Nature genetics最新文献

{"title":"Custom microfluidic chip design enables cost-effective three-dimensional spatiotemporal transcriptomics with a wide field of view","authors":"Junjie Zhu, Kun Pang, Beiyu Hu, Ruiqiao He, Ning Wang, Zewen Jiang, Peifeng Ji, Fangqing Zhao","doi":"10.1038/s41588-024-01906-4","DOIUrl":"10.1038/s41588-024-01906-4","url":null,"abstract":"Spatial transcriptomic techniques offer unprecedented insights into the molecular organization of complex tissues. However, integrating cost-effectiveness, high throughput, a wide field of view and compatibility with three-dimensional (3D) volumes has been challenging. Here we introduce microfluidics-assisted grid chips for spatial transcriptome sequencing (MAGIC-seq), a new method that combines carbodiimide chemistry, spatial combinatorial indexing and innovative microfluidics design. This technique allows sensitive and reproducible profiling of diverse tissue types, achieving an eightfold increase in throughput, minimal cost and reduced batch effects. MAGIC-seq breaks conventional microfluidics limits by enhancing barcoding efficiency and enables analysis of whole postnatal mouse sections, providing comprehensive cellular structure elucidation at near single-cell resolution, uncovering transcriptional variations and dynamic trajectories of mouse organogenesis. Our 3D transcriptomic atlas of the developing mouse brain, consisting of 93 sections, reveals the molecular and cellular landscape, serving as a valuable resource for neuroscience and developmental biology. Overall, MAGIC-seq is a high-throughput, cost-effective, large field of view and versatile method for spatial transcriptomic studies. Microfluidics-assisted grid chips for spatial transcriptome sequencing (MAGIC-seq) is a spatial transcriptomics method combining multiple-grid microfluidic design and prefabricated DNA arrays for increased throughput and reduced cost, with applications for large fields of view and 3D spatial mapping.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01906-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160458","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":"Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function","authors":"Gabriel B. Loeb, Pooja Kathail, Richard W. Shuai, Ryan Chung, Reinier J. Grona, Sailaja Peddada, Volkan Sevim, Scot Federman, Karl Mader, Audrey Y. Chu, Jonathan Davitte, Juan Du, Alexander R. Gupta, Chun Jimmie Ye, Shawn Shafer, Laralynne Przybyla, Radu Rapiteanu, Nilah M. Ioannidis, Jeremy F. Reiter","doi":"10.1038/s41588-024-01904-6","DOIUrl":"10.1038/s41588-024-01904-6","url":null,"abstract":"Kidney failure, the decrease of kidney function below a threshold necessary to support life, is a major cause of morbidity and mortality. We performed a genome-wide association study (GWAS) of 406,504 individuals in the UK Biobank, identifying 430 loci affecting kidney function in middle-aged adults. To investigate the cell types affected by these loci, we integrated the GWAS with human kidney candidate cis-regulatory elements (cCREs) identified using single-cell assay for transposase-accessible chromatin sequencing (scATAC–seq). Overall, 56% of kidney function heritability localized to kidney tubule epithelial cCREs and an additional 7% to kidney podocyte cCREs. Thus, most heritable differences in adult kidney function are a result of altered gene expression in these two cell types. Using enhancer assays, allele-specific scATAC–seq and machine learning, we found that many kidney function variants alter tubule epithelial cCRE chromatin accessibility and function. Using CRISPRi, we determined which genes some of these cCREs regulate, implicating NDRG1, CCNB1 and STC1 in human kidney function. Integration of genome-wide association analysis of 406,504 individuals in the UK Biobank and scATAC–seq data reveals that variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160475","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":"Defining and pursuing diversity in human genetic studies","authors":"Maili C. Raven-Adams, Tina Hernandez-Boussard, Yann Joly, Bartha Maria Knoppers, Subhashini Chandrasekharan, Adrian Thorogood, Judit Kumuthini, Calvin Wai Loon Ho, Ariana Gonzlez, Sarah C. Nelson, Yvonne Bombard, Donrich Thaldar, Hanshi Liu, Alessia Costa, Vijaytha Muralidharan, Sasha Henriques, Jamal Nasir, Aimé Lumaka, Beatrice Kaiser, Saumya Shekhar Jamuar, Anna C. F. Lewis","doi":"10.1038/s41588-024-01903-7","DOIUrl":"10.1038/s41588-024-01903-7","url":null,"abstract":"Calls for more diverse data in genetics studies typically fall short of offering further guidance. Here we summarize a policy framework from the Global Alliance for Genomics and Health designed to fill this gap. The framework prompts researchers to consider both what types of diversity are needed and why, and how aims can be achieved through choices made throughout the data life cycle.