Nature genetics最新文献

{"title":"Spatial organization of chromatin restricts activation of poised alternative promoters in LTRs","authors":"","doi":"10.1038/s41588-025-02238-7","DOIUrl":"10.1038/s41588-025-02238-7","url":null,"abstract":"Transposable elements (TEs) are important in the evolution of genomic functions but the mechanisms of their precise role in cancer pathogenesis is unclear. Alternative promoters at the TE subclass long terminal repeats (LTRs) are activated when topologically associating domain (TAD) hierarchy maintained by NIPBL is lost, potentially leading to aberrant transcription of oncogenes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1576-1577"},"PeriodicalIF":31.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546933","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":"Single-cell Micro-C profiles 3D genome structures at high resolution and characterizes multi-enhancer hubs","authors":"Honggui Wu, Jiankun Zhang, Longzhi Tan, Xiaoliang Sunney Xie","doi":"10.1038/s41588-025-02247-6","DOIUrl":"10.1038/s41588-025-02247-6","url":null,"abstract":"In animal genomes, regulatory DNA elements called enhancers govern precise spatiotemporal gene expression patterns in specific cell types. However, the spatial organization of enhancers within the nucleus to regulate target genes remains poorly understood. Here we report single-cell Micro-C (scMicro-C), a micrococcal nuclease-based three-dimensional (3D) genome mapping technique with an improved spatial resolution of 5 kb, and identified a specialized 3D enhancer structure termed ‘promoter–enhancer stripes (PESs)’, connecting a gene’s promoter to multiple enhancers. PES are formed by cohesin-mediated loop extrusion, which potentially brings multiple enhancers to the promoter. Further, we observed the prevalence of multi-enhancer hubs on genes with PES within single-cell 3D genome structures, wherein multiple enhancers form a spatial cluster in association with the gene promoter. Through its improved resolution, scMicro-C elucidates how enhancers are spatially coordinated to control genes. scMicro-C is a new method that provides high-resolution maps of the 3D genome. scMicro-C identifies structures called ‘promoter stripes’, which link a gene promoter to multiple downstream enhancers.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1777-1786"},"PeriodicalIF":31.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02247-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533083","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}

{"title":"The long-term effects of chemotherapy on normal blood cells","authors":"Emily Mitchell, My H. Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I. Hsu, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E. Machado, E. Joanna Baxter, George Follows, Daniel J. Hodson, Ultan McDermott, Gary J. Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A. Goodell, David Kent, Elisa Laurenti, Peter J. Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R. Stratton","doi":"10.1038/s41588-025-02234-x","DOIUrl":"10.1038/s41588-025-02234-x","url":null,"abstract":"Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3–80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects. Mutational signature analysis of blood cells isolated from 23 chemotherapy-exposed samples and 9 nonexposed controls characterizes the effects of various drugs on mutational burden, signature exposure and cell types.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1684-1694"},"PeriodicalIF":31.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02234-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520413","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}

{"title":"Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation","authors":"Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Li Zhao, Joanne I. Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z. Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P. Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi","doi":"10.1038/s41588-025-02235-w","DOIUrl":"10.1038/s41588-025-02235-w","url":null,"abstract":"The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy. Analysis of whole-genome sequencing data from hematopoietic stem and progenitor cells taken from patients with myeloma shows how treatment shapes clonal architecture and sheds light on the evolution of treatment-related myeloid neoplasms.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1695-1707"},"PeriodicalIF":31.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02235-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520459","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}

