Nature genetics最新文献

{"title":"Establishing Polycomb regulatory landscapes in human early development","authors":"Xiaoyu Hu, Chuanxin Zhang, Bofeng Liu, Fangnong Lai, Shuiying Ma, Zhenzhen Hou, Qizhe Shao, Ling Liu, Xukun Lu, Guanling Yu, Hui Liu, Zhen Yang, Ning Wang, Xi Wu, Zili Lin, Lijuan Wang, Yongli Shan, Guangjin Pan, Di Chen, Bo Zhang, Lei Jin, Han Zhao, Keliang Wu, Zi-Jiang Chen, Wei Xie","doi":"10.1038/s41588-026-02764-y","DOIUrl":"https://doi.org/10.1038/s41588-026-02764-y","url":null,"abstract":"H2AK119ub (H2Aub) and H3K27me3, which are deposited by the Polycomb group (PcG) complexes PRC1 and PRC2, respectively, cooperatively repress developmental genes. However, in human preimplantation embryos, H3K27me3 undergoes genome-wide erasure and subsequent restoration. How H3K27me3 is reestablished and whether PcG complexes still regulate gene repression in human embryos remain unknown. Here, we profiled H2Aub dynamics from human gametes to blastocysts. H2Aub emerges in GC-rich regions as early as the two-cell stage, progressively accumulates at both active and inactive genes, and further culminates at PcG targets in later stages. H3K27me3 is weakly correlated with H2Aub in oocytes and two-cell embryos but colocalizes with H2Aub at H3K4me3-depleted, inactive PcG targets in blastocysts. Loss of H2Aub abolishes H3K27me3 reestablishment at PcG targets causing moderate derepression, accompanied by ectopic H3K27me3 deposition and impaired embryonic development. Finally, H2Aub and DNA methylation cooperatively maintain H3K27me3 patterning in human embryonic stem cells. Therefore, H2Aub-dependent H3K27me3 deposition underlies the earliest establishment of Polycomb repression in humans.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"11 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218247","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":"RNA ends connect genetic risk to brain disease.","authors":"Michael J Ziller","doi":"10.1038/s41588-026-02791-9","DOIUrl":"https://doi.org/10.1038/s41588-026-02791-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224466","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: Gb3 encodes a unique kinase fusion protein conferring greenbug resistance in wheat.","authors":"Dhondup Lhamo, Jianqiang Shen, Genqiao Li, Toni Mohr, Roger Thilmony, Prakitchai Chotewutmontri, Han-Chang Chang, Honglian Ye, Mingcheng Luo, Shuyu Liu, Guihua Bai, Jackie Rudd, Brett F Carver, Yong Q Gu, Xiangyang Xu, Steven S Xu","doi":"10.1038/s41588-026-02835-0","DOIUrl":"https://doi.org/10.1038/s41588-026-02835-0","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207233","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":"Author Correction: Histone H3 proline 16 hydroxylation regulates mammalian gene expression.","authors":"Xijuan Liu, Jun Wang, Joshua A Boyer, Weida Gong, Shuai Zhao, Ling Xie, Qiong Wu, Cheng Zhang, Kanishk Jain, Yiran Guo, Javier Rodriguez, Mingjie Li, Hidetaka Uryu, Chengheng Liao, Lianxin Hu, Jin Zhou, Xiaobing Shi, Yi-Hsuan Tsai, Qin Yan, Weibo Luo, Xian Chen, Brian D Strahl, Alex von Kriegsheim, Qi Zhang, Gang Greg Wang, Albert S Baldwin, Qing Zhang","doi":"10.1038/s41588-026-02828-z","DOIUrl":"https://doi.org/10.1038/s41588-026-02828-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183215","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":"Clonal heterogeneity in human pancreatic ductal adenocarcinoma and its impact on tumor progression.","authors":"Despoina Kalfakakou, Daniel C Cameron, Emily A Kawaler, Motoyuki Tsuda, Lidong Wang, Qi Su, Sungsik Kim, Elektra Manolakos, Xiaohong Jing, Cristina Hajdu, Dylan L Tamayo, Yoona Shim, Amanda Ackermann, Daniel Weissinger, Hayley Zimny, Rosmel Hernandez, Matthew Beier, Dacia Dimartino, Peter Meyn, Kalina Rice, Shanmugapriya Selvaraj, Cynthia Loomis, Adriana Heguy, Amanda W Lund, Hannah Carter, Rosalie C Sears, Theodore H Welling, Igor Dolgalev, Aristotelis Tsirigos, Diane M Simeone","doi":"10.1038/s41588-026-02779-5","DOIUrl":"https://doi.org/10.1038/s41588-026-02779-5","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by profound desmoplasia and cellular heterogeneity, which cannot be fully resolved using traditional bulk sequencing approaches. To understand how this heterogeneity contributes to PDAC biology, we analyzed a large cohort of primary tumors (n = 62) profiled using single-cell RNA sequencing (443,451 single cells), including a subset of 11 tumors with matched spatial transcriptomics (53,236 spots), to map clonal, transcriptional and spatial diversity. Moreover, our sample set includes a unique cohort of matched samples from six tumors collected before and after treatment with chemotherapy. Our analysis revealed notable intratumoral heterogeneity, with multiple genetically distinct neoplastic clones coexisting within individual tumors. We observed clone-specific ligand-receptor programs that are modulated by genomic dosage: amplifications of ligands or receptors enriched corresponding interactions, while deletions suppressed them, with genetically encoded differences supported by spatial transcriptomics and multiplex immunofluorescence. Phylogenetic