Nature genetics最新文献_第3页

Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation 自体干细胞移植后造血干细胞的克隆进化

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-01 DOI: 10.1038/s41588-025-02235-w

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

{"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":"https://doi.org/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.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"74 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How chemotherapy shapes hematopoietic stem cells 化疗如何塑造造血干细胞

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-07-01 DOI: 10.1038/s41588-025-02231-0

Terrence N. Wong, Daniel C. Link

引用次数: 0

Tumor aneuploidy as a prognostic and predictive biomarker in immune checkpoint blockade 肿瘤非整倍体作为免疫检查点阻断的预后和预测性生物标志物

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-30 DOI: 10.1038/s41588-025-02226-x

Daniel Huang, Liam F. Spurr, Ralph R. Weichselbaum, Sean P. Pitroda

引用次数: 0

Disruption of TAD hierarchy promotes LTR co-option in cancer TAD层级的破坏促进LTR在癌症中的协同选择

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-30 DOI: 10.1038/s41588-025-02239-6

Elissa W. P. Wong, Merve Sahin, Rui Yang, UkJin Lee, Dan Li, Yingqian A. Zhan, Rohan Misra, Fanny Tomas, Nawaf Alomran, Alexander Polyzos, Cindy J. Lee, Tuan Trieu, Alexander Martinez-Fundichely, Thomas Wiesner, Andrew Rosowicz, Shuyuan Cheng, Christina Liu, Morgan Lallo, Alexander N. Shoushtari, Taha Merghoub, Pierre-Jacques Hamard, Richard Koche, Ekta Khurana, Effie Apostolou, Deyou Zheng, Yu Chen, Christina S. Leslie, Ping Chi

{"title":"Disruption of TAD hierarchy promotes LTR co-option in cancer","authors":"Elissa W. P. Wong, Merve Sahin, Rui Yang, UkJin Lee, Dan Li, Yingqian A. Zhan, Rohan Misra, Fanny Tomas, Nawaf Alomran, Alexander Polyzos, Cindy J. Lee, Tuan Trieu, Alexander Martinez-Fundichely, Thomas Wiesner, Andrew Rosowicz, Shuyuan Cheng, Christina Liu, Morgan Lallo, Alexander N. Shoushtari, Taha Merghoub, Pierre-Jacques Hamard, Richard Koche, Ekta Khurana, Effie Apostolou, Deyou Zheng, Yu Chen, Christina S. Leslie, Ping Chi","doi":"10.1038/s41588-025-02239-6","DOIUrl":"https://doi.org/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.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"67 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: Incorporating genetic data improves target trial emulations and informs the use of polygenic scores in randomized controlled trial design 作者更正：纳入基因数据可以改善靶试验模拟，并为随机对照试验设计中多基因评分的使用提供信息

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-27 DOI: 10.1038/s41588-025-02275-2

Jakob German, Zhiyu Yang, Sarah Urbut, Pekka Vartiainen, Pradeep Natarajan, Elisabetta Patorno, Zoltan Kutalik, Anthony Philippakis, Andrea Ganna

引用次数: 0

How and when organisms edit their own genomes 生物体如何以及何时编辑自己的基因组

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-27 DOI: 10.1038/s41588-025-02230-1

Vincent C. T. Hanlon, Alex Cagan, Sebastian Eves-van den Akker

引用次数: 0

Spatial and temporal dynamics in progressive gallbladder cancer 进展性胆囊癌的时空动力学

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-26 DOI: 10.1038/s41588-025-02232-z

Colm J. O’Rourke, Jesper B. Andersen

引用次数: 0

Multi-omic analysis of gallbladder cancer identifies distinct tumor microenvironments associated with disease progression 胆囊癌的多组学分析确定了与疾病进展相关的不同肿瘤微环境

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-26 DOI: 10.1038/s41588-025-02236-9

Tao Zhou, Yanhong Wu, Shuai Li, Xinyao Qiu, Erdong Liu, Zhihua Xie, Xuebing Shi, Yani Zhang, Guosheng Ma, Wenbo Guo, Xiang Wang, Kaiting Wang, Xiaomeng Yao, Ji Hu, Siyun Shen, Shuai Yang, Xiaoqing Jiang, Jing Fu, Hongyang Wang, Jin Gu, Lei Chen