{"title":"How chemotherapy shapes hematopoietic stem cells","authors":"Terrence N. Wong, Daniel C. Link","doi":"10.1038/s41588-025-02231-0","DOIUrl":"10.1038/s41588-025-02231-0","url":null,"abstract":"Two complementary studies used whole-genome sequencing of single cell-derived hematopoietic colonies to show that chemotherapy results in a marked decrease in hematopoietic stem and progenitor cell (HSPC) diversity, with the parallel evolution of multiple independent HSPCs harboring mutations in DNA damage response genes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1566-1567"},"PeriodicalIF":31.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520409","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":"Tumor aneuploidy as a prognostic and predictive biomarker in immune checkpoint blockade","authors":"Daniel Huang, Liam F. Spurr, Ralph R. Weichselbaum, Sean P. Pitroda","doi":"10.1038/s41588-025-02226-x","DOIUrl":"https://doi.org/10.1038/s41588-025-02226-x","url":null,"abstract":"<p>Aneuploidy, a hallmark of cancer characterized by chromosome imbalances, drives tumorigenesis and facilitates cancer immune evasion. While high tumor aneuploidy is linked to immune checkpoint blockade (ICB) resistance and poor prognosis, evidence suggests that this resistance can be overcome through treatment intensification, for example, with the addition of ablative radiotherapy to ICB. In this Perspective, we argue that the predictive value of aneuploidy complements established biomarkers, such as tumor mutational burden (TMB) or programmed death ligand 1 (PD-L1) expression. We review contemporary methods for quantifying aneuploidy, explore novel approaches that target mitotic vulnerabilities in aneuploid tumors and highlight potential areas where aneuploidy-based stratification could be incorporated into ICB-based treatment paradigms across early-stage, locally advanced and metastatic cancers. Prospective trials incorporating aneuploidy-based stratification will be essential to validate its role in personalized cancer therapy.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"27 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515477","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":"Disruption of TAD hierarchy promotes LTR co-option in cancer","authors":"Elissa W. P. Wong,&nbsp;Merve Sahin,&nbsp;Rui Yang,&nbsp;UkJin Lee,&nbsp;Dan Li,&nbsp;Yingqian A. Zhan,&nbsp;Rohan Misra,&nbsp;Fanny Tomas,&nbsp;Nawaf Alomran,&nbsp;Alexander Polyzos,&nbsp;Cindy J. Lee,&nbsp;Tuan Trieu,&nbsp;Alexander Martinez-Fundichely,&nbsp;Thomas Wiesner,&nbsp;Andrew Rosowicz,&nbsp;Shuyuan Cheng,&nbsp;Christina Liu,&nbsp;Morgan Lallo,&nbsp;Alexander N. Shoushtari,&nbsp;Taha Merghoub,&nbsp;Pierre-Jacques Hamard,&nbsp;Richard Koche,&nbsp;Ekta Khurana,&nbsp;Effie Apostolou,&nbsp;Deyou Zheng,&nbsp;Yu Chen,&nbsp;Christina S. Leslie,&nbsp;Ping Chi","doi":"10.1038/s41588-025-02239-6","DOIUrl":"10.1038/s41588-025-02239-6","url":null,"abstract":"Transposable elements (TEs) are abundant in the human genome, and they provide the source for genetic and functional diversity. Previous studies have suggested that TEs are repressed by DNA methylation and chromatin modifications. Here through integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters (altPs) at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and the recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. Perturbation of hierarchical chromatin topology can lead to co-option of LTRs as functional altPs, driving aberrant transcriptional activation of oncogenes. These data uncovered a new layer of regulatory mechanisms of TE expression and posit TAD hierarchy dysregulation as a new mechanism for altP-mediated oncogene activation and transcriptional diversity in cancer. NIPBL perturbation activates long terminal repeat (LTR)-derived alternative promoters due to reorganization of chromatin’s hierarchical structure, leading to LTR co-option and oncogene activation in melanoma cell lines.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 7","pages":"1754-1765"},"PeriodicalIF":31.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02239-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515470","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}

{"title":"Author Correction: Incorporating genetic data improves target trial emulations and informs the use of polygenic scores in randomized controlled trial design","authors":"Jakob German, Zhiyu Yang, Sarah Urbut, Pekka Vartiainen, Pradeep Natarajan, Elisabetta Patorno, Zoltan Kutalik, Anthony Philippakis, Andrea Ganna","doi":"10.1038/s41588-025-02275-2","DOIUrl":"https://doi.org/10.1038/s41588-025-02275-2","url":null,"abstract":"<p>Correction to: <i>Nature Genetics</i> https://doi.org/10.1038/s41588-025-02229-8. Published online 18 June 2025.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"7 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503358","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":"How and when organisms edit their own genomes","authors":"Vincent C. T. Hanlon, Alex Cagan, Sebastian Eves-van den Akker","doi":"10.1038/s41588-025-02230-1","DOIUrl":"https://doi.org/10.1038/s41588-025-02230-1","url":null,"abstract":"<p>Mutations are often thought of as untargeted and non-adaptive, but in rare cases, organisms perform programmed, targeted and adaptive rearrangements of their own DNA sequences. Notable examples include the somatic diversification of immunoglobulin genes, which is the foundation of the vertebrate immune system, and natural CRISPR spacer arrays in bacteria, which recognize and cleave foreign DNA. These systems, along with a dozen known analogs scattered across the tree of life, often underlie critical biological functions, particularly in host–pathogen conflicts. In this Review, we compare the mechanisms by which organisms edit their own genomes. We show that superficially dissimilar editing systems often rely on surprisingly similar genetic mechanisms, regardless of function or taxon. Finally, we argue that the recurrence of editing in host–pathogen conflicts and the bias to a handful of well-studied organisms strongly suggest that new editing systems will be found in understudied pathogens and their hosts.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"16 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500404","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":"Spatial and temporal dynamics in progressive gallbladder cancer","authors":"Colm J. O’Rourke, Jesper B. Andersen","doi":"10.1038/s41588-025-02232-z","DOIUrl":"https://doi.org/10.1038/s41588-025-02232-z","url":null,"abstract":"How primary gallbladder tumors evolve to acquire immunosuppressive and pro-metastatic capabilities remains unclear. A study using single-cell RNA sequencing coupled with spatial profiling and functional experiments has pinpointed mechanisms of immune-mediated tumor cell reprogramming, fostering disease progression.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"102 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488382","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}