Pub Date : 2025-01-22DOI: 10.1016/j.cell.2024.12.017
Richard J. Abdill, Samantha P. Graham, Vincent Rubinetti, Mansooreh Ahmadian, Parker Hicks, Ashwin Chetty, Daniel McDonald, Pamela Ferretti, Elizabeth Gibbons, Marco Rossi, Arjun Krishnan, Frank W. Albert, Casey S. Greene, Sean Davis, Ran Blekhman
The factors shaping human microbiome variation are a major focus of biomedical research. While other fields have used large sequencing compendia to extract insights requiring otherwise impractical sample sizes, the microbiome field has lacked a comparably sized resource for the 16S rRNA gene amplicon sequencing commonly used to quantify microbiome composition. To address this gap, we processed 168,464 publicly available human gut microbiome samples with a uniform pipeline. We use this compendium to evaluate geographic and technical effects on microbiome variation. We find that regions such as Central and Southern Asia differ significantly from the more thoroughly characterized microbiomes of Europe and Northern America and that composition alone can be used to predict a sample’s region of origin. We also find strong associations between microbiome variation and technical factors such as primers and DNA extraction. We anticipate this growing work, the Human Microbiome Compendium, will enable advanced applied and methodological research.
{"title":"Integration of 168,000 samples reveals global patterns of the human gut microbiome","authors":"Richard J. Abdill, Samantha P. Graham, Vincent Rubinetti, Mansooreh Ahmadian, Parker Hicks, Ashwin Chetty, Daniel McDonald, Pamela Ferretti, Elizabeth Gibbons, Marco Rossi, Arjun Krishnan, Frank W. Albert, Casey S. Greene, Sean Davis, Ran Blekhman","doi":"10.1016/j.cell.2024.12.017","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.017","url":null,"abstract":"The factors shaping human microbiome variation are a major focus of biomedical research. While other fields have used large sequencing compendia to extract insights requiring otherwise impractical sample sizes, the microbiome field has lacked a comparably sized resource for the 16S rRNA gene amplicon sequencing commonly used to quantify microbiome composition. To address this gap, we processed 168,464 publicly available human gut microbiome samples with a uniform pipeline. We use this compendium to evaluate geographic and technical effects on microbiome variation. We find that regions such as Central and Southern Asia differ significantly from the more thoroughly characterized microbiomes of Europe and Northern America and that composition alone can be used to predict a sample’s region of origin. We also find strong associations between microbiome variation and technical factors such as primers and DNA extraction. We anticipate this growing work, the Human Microbiome Compendium, will enable advanced applied and methodological research.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"25 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991910","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}
Pub Date : 2025-01-21DOI: 10.1016/j.cell.2024.12.018
Rong Zeng, Yiting Shi, Li Guo, Diyi Fu, Minze Li, Xiaoyan Zhang, Zhuoyang Li, Junhong Zhuang, Xiaohong Yang, Jianru Zuo, Zhizhong Gong, Feng Tian, Shuhua Yang
Low temperature severely limits the growth, yield, and geographical distribution of maize (Zea mays L.). How maize adapts to cold climates remains largely unclear. Here, we identify a basic helix-loop-helix (bHLH) transcription factor, COLD-RESPONSIVE OPERATION LOCUS 1 (COOL1), as a crucial regulator of maize cold tolerance through genome-wide association studies. Natural variations in the COOL1 promoter affect the binding affinity of ELONGATED HYPOCOTYL5 (HY5), a transcriptional factor repressing COOL1 transcription. COOL1, in turn, negatively regulates downstream cold-responsive genes, thereby modulating cold tolerance. Moreover, calcium-dependent protein kinase CPK17 translocates to the nucleus and stabilizes COOL1 in response to cold stress. Intriguingly, the cold-tolerant allele of COOL1 is predominantly distributed in northern high latitudes with cold climates. This study defines a previously unknown pathway by which the COOL1-centered module regulates cold tolerance for high latitudinal adaptation in maize.