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158749","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":"High-quality genome of a modern soybean cultivar and resequencing of 547 accessions provide insights into the role of structural variation","authors":"Caiying Zhang, Zhenqi Shao, Youbin Kong, Hui Du, Wenlong Li, Zhanwu Yang, Xiangkong Li, Huifeng Ke, Zhengwen Sun, Jiabiao Shao, Shiliang Chen, Hua Zhang, Jiahao Chu, Xinzhu Xing, Rui Tian, Ning Qin, Junru Li, Meihong Huang, Yaqian Sun, Xiaobo Huo, Chengsheng Meng, Guoning Wang, Yuan Liu, Zhiying Ma, Shilin Tian, Xihuan Li","doi":"10.1038/s41588-024-01901-9","DOIUrl":"10.1038/s41588-024-01901-9","url":null,"abstract":"Soybean provides protein, oil and multiple health-related compounds. Understanding the effects of structural variations (SVs) on economic traits in modern breeding is important for soybean improvement. Here we assembled the high-quality genome of modern cultivar Nongdadou2 (NDD2) and identified 25,814 SV–gene pairs compared to 29 reported genomes, with 13 NDD2-private SVs validated in 547 deep-resequencing (average = 18.05-fold) accessions, which advances our understanding of genomic variation biology. We found some insertions/deletions involved in seed protein and weight formation, an inversion related to adaptation to drought and a large intertranslocation implicated in a key divergence event in soybean. Of 749,714 SVs from 547 accessions, 6,013 were significantly associated with 22 yield-related and seed-quality-related traits determined in ten location × year environments. We uncovered 1,761 associated SVs that hit genes or regulatory regions, with 12 in GmMQT influencing oil and isoflavone contents. Our work provides resources and insights into SV roles in soybean improvement. High-quality genome of the modern soybean cultivar Nongdadou2 and deep resequencing of 547 accessions provide insights into the role of structural variations in soybean improvement.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158751","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":"NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis","authors":"Abhijit Parolia, Sanjana Eyunni, Brijesh Kumar Verma, Eleanor Young, Yihan Liu, Lianchao Liu, James George, Shweta Aras, Chandan Kanta Das, Rahul Mannan, Reyaz ur Rasool, Erick Mitchell-Velasquez, Somnath Mahapatra, Jie Luo, Sandra E. Carson, Lanbo Xiao, Prathibha R. Gajjala, Sharan Venkatesh, Mustapha Jaber, Xiaoju Wang, Tongchen He, Yuanyuan Qiao, Matthew Pang, Yuping Zhang, Jean Ching-Yi Tien, Micheala Louw, Mohammed Alhusayan, Xuhong Cao, Fengyun Su, Omid Tavana, Caiyun Hou, Zhen Wang, Ke Ding, Arul M. Chinnaiyan, Irfan A. Asangani","doi":"10.1038/s41588-024-01893-6","DOIUrl":"10.1038/s41588-024-01893-6","url":null,"abstract":"Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer. CRISPR screen identifies coactivators of the androgen receptor (AR) complex, including NSD2. NSD2 contributes to AR cistrome reprogramming during prostate cancer progression, and its degradation via a novel PROTAC reduces prostate cancer cell viability in vitro.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01893-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158750","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":"In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions","authors":"Peiran Su, Yin Liu, Tianyi Chen, Yibo Xue, Yong Zeng, Guanghui Zhu, Sujun Chen, Mona Teng, Xinpei Ci, Mengdi Guo, Michael Y. He, Jun Hao, Vivian Chu, Wenxi Xu, Shiyan Wang, Parinaz Mehdipour, Xin Xu, Sajid A. Marhon, Fraser Soares, Nhu-An Pham, Bell Xi Wu, Peter Hyunwuk Her, Shengrui Feng, Najd Alshamlan, Maryam Khalil, Rehna Krishnan, Fangyou Yu, Chang Chen, Francis Burrows, Razqallah Hakem, Mathieu Lupien, Shane Harding, Benjamin H. Lok, Catherine O’Brien, Alejandro Berlin, Daniel D. De Carvalho, David G. Brooks, Daniel Schramek, Ming-Sound Tsao, Housheng Hansen He","doi":"10.1038/s41588-024-01874-9","DOIUrl":"10.1038/s41588-024-01874-9","url":null,"abstract":"Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin–MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers. Loss of MEN1 affects tumor growth, varing with the components of the tumor microenvironment. These tumors show redistribution of MLL1 on chromatin and the activation of a viral mimicry response.