebecca Vinding, Erik A Ehli, Fiona A Hagenbeek, Eske M Derks, Henrik Larsson, Harold Snieder, Charlotte Cecil, Alyce M Whipp, Tellervo Korhonen, Eero Vuoksimaa, Richard J Rose, André G Uitterlinden, Jan Haavik, Jennifer R Harris, Øyvind Helgeland, Stefan Johansson, Gun Peggy S Knudsen, Pal Rasmus Njolstad, Qing Lu, Alina Rodriguez, Anjali K Henders, Abdullah Mamun, Jackob M Najman, Sandy Brown, Christian Hopfer, Kenneth Krauter, Chandra A Reynolds, Andrew Smolen, Michael Stallings, Sally Wadsworth, Tamara L Wall, Lindon Eaves, Judy L Silberg, Allison Miller, Alexandra Havdahl, Sabrina Llop, Maria-Jose Lopez-Espinosa, Klaus Bønnelykke, Jordi Sunyer, Louise Arseneault, Marie Standl, Joachim Heinrich, Joseph Boden, John Pearson, John Horwood, Martin Kennedy, Richie Poulton, Hermine H Maes, John Hewitt, William E Copeland, Christel M Middeldorp, Gail M Williams, Naomi Wray, Marjo-Riitta Järvelin, Matt McGue, William Iacono, Avshalom Caspi, Terrie E Moffitt, Andrew J O Whitehouse, Craig E Pennell, Kelly L Klump, Chang Jiang, Danielle M Dick, Ted Reichborn-Kjennerud, Nicholas G Martin, Sarah E Medland, Tanja Vrijkotte, Jaakko Kaprio, Henning Tiemeier, George Davey Smith, Catharina A Hartman, Albertine J Oldehinkel, Miquel Casas, Marta Ribasés, Paul Lichtenstein, Sebastian Lundström, Robert Plomin, Meike Bartels, Michel G Nivard, Dorret I Boomsma","doi":"10.1038/s41588-025-02383-z","DOIUrl":"10.1038/s41588-025-02383-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192091","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":"A standardized framework for circulating blood proteomics.","authors":"Xue Cai,Philipp E Geyer,Yasset Perez-Riverol,Gilbert S Omenn,Lianhua Dong,Robert Winkler,Sara Ahadi,Philip Lössl,Xiaobo Yu,Cheng Chang,Markus Ralser,Connie R Jimenez,Yang Zhao,Yu-Ju Chen,Terence C W Poon,Nicolai Bache,Leming Shi,Xinhua Dai,Ziyue Wang,Yi Zhu,Xiang Fang,Jochen M Schwenk,Jennifer E Van Eyk,Uwe Völker,Tiannan Guo","doi":"10.1038/s41588-025-02319-7","DOIUrl":"https://doi.org/10.1038/s41588-025-02319-7","url":null,"abstract":"The circulating blood proteome holds immense potential for biomarker discovery and understanding disease mechanisms. Notable advances in mass spectrometry and affinity-based technologies have been made, but data integration across studies and platforms is hindered by the absence of unified analytical standards. This limitation impedes comprehensive exploration of human biology across diverse phenotypes and cohorts as well as the translation of findings into clinical applications. The disparities between datasets, stemming from a combination of factors related to differences in sample collection, pre-analytical handling, measurement methods and instrumentation, further complicate data integration. In this Perspective, we outline key challenges in blood-based proteomics and propose actionable strategies. Central to our recommendations are high-quality, technology-agnostic reference samples, which can bridge disparate datasets and enable robust cross-study comparisons. By fostering interconnected investigations across proteomic technologies, blood sample collections, clinical phenotypes and different populations, these references will accelerate the field and its translation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"3 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127187","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":"Bryophytes hold a larger gene family space than vascular plants.","authors":"Shanshan Dong,Sibo Wang,Linzhou Li,Jin Yu,Yongxia Zhang,Jia-Yu Xue,Hengchi Chen,Jianchao Ma,Yuying Zeng,Yuqing Cai,Wei Huang,Xuping Zhou,Jiayi Wu,Jianyou Li,Yifeng Yao,Ruoyang Hu,Tao Zhao,Juan Carlos Villarreal A,Leon Dirick,Li Liu,Michael Ignatov,Minghui Jin,Jue Ruan,Yikun He,Haifeng Wang,Bo Xu,Ricardo Rozzi,Jill Wegrzyn,Dennis William Stevenson,Karen S Renzaglia,Hongfeng Chen,Li Zhang,Shouzhou Zhang,Roy Mackenzie,Javier E Moreno,Michael Melkonian,Tong Wei,Ying Gu,Xun Xu,Stefan A Rensing,Jinling Huang,Manyuan Long,Bernard Goffinet,John L Bowman,Yves Van de Peer,Huan Liu,Yang Liu","doi":"10.1038/s41588-025-02325-9","DOIUrl":"https://doi.org/10.1038/s41588-025-02325-9","url":null,"abstract":"After 500 million years of evolution, extant land plants compose the following two sister groups: the bryophytes and the vascular plants. Despite their small size and simple structure, bryophytes thrive in a wide variety of habitats, including extreme conditions. However, the genetic basis for their ecological adaptability and long-term survival is not well understood. A comprehensive super-pangenome analysis, incorporating 123 newly sequenced bryophyte genomes, reveals that bryophytes possess a substantially greater diversity of gene families than vascular plants. This includes a higher number of unique and lineage-specific gene families, originating from extensive new gene formation and continuous horizontal transfer of microbial genes over their long evolutionary history. The evolution of bryophytes' rich and diverse genetic toolkit, which includes new physiological innovations like unique immune receptors, likely facilitated their spread across different biomes. These newly sequenced bryophyte genomes offer a valuable resource for exploring alternative evolutionary strategies for terrestrial success.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"53 89 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116683","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":"The dawn of bryophyte genomics is here.","authors":"Giacomo Potente,Yuling Yue,Péter Szövényi","doi":"10.1038/s41588-025-02240-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02240-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"25 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116689","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}