低温严重限制了玉米（Zea mays L.）的生长、产量和地理分布。玉米如何适应寒冷气候在很大程度上仍不清楚。在此，我们通过全基因组关联研究确定了一个基本的螺旋-环-螺旋（bHLH）转录因子，cold - responsive OPERATION LOCUS 1 (COOL1)，作为玉米耐寒性的关键调控因子。COOL1启动子的自然变异影响了抑制COOL1转录的转录因子伸长下cotyl5 （HY5）的结合亲和力。COOL1反过来负向调节下游冷反应基因，从而调节耐寒性。此外，钙依赖性蛋白激酶CPK17在冷胁迫下易位到细胞核并稳定COOL1。有趣的是，COOL1的耐寒等位基因主要分布在气候寒冷的北方高纬度地区。这项研究确定了一个以前未知的途径，通过该途径，以cool1为中心的模块调节玉米的耐冷性以适应高纬度环境。
{"title":"A natural variant of COOL1 gene enhances cold tolerance for high-latitude adaptation in maize","authors":"Rong Zeng, Yiting Shi, Li Guo, Diyi Fu, Minze Li, Xiaoyan Zhang, Zhuoyang Li, Junhong Zhuang, Xiaohong Yang, Jianru Zuo, Zhizhong Gong, Feng Tian, Shuhua Yang","doi":"10.1016/j.cell.2024.12.018","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.018","url":null,"abstract":"Low temperature severely limits the growth, yield, and geographical distribution of maize (<em>Zea mays</em> L.). How maize adapts to cold climates remains largely unclear. Here, we identify a basic helix-loop-helix (bHLH) transcription factor, COLD-RESPONSIVE OPERATION LOCUS 1 (COOL1), as a crucial regulator of maize cold tolerance through genome-wide association studies. Natural variations in the <em>COOL1</em> promoter affect the binding affinity of ELONGATED HYPOCOTYL5 (HY5), a transcriptional factor repressing <em>COOL1</em> transcription. COOL1, in turn, negatively regulates downstream cold-responsive genes, thereby modulating cold tolerance. Moreover, calcium-dependent protein kinase CPK17 translocates to the nucleus and stabilizes COOL1 in response to cold stress. Intriguingly, the cold-tolerant allele of <em>COOL1</em> is predominantly distributed in northern high latitudes with cold climates. This study defines a previously unknown pathway by which the COOL1-centered module regulates cold tolerance for high latitudinal adaptation in maize.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"74 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991914","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}
Pub Date : 2025-01-21DOI: 10.1016/j.cell.2024.12.019
Tara I. McIntyre, Omar Valdez, Nathan P. Kochhar, Brittany Davidson, Bushra Samad, Longhui Qiu, Kenneth Hu, Alexis J. Combes, Adrian Erlebacher
Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.
{"title":"KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice","authors":"Tara I. McIntyre, Omar Valdez, Nathan P. Kochhar, Brittany Davidson, Bushra Samad, Longhui Qiu, Kenneth Hu, Alexis J. Combes, Adrian Erlebacher","doi":"10.1016/j.cell.2024.12.019","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.019","url":null,"abstract":"Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"25 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990655","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.021
Side Hu, Heesu Kim, Pan Yang, Zishuo Yu, Barbara Ludeke, Shawna Mobilia, Junhua Pan, Margaret Stratton, Yuemin Bian, Rachel Fearns, Jonathan Abraham
Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.
{"title":"Structural and functional analysis of the Nipah virus polymerase complex","authors":"Side Hu, Heesu Kim, Pan Yang, Zishuo Yu, Barbara Ludeke, Shawna Mobilia, Junhua Pan, Margaret Stratton, Yuemin Bian, Rachel Fearns, Jonathan Abraham","doi":"10.1016/j.cell.2024.12.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.021","url":null,"abstract":"Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L) and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"78 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990312","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.016
Rafael Valdés-Mas, Avner Leshem, Danping Zheng, Yotam Cohen, Lara Kern, Niv Zmora, Yiming He, Corine Katina, Shimrit Eliyahu-Miller, Tal Yosef-Hevroni, Liron Richman, Barbara Raykhel, Shira Allswang, Reut Better, Merav Shmueli, Aurelia Saftien, Nyssa Cullin, Fernando Slamovitz, Dragos Ciocan, Kyanna S. Ouyang, Eran Elinav
Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.
{"title":"Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease","authors":"Rafael Valdés-Mas, Avner Leshem, Danping Zheng, Yotam Cohen, Lara Kern, Niv Zmora, Yiming He, Corine Katina, Shimrit Eliyahu-Miller, Tal Yosef-Hevroni, Liron Richman, Barbara Raykhel, Shira Allswang, Reut Better, Merav Shmueli, Aurelia Saftien, Nyssa Cullin, Fernando Slamovitz, Dragos Ciocan, Kyanna S. Ouyang, Eran Elinav","doi":"10.1016/j.cell.2024.12.016","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.016","url":null,"abstract":"Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a “compositional dysbiosis” and a concomitant species-specific “functional dysbiosis” driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989764","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.013
Marlies E. Oomen, Diego Rodriguez-Terrones, Mayuko Kurome, Valeri Zakhartchenko, Lorenza Mottes, Kilian Simmet, Camille Noll, Tsunetoshi Nakatani, Carlos Michel Mourra-Diaz, Irene Aksoy, Pierre Savatier, Jonathan Göke, Eckhard Wolf, Henrik Kaessmann, Maria-Elena Torres-Padilla
Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5′ for high sensitivity, full-length transcript coverage and simultaneous capture of 5′ transcript information from single cells and single embryos. Using Smart-seq+5′, we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.