{"title":"Multi-omic analysis of gallbladder cancer identifies distinct tumor microenvironments associated with disease progression","authors":"Tao Zhou, Yanhong Wu, Shuai Li, Xinyao Qiu, Erdong Liu, Zhihua Xie, Xuebing Shi, Yani Zhang, Guosheng Ma, Wenbo Guo, Xiang Wang, Kaiting Wang, Xiaomeng Yao, Ji Hu, Siyun Shen, Shuai Yang, Xiaoqing Jiang, Jing Fu, Hongyang Wang, Jin Gu, Lei Chen","doi":"10.1038/s41588-025-02236-9","DOIUrl":"https://doi.org/10.1038/s41588-025-02236-9","url":null,"abstract":"Gallbladder carcinoma (GBC) is the most aggressive biliary tract cancer and is associated with a high mortality rate. Treatment of GBC faces therapeutic challenges owing to the elusive nature of in situ drivers within the local tumor microenvironment that drive its progression. Here, we created a single-cell atlas of 1,117,245 cells and a mutational landscape from 102 patients, which unveiled spatial–temporal characterizations of cellular constitutions, spatial interplays and molecular functions, and generalized five local ecosystems stratifying clinical outcomes. An integrated epithelial program, AI-EPI, combined with spatial transcriptome analysis, revealed the concurrent localization of a highly malignant tumor subtype (GM16) and AREG+ T cell, B cell, dendritic cell and macrophage subtypes within the pro-metastatic niche of primary adenocarcinomas. In vitro and in vivo experiments suggest that in addition to promoting metastasis, AREG facilitates CXCL5 expression in tumor cells through EGFR–pERK–EGR1 signaling, leading to increased neutrophil infiltration and impeding the effectiveness of immunotherapy. Our study provides a spatial–temporal landscape of the GBC microenvironment and sheds light on potential strategies for preventing immunotherapy resistance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"20 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488428","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}

引用次数: 0

Single-cell and spatial transcriptomics of stricturing Crohn’s disease highlights a fibrosis-associated network 狭窄性克罗恩病的单细胞和空间转录组学强调了纤维化相关网络

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-25 DOI: 10.1038/s41588-025-02225-y

Lingjia Kong, Sathish Subramanian, Åsa Segerstolpe, Vy Tran, Angela R. Shih, Grace T. Carter, Hiroko Kunitake, Shaina W. Twardus, Jasmine Li, Shivam Gandhi, Marco E. Kaper, Christy Cauley, Eric J. Chen, Caroline B. M. Porter, Toni M. Delorey, Liliana Bordeianou, Rocco Ricciardi, Ashwin N. Ananthakrishnan, Helena Lau, Daniel B. Graham, Richard Hodin, Jacques Deguine, Christopher S. Smillie, Ramnik J. Xavier

{"title":"Single-cell and spatial transcriptomics of stricturing Crohn’s disease highlights a fibrosis-associated network","authors":"Lingjia Kong, Sathish Subramanian, Åsa Segerstolpe, Vy Tran, Angela R. Shih, Grace T. Carter, Hiroko Kunitake, Shaina W. Twardus, Jasmine Li, Shivam Gandhi, Marco E. Kaper, Christy Cauley, Eric J. Chen, Caroline B. M. Porter, Toni M. Delorey, Liliana Bordeianou, Rocco Ricciardi, Ashwin N. Ananthakrishnan, Helena Lau, Daniel B. Graham, Richard Hodin, Jacques Deguine, Christopher S. Smillie, Ramnik J. Xavier","doi":"10.1038/s41588-025-02225-y","DOIUrl":"https://doi.org/10.1038/s41588-025-02225-y","url":null,"abstract":"Fibrosis is a major complication of Crohn’s disease (CD) marked by excess deposition of extracellular matrix, leading to stricturing and functional impairment. As mechanistic characterization and therapeutic options are lacking, we paired single-cell and spatial transcriptomics in 61 samples from 21 patients with CD and 10 patients without inflammatory bowel disease (IBD). Intestinal strictures were characterized by increased immune cells, including IgG+ plasma cells, CCR7-hi CD4+ T cells and inflammatory fibroblasts. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Furthermore, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"61 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478989","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}

引用次数: 0

Single-cell eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis 单细胞eQTL分析确定代谢功能障碍相关脂肪性肝炎的遗传变异

IF 30.8 1区生物学

Nature genetics Pub Date : 2025-06-25 DOI: 10.1038/s41588-025-02237-8

Sung Eun Hong, Seon Ju Mun, Young Joo Lee, Taekyeong Yoo, Kyung-Suk Suh, Keon Wook Kang, Myung Jin Son, Won Kim, Murim Choi

{"title":"Single-cell eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis","authors":"Sung Eun Hong, Seon Ju Mun, Young Joo Lee, Taekyeong Yoo, Kyung-Suk Suh, Keon Wook Kang, Myung Jin Son, Won Kim, Murim Choi","doi":"10.1038/s41588-025-02237-8","DOIUrl":"https://doi.org/10.1038/s41588-025-02237-8","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized for its medical and socioeconomic impacts, driven by diverse genetic and environmental factors. Here, to address the urgent need for individually tailored therapies, we show results from single-cell expression quantitative trait locus (sc-eQTL) analysis on liver biopsies from 25 patients with MASLD and 23 controls. This approach identified over 3,500 sc-eQTLs across major liver cell types and cell-state-interacting eQTLs (ieQTLs) with significant enrichment for disease heritability (for MASLD trait, ieQTL enrichment odds ratio 10.27). We integrated transcription factors as upstream regulators of ieQTLs, revealing 601 functional units (‘quartets’) composed of transcription factors, cell states, SNP components of ieQTL (ieSNPs) and Gene component of ieQTL (ieGenes). From these results, we pinpoint the loss of an eQTL in EFHD1 during hepatocyte maladaptation associated with genotype-specific regulation by FOXO1, further contributing to the risk of MASLD. Our approach underscores the role of eQTL analysis in capturing crucial genetic variations that influence gene expression and clinical outcomes in complex diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"193 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478990","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}

引用次数: 0