integration identified focal 8q24 (MYC) amplification as recurrently associated with classical-to-basal transitions occurring within tumor lineages at a frequency above chance; these transitions were accompanied by coordinated depletion of immune-response programs. Functional perturbation experiments in murine and primary human models showed that MYC knockdown reactivates classical transcriptional programs and restores immune-response pathways, supporting a role for MYC in maintaining a basal, immune-depleted state. Spatial analyses further revealed dispersed clones enriched for epithelial-to-mesenchymal transition activity and immune suppression, correlating with metastatic potential and colonization of lymph node niches. These dispersed clones shifted toward a basal phenotype, contributing to disease progression. Our findings highlight the critical role of clonal diversity, transcriptional plasticity and tumor microenvironment interactions in shaping human PDAC biology. This work provides a detailed view of the molecular and spatial heterogeneity of PDAC and offers potential avenues for therapeutic intervention targeting clonal evolution and the mechanisms driving metastasis.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183175","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":"Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival.","authors":"Lotte Brückner, Robin Xu, Jun Tang, Aditi Gnanasekar, Alexander Herrmann, Ivy Tsz-Lo Wong, Shu Zhang, Fengyu Tu, Madison Pilon, Alexander Kukalev, Katharina Pardon, Olga Sidorova, Joshua Atta, Qinghao Yu, Giulia Montuori, Davide Pradella, Mila Ilić, Kentaro Suina, Marco Novais-Cruz, Sarah Kaltenbach, Denise Treue, Mădălina Giurgiu-Kraljič, Sergej Herzog, Ann-Sophie Hollinger, Nadine Wittstruck, Martina Fernandez, Nicole Wolozyn, Finnja Becker, Varvara-Rigina Louma, Xiaowei Yan, Rachel Schmargon, Jan R Dörr, David Gamlin, Annika Lehmann, Dennis Gürgen, Matthias Richter, Frank Dubois, Fabrizio Simeoni, Betheney R Pennycook, Alastair Hamilton, Ralph K Lindemann, Courtney Dawes, Gabriel Balmus, Barbara Hero, Matthias Fischer, Vineet Bafna, Roel Verhaak, Geoffrey Wahl, Yang Liu, Richard P Koche, Stamatis Papathanasiou, René Medema, Bastiaan Spanjaard, Andrea Ventura, Ana Pombo, Weini Huang, Monika Scheer, Benjamin Werner, Howard Y Chang, Paul S Mischel, Anton G Henssen","doi":"10.1038/s41588-026-02782-w","DOIUrl":"https://doi.org/10.1038/s41588-026-02782-w","url":null,"abstract":"<p><p>Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification and genetic intratumoral heterogeneity. Micronuclei (MNs) are common in chromosomally unstable cancers, yet their role in ecDNA-driven tumors remains unclear. Here we investigate how ecDNA damage, mitotic segregation and MN formation are linked. We find that ecDNAs are a major source of MNs following their damage, particularly under replication stress. Replication stress promotes mitotic ecDNA clustering, asymmetric inheritance, mis-segregation into MNs and reduced transcriptional output. Single-MN sequencing reveals that multiple distinct ecDNA species coalesce within individual MNs. Cells inheriting ecDNA⁺ MNs display impaired proliferative capacity and are more likely to undergo cell death. In patients with MYCN-amplified neuroblastoma, higher frequencies of ecDNA⁺ MNs at diagnosis are associated with improved overall survival. Together, these findings identify ecDNA mis-segregation as a mechanism that limits tumor fitness, highlighting mitotic ecDNA retention as a potential therapeutic vulnerability.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":" ","pages":""},"PeriodicalIF":25.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168163","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":"Phylogeny-informed genomic prediction with GPN-Star","authors":"Wei Li","doi":"10.1038/s41588-026-02804-7","DOIUrl":"10.1038/s41588-026-02804-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2424-2424"},"PeriodicalIF":25.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125993","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":"Calorie restriction reduces somatic mutation burden in mice","authors":"Hui Hua","doi":"10.1038/s41588-026-02803-8","DOIUrl":"10.1038/s41588-026-02803-8","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2424-2424"},"PeriodicalIF":25.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125995","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":"Live-cell transcriptomics","authors":"Petra Gross","doi":"10.1038/s41588-026-02802-9","DOIUrl":"10.1038/s41588-026-02802-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2424-2424"},"PeriodicalIF":25.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125994","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":"Overcoming hybrid sterility in rice","authors":"Tiago Faial","doi":"10.1038/s41588-026-02801-w","DOIUrl":"10.1038/s41588-026-02801-w","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 10","pages":"2424-2424"},"PeriodicalIF":25.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125997","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}