Cell Discovery最新文献

{"title":"Mycobacterium tuberculosis inhibits METTL14-mediated m⁶A methylation of Nox2 mRNA and suppresses anti-TB immunity.","authors":"Mingtong Ma, Yongjia Duan, Cheng Peng, You Wu, Xinning Zhang, Boran Chang, Fei Wang, Hua Yang, Ruijuan Zheng, Hongyu Cheng, Yuanna Cheng, Yifan He, Jingping Huang, Jinming Lei, Hanyu Ma, Liru Li, Jie Wang, Xiaochen Huang, Fen Tang, Jun Liu, Jinsong Li, Ruoyan Ying, Peng Wang, Wei Sha, Yawei Gao, Lin Wang, Baoxue Ge","doi":"10.1038/s41421-024-00653-4","DOIUrl":"10.1038/s41421-024-00653-4","url":null,"abstract":"<p><p>Internal N⁶-methyladenosine (m⁶A) modifications are among the most abundant modifications of messenger RNA, playing a critical role in diverse biological and pathological processes. However, the functional role and regulatory mechanism of m⁶A modifications in the immune response to Mycobacterium tuberculosis infection remains unknown. Here, we report that methyltransferase-like 14 (METTL14)-dependent m⁶A methylation of NAPDH oxidase 2 (Nox2) mRNA was crucial for the host immune defense against M. tuberculosis infection and that M. tuberculosis-secreted antigen EsxB (Rv3874) inhibited METTL14-dependent m⁶A methylation of Nox2 mRNA. Mechanistically, EsxB interacted with p38 MAP kinase and disrupted the association of TAB1 with p38, thus inhibiting the TAB1-mediated autophosphorylation of p38. Interaction of EsxB with p38 also impeded the binding of p38 with METTL14, thereby inhibiting the p38-mediated phosphorylation of METTL14 at Thr72. Inhibition of p38 by EsxB restrained liquid-liquid phase separation (LLPS) of METTL14 and its subsequent interaction with METTL3, preventing the m⁶A modification of Nox2 mRNA and its association with the m⁶A-binding protein IGF2BP1 to destabilize Nox2 mRNA, reduce ROS levels, and increase intracellular survival of M. tuberculosis. Moreover, deletion or mutation of the phosphorylation site on METTL14 impaired the inhibition of ROS level by EsxB and increased bacterial burden or histological damage in the lungs during infection in mice. These findings identify a previously unknown mechanism that M. tuberculosis employs to suppress host immunity, providing insights that may empower the development of effective immunomodulators that target M. tuberculosis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"36"},"PeriodicalIF":33.5,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10978938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317855","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":"Fast and flexible profiling of chromatin accessibility and total RNA expression in single nuclei using Microwell-seq3.","authors":"Fang Ye, Shuang Zhang, Yuting Fu, Lei Yang, Guodong Zhang, Yijun Wu, Jun Pan, Haide Chen, Xinru Wang, Lifeng Ma, Haofu Niu, Mengmeng Jiang, Tingyue Zhang, Danmei Jia, Jingjing Wang, Yongcheng Wang, Xiaoping Han, Guoji Guo","doi":"10.1038/s41421-023-00642-z","DOIUrl":"10.1038/s41421-023-00642-z","url":null,"abstract":"<p><p>Single cell chromatin accessibility profiling and transcriptome sequencing are the most widely used technologies for single-cell genomics. Here, we present Microwell-seq3, a high-throughput and facile platform for high-sensitivity single-nucleus chromatin accessibility or full-length transcriptome profiling. The method combines a preindexing strategy and a penetrable chip-in-a-tube for single nucleus loading and DNA amplification and therefore does not require specialized equipment. We used Microwell-seq3 to profile chromatin accessibility in more than 200,000 single nuclei and the full-length transcriptome in ~50,000 nuclei from multiple adult mouse tissues. Compared with the existing polyadenylated transcript capture methods, integrative analysis of cell type-specific regulatory elements and total RNA expression uncovered comprehensive cell type heterogeneity in the brain. Gene regulatory networks based on chromatin accessibility profiling provided an improved cell type communication model. Finally, we demonstrated that Microwell-seq3 can identify malignant cells and their specific regulons in spontaneous lung tumors of aged mice. We envision a broad application of Microwell-seq3 in many areas of research.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"33"},"PeriodicalIF":13.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10966074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292940","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: Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.","authors":"Alexandre G Casanova, Gael S Roth, Simone Hausmann, Xiaoyin Lu, Ludivine J M Bischoff, Emilie M Froeliger, Lucid Belmudes, Ekaterina Bourova-Flin, Natasha M Flores, Ana Morales Benitez, Tourkian Chasan, Marcello Caporicci, Jessica Vayr, Sandrine Blanchet, Francesco Ielasi, Sophie Rousseaux, Pierre Hainaut, Or Gozani, Muriel Le Romancer, Yohann Couté, Andres Palencia, Pawel K Mazur, Nicolas Reynoird","doi":"10.1038/s41421-024-00661-4","DOIUrl":"10.1038/s41421-024-00661-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"34"},"PeriodicalIF":33.5,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10965994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292939","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":"RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation.","authors":"Peng Lin, Wenyan Chen, Zhilin Long, Jichuan Yu, Jiayao Yang, Zhen Xia, Qiulian Wu, Xinyu Min, Jing Tang, Ya Cui, Fuyi Liu, Chun Wang, Jian Zheng, Wei Li, Jeremy N Rich, Lei Li, Qi