{"title":"An atlas of transcription initiation reveals regulatory principles of gene and transposable element expression in early mammalian development","authors":"Marlies E. Oomen, Diego Rodriguez-Terrones, Mayuko Kurome, Valeri Zakhartchenko, Lorenza Mottes, Kilian Simmet, Camille Noll, Tsunetoshi Nakatani, Carlos Michel Mourra-Diaz, Irene Aksoy, Pierre Savatier, Jonathan Göke, Eckhard Wolf, Henrik Kaessmann, Maria-Elena Torres-Padilla","doi":"10.1016/j.cell.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.013","url":null,"abstract":"Transcriptional activation of the embryonic genome (EGA) is a major developmental landmark enabling the embryo to become independent from maternal control. The magnitude and control of transcriptional reprogramming during this event across mammals remains poorly understood. Here, we developed Smart-seq+5′ for high sensitivity, full-length transcript coverage and simultaneous capture of 5′ transcript information from single cells and single embryos. Using Smart-seq+5′, we profiled 34 developmental stages in 5 mammalian species and provide an extensive characterization of the transcriptional repertoire of early development before, during, and after EGA. We demonstrate widespread transposable element (TE)-driven transcription across species, including, remarkably, of DNA transposons. We identify 19,657 TE-driven genic transcripts, suggesting extensive TE co-option in early development over evolutionary timescales. TEs display similar expression dynamics across species and species-specific patterns, suggesting shared and divergent regulation. Our work provides a powerful resource for understanding transcriptional regulation of mammalian development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"77 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989765","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}
Pub Date : 2025-01-20DOI: 10.1016/j.cell.2024.12.014
Qi Chen, Binbin Zhao, Ziyang Tan, Gustav Hedberg, Jun Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Erika Negrini, Laura Piñero Páez, Lucie Rodriguez, Anna James, Yang Chen, Jaromír Mikeš, Anna Karin Bernhardsson, Stefan Markus Reitzner, Ferdinand von Walden, Olivia O’Neill, Hugo Barcenilla, Chunlin Wang, Petter Brodin
Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.
{"title":"Systems-level immunomonitoring in children with solid tumors to enable precision medicine","authors":"Qi Chen, Binbin Zhao, Ziyang Tan, Gustav Hedberg, Jun Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Erika Negrini, Laura Piñero Páez, Lucie Rodriguez, Anna James, Yang Chen, Jaromír Mikeš, Anna Karin Bernhardsson, Stefan Markus Reitzner, Ferdinand von Walden, Olivia O’Neill, Hugo Barcenilla, Chunlin Wang, Petter Brodin","doi":"10.1016/j.cell.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.014","url":null,"abstract":"Cancer is the leading cause of death from disease in children. Survival depends not only on surgery, cytostatic drugs, and radiation but also on systemic immune responses. Factors influencing these immune responses in children of different ages and tumor types are unknown. Novel immunotherapies can enhance anti-tumor immune responses, but few children have benefited, and markers of effective responses are lacking. Here, we present a systems-level analysis of immune responses in 191 children within a population-based cohort with diverse tumors and reveal that age and tumor type shape immune responses differently. Systemic inflammation and cytotoxic T cell responses correlate with tumor mutation rates and immune cell infiltration. Clonally expanded T cell responses are rarely detected in blood or tumors at diagnosis but are sometimes elicited during treatment. Expanded T cells are similarly regulated in children and adults with more immunogenic cancers. This research aims to facilitate the development of precision immunotherapies for children with cancer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"56 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990311","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}
Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.