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01874-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123704","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":"Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment","authors":"Carina Shiau, Jingyi Cao, Dennis Gong, Mark T. Gregory, Nicholas J. Caldwell, Xunqin Yin, Jae-Won Cho, Peter L. Wang, Jennifer Su, Steven Wang, Jason W. Reeves, Tae Kyung Kim, Youngmi Kim, Jimmy A. Guo, Nicole A. Lester, Jung Woo Bae, Ryan Zhao, Nathan Schurman, Jamie L. Barth, Maria L. Ganci, Ralph Weissleder, Tyler Jacks, Motaz Qadan, Theodore S. Hong, Jennifer Y. Wo, Hannah Roberts, Joseph M. Beechem, Carlos Fernandez-del Castillo, Mari Mino-Kenudson, David T. Ting, Martin Hemberg, William L. Hwang","doi":"10.1038/s41588-024-01890-9","DOIUrl":"10.1038/s41588-024-01890-9","url":null,"abstract":"In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell–cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand–receptor gene expression. Our results uncovered a marked change in ligand–receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts. Spatial molecular imaging analysis of human pancreatic adenocarcinomas describes multicellular neighborhoods in the tumor microenvironment. Ligand–receptor analysis using optimal transport-based SCOTIA identifies interleukin-6 as a mediator of chemoresistance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123705","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":"Activating the dark genome to illuminate cancer vaccine targets","authors":"Darwin W. Kwok, Hideho Okada, Joseph F. Costello","doi":"10.1038/s41588-024-01850-3","DOIUrl":"10.1038/s41588-024-01850-3","url":null,"abstract":"Epigenetic therapy triggers myriad transposable elements to generate new antigens that could prime tumor cells for immunotherapy. A study of glioblastoma discovers indiscriminate activation in healthy cells as well, and presents a more selective strategy for potential therapeutic targeting.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118127","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":"Global impact of unproductive splicing on human gene expression","authors":"Benjamin Fair, Carlos F. Buen Abad Najar, Junxing Zhao, Stephanie Lozano, Austin Reilly, Gabriela Mossian, Jonathan P. Staley, Jingxin Wang, Yang I. Li","doi":"10.1038/s41588-024-01872-x","DOIUrl":"10.1038/s41588-024-01872-x","url":null,"abstract":"Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing ‘unproductive’ transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS–NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared with prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Our findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome. Genomic analyses suggest that ~15% of transcript molecules are spliced into unproductive transcripts targeted by nonsense-mediated decay, which have a larger effect on gene expression than previously thought.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01872-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118130","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":"Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells","authors":"H. Josh Jang, Nakul M. Shah, Ju Heon Maeng, Yonghao Liang, Noah L. Basri, Jiaxin Ge, Xuan Qu, Tatenda Mahlokozera, Shin-Cheng Tzeng, Russell B. Williams, Michael J. Moore, Devi Annamalai, Justin Y. Chen, Hyung Joo Lee, Patrick A. DeSouza, Daofeng Li, Xiaoyun Xing, Albert H. Kim, Ting Wang","doi":"10.1038/s41588-024-01880-x","DOIUrl":"10.1038/s41588-024-01880-x","url":null,"abstract":"Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy. Treatment of primary glioblastoma cell lines with epigenetic therapy reactivates transposable elements (TEs). TE-derived transcripts can produce human leukocyte antigen class I-presented antigens, which could potentially be therapeutically targeted.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118131","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}