Xie","doi":"10.1038/s41421-024-00654-3","DOIUrl":"10.1038/s41421-024-00654-3","url":null,"abstract":"<p><p>Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3'UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"32"},"PeriodicalIF":33.5,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10951364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173867","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":"Hypercompact TnpB and truncated TnpB systems enable efficient genome editing in vitro and in vivo","authors":"Ming Wang, Zhaolin Sun, Yue Liu, Pengbin Yin, Chuanyu Liang, Lin Tan, Lei Wei, Yuzhan Wang, Haikuan Yu, Yunfei Zhu, Xiaoxiang Hu, Ning Li, Ran Zhang","doi":"10.1038/s41421-023-00645-w","DOIUrl":"https://doi.org/10.1038/s41421-023-00645-w","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"53 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140172696","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":"Structural insights into human organic cation transporter 1 transport and inhibition.","authors":"Shuhao Zhang, Angqi Zhu, Fang Kong, Jianan Chen, Baoliang Lan, Guodong He, Kaixuan Gao, Lili Cheng, Xiaoou Sun, Chuangye Yan, Ligong Chen, Xiangyu Liu","doi":"10.1038/s41421-024-00664-1","DOIUrl":"10.1038/s41421-024-00664-1","url":null,"abstract":"<p><p>The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"30"},"PeriodicalIF":33.5,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10940649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130825","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: Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities.","authors":"Claudio Pulito, Federica Mori, Andrea Sacconi, Frauke Goeman, Maria Ferraiuolo, Patrizia Pasanisi, Carlo Campagnoli, Franco Berrino, Maurizio Fanciulli, Rebecca J Ford, Massimo Levrero, Natalia Pediconi, Ludovica Ciuffreda, Michele Milella, Gregory R Steinberg, Mario Cioce, Paola Muti, Sabrina Strano, Giovanni Blandino","doi":"10.1038/s41421-024-00655-2","DOIUrl":"10.1038/s41421-024-00655-2","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"29"},"PeriodicalIF":33.5,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10937647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118891","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":"Multi-modal molecular determinants of clinically relevant osteoporosis subtypes.","authors":"Chunchun Yuan, Xiang-Tian Yu, Jing Wang, Bing Shu, Xiao-Yun Wang, Chen Huang, Xia Lv, Qian-Qian Peng, Wen-Hao Qi, Jing Zhang, Yan Zheng, Si-Jia Wang, Qian-Qian Liang, Qi Shi, Ting Li, He Huang, Zhen-Dong Mei, Hai-Tao Zhang, Hong-Bin Xu, Jiarui Cui, Hongyu Wang, Hong Zhang, Bin-Hao Shi, Pan Sun, Hui Zhang, Zhao-Long Ma, Yuan Feng, Luonan Chen, Tao Zeng, De-Zhi Tang, Yong-Jun Wang","doi":"10.1038/s41421-024-00652-5","DOIUrl":"10.1038/s41421-024-00652-5","url":null,"abstract":"<p><p>Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"28"},"PeriodicalIF":33.5,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10933295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109302","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":"Cryo-EM structures reveal variant Tau amyloid fibrils between the rTg4510 mouse model and sporadic human tauopathies.","authors":"Wanbing Zhao, Kaien Liu, Yun Fan, Qinyue Zhao, Youqi Tao, Mengwei Zhang, Linhua Gan, Wenbo Yu, Bo Sun, Dan Li, Cong Liu, Jian Wang","doi":"10.1038/s41421-023-00637-w","DOIUrl":"10.1038/s41421-023-00637-w","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"27"},"PeriodicalIF":33.5,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048821","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":"Mapping crossover events of mouse meiotic recombination by restriction fragment ligation-based Refresh-seq","authors":"Yan Wang, Yijun Chen, Junpeng Gao, Haoling Xie, Yuqing Guo, Jingwei Yang, Jun’e Liu, Zonggui Chen, Qingqing Li, Mengyao Li, Jie Ren, Lu Wen, Fuchou Tang","doi":"10.1038/s41421-023-00638-9","DOIUrl":"https://doi.org/10.1038/s41421-023-00638-9","url":null,"abstract":"<p>Single-cell whole-genome sequencing methods have undergone great improvements over the past decade. However, allele dropout, which means the inability to detect both alleles simultaneously in an individual diploid cell, largely restricts the application of these methods particularly for medical applications. Here, we develop a new single-cell whole-genome sequencing method based on third-generation sequencing (TGS) platform named Refresh-seq (restriction fragment ligation-based genome amplification and TGS). It is based on restriction endonuclease cutting and ligation strategy in which two alleles in an individual cell can be cut into equal fragments and tend to be amplified simultaneously. As a new single-cell long-read genome sequencing method, Refresh-seq features much lower allele dropout rate compared with SMOOTH-seq. Furthermore, we apply Refresh-seq to 688 sperm cells and 272 female haploid cells (secondary polar bodies and parthenogenetic oocytes) from F1 hybrid mice. We acquire high-resolution genetic map of mouse meiosis recombination at low sequencing depth and reveal the sexual dimorphism in meiotic crossovers. We also phase the structure variations (deletions and insertions) in sperm cells and female haploid cells with high precision. Refresh-seq shows great performance in screening aneuploid sperm cells and oocytes due to the low allele dropout rate and has great potential for medical applications such as preimplantation genetic diagnosis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"30 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037107","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}