{"title":"Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients","authors":"Liping Zhong, Lu Gan, Bing Wang, Tao Wu, Fei Yao, Wenlin Gong, Hongmei Peng, Zhiming Deng, Guoyou Xiao, Xiyu Liu, Jintong Na, Desong Xia, Xianjun Yu, Zhikun Zhang, Bangde Xiang, Yu Huo, Dan Yan, Zhixin Dong, Fang Fang, Yun Ma, Yongxiang Zhao","doi":"10.1016/j.cell.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.010","url":null,"abstract":"Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine <em>α1,3GT</em> gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"30 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987537","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}
Pub Date : 2025-01-17DOI: 10.1016/j.cell.2024.12.009
Giuseppe Quarto, Andrea Li Greci, Martin Bizet, Audrey Penning, Irina Primac, Frédéric Murisier, Liliana Garcia-Martinez, Rodrigo L. Borges, Qingzeng Gao, Pradeep K.R. Cingaram, Emilie Calonne, Bouchra Hassabi, Céline Hubert, Adèle Herpoel, Pascale Putmans, Frédérique Mies, Jérôme Martin, Louis Van der Linden, Gaurav Dube, Pankaj Kumar, François Fuks
The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m6A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m6A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m6A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m6A are both essential for the differentiation of embryonic stem cells into embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m6A. Our findings add a surprising dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development and likely other biological processes.
{"title":"Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation","authors":"Giuseppe Quarto, Andrea Li Greci, Martin Bizet, Audrey Penning, Irina Primac, Frédéric Murisier, Liliana Garcia-Martinez, Rodrigo L. Borges, Qingzeng Gao, Pradeep K.R. Cingaram, Emilie Calonne, Bouchra Hassabi, Céline Hubert, Adèle Herpoel, Pascale Putmans, Frédérique Mies, Jérôme Martin, Louis Van der Linden, Gaurav Dube, Pankaj Kumar, François Fuks","doi":"10.1016/j.cell.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.009","url":null,"abstract":"The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (m<sup>6</sup>A), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between m<sup>6</sup>A and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation. We identify a set of genes whose expression is fine-tuned by both gene-body 5mC, which promotes transcription, and m<sup>6</sup>A, which destabilizes transcripts. We demonstrate that METTL3-METTL14-dependent 5mC and m<sup>6</sup>A are both essential for the differentiation of embryonic stem cells into embryoid bodies and that the upregulation of key differentiation genes during early differentiation depends on the dynamic balance between increased 5mC and decreased m<sup>6</sup>A. Our findings add a surprising dimension to our understanding of how epigenetics and epitranscriptomics combine to regulate gene expression and impact development and likely other biological processes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"83 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987695","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}
Pub Date : 2025-01-17DOI: 10.1016/j.cell.2024.12.008
Jan Philipp Kreysing, Maziar Heidari, Vojtech Zila, Sergio Cruz-León, Agnieszka Obarska-Kosinska, Vibor Laketa, Lara Rohleder, Sonja Welsch, Jürgen Köfinger, Beata Turoňová, Gerhard Hummer, Hans-Georg Kräusslich, Martin Beck
Upon infection, human immunodeficiency virus type 1 (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T cells and macrophages. The capsid enters the nuclear pore complex (NPC), driven by interactions with numerous phenylalanine-glycine (FG)-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however. Here, we combined super-resolution and correlative microscopy with cryoelectron tomography and molecular simulations to study the nuclear entry of HIV-1 capsids in primary human macrophages. Our data indicate that cytosolically bound cyclophilin A is stripped off capsids entering the NPC, and the capsid hexagonal lattice remains largely intact inside and beyond the central channel. Strikingly, the NPC scaffold rings frequently crack during capsid passage, consistent with computer simulations indicating the need for NPC widening. The unique cone shape of the HIV-1 capsid facilitates its entry into NPCs and helps to crack their rings.
{"title":"Passage of the HIV capsid cracks the nuclear pore","authors":"Jan Philipp Kreysing, Maziar Heidari, Vojtech Zila, Sergio Cruz-León, Agnieszka Obarska-Kosinska, Vibor Laketa, Lara Rohleder, Sonja Welsch, Jürgen Köfinger, Beata Turoňová, Gerhard Hummer, Hans-Georg Kräusslich, Martin Beck","doi":"10.1016/j.cell.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.cell.2024.12.008","url":null,"abstract":"Upon infection, human immunodeficiency virus type 1 (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T cells and macrophages. The capsid enters the nuclear pore complex (NPC), driven by interactions with numerous phenylalanine-glycine (FG)-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown, however. Here, we combined super-resolution and correlative microscopy with cryoelectron tomography and molecular simulations to study the nuclear entry of HIV-1 capsids in primary human macrophages. Our data indicate that cytosolically bound cyclophilin A is stripped off capsids entering the NPC, and the capsid hexagonal lattice remains largely intact inside and beyond the central channel. Strikingly, the NPC scaffold rings frequently crack during capsid passage, consistent with computer simulations indicating the need for NPC widening. The unique cone shape of the HIV-1 capsid facilitates its entry into NPCs and helps to crack their rings.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987694","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}
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