Cell Discovery最新文献_第7页

Mediator MED23 controls oligodendrogenesis and myelination by modulating Sp1/P300-directed gene programs. 介导因子 MED23 通过调节 Sp1/P300 引导的基因程序控制少突形成和髓鞘化。

IF 13 1区生物学

Cell Discovery Pub Date : 2024-10-15 DOI: 10.1038/s41421-024-00730-8

Shuai Zhang, Xue Feng, Chong-Hui Li, Yuan-Ming Zheng, Meng-Ya Wang, Jun-Jie Li, Yun-Peng Dai, Naihe Jing, Jia-Wei Zhou, Gang Wang

{"title":"Mediator MED23 controls oligodendrogenesis and myelination by modulating Sp1/P300-directed gene programs.","authors":"Shuai Zhang, Xue Feng, Chong-Hui Li, Yuan-Ming Zheng, Meng-Ya Wang, Jun-Jie Li, Yun-Peng Dai, Naihe Jing, Jia-Wei Zhou, Gang Wang","doi":"10.1038/s41421-024-00730-8","DOIUrl":"https://doi.org/10.1038/s41421-024-00730-8","url":null,"abstract":"Gaining the molecular understanding for myelination development and regeneration has been a long-standing goal in neurological research. Mutations in the transcription cofactor Mediator Med23 subunit are often associated with intellectual disability and white matter defects, although the precise functions and mechanisms of Mediator in myelination remain unclear. In this study, we generated a mouse model carrying an Med23Q649R mutation that has been identified in a patient with hypomyelination features. The MED23Q649R mouse model develops white matter thinning and cognitive decline, mimicking common clinical phenotypes. Further, oligodendrocyte-lineage specific Med23 knockout mice verified the important function of MED23 in regulating central nervous system myelination and postinjury remyelination. Utilizing the in vitro cellular differentiation assay, we found that the oligodendrocyte progenitor cells, either carrying the Q649R mutation or lacking Med23, exhibit significant deficits in their capacity to differentiate into mature oligodendrocytes. Gene profiling combined with reporter assays demonstrated that Mediator Med23 controls Sp1-directed gene programs related to oligodendrocyte differentiation and cholesterol metabolism. Integrative analysis demonstrated that Med23 modulates the P300 binding to Sp1-targeted genes, thus orchestrating the H3K27 acetylation and enhancer activation for the oligodendrocyte lineage progression. Collectively, our findings identified the critical role for the Mediator Med23 in oligodendrocyte fate determination and provide mechanistic insights into the myelination pathogenesis associated with MED23 mutations.","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"102"},"PeriodicalIF":13.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458786","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}

引用次数: 0

Intercellular genetic tracing by alternative synthetic Notch signaling. 通过替代合成 Notch 信号进行细胞间基因追踪。

IF 13 1区生物学

Cell Discovery Pub Date : 2024-10-15 DOI: 10.1038/s41421-024-00721-9

Kuo Liu, Shaohua Zhang, Xinfeng Meng, Hongxin Li, Jingting Zhu, Enci Wang, Muxue Tang, Mingjun Zhang, Bin Zhou, Lixin Wang

引用次数: 0

Pathogenic BALB/c mice infection model for evaluation of mpox countermeasures. 用于评估 mpox 对策的致病性 BALB/c 小鼠感染模型。

IF 13 1区生物学

Cell Discovery Pub Date : 2024-10-13 DOI: 10.1038/s41421-024-00739-z

Lin Cheng, Wenqi Huang, Meimei Duan, Zhuohuan Li, Qi Chen, Mingxia Zhang, Zheng Zhang

引用次数: 0

Programmable broad-spectrum resistance to bacterial blight using targeted insertion in rice. 利用水稻中的靶向插入技术对细菌性枯萎病产生可编程的广谱抗性。

IF 13 1区生物学

Cell Discovery Pub Date : 2024-10-08 DOI: 10.1038/s41421-024-00714-8

Xuening Zhang, Minglei Song, Yingying Wang, Qi Yao, Rundong Shen, Yifu Tian, Yuming Lu, Jian-Kang Zhu

引用次数: 0

Developing an erythrocyte‒MHC-I conjugate for cancer treatment. 开发用于癌症治疗的红细胞-MHC-I 结合物。

IF 13 1区生物学

Cell Discovery Pub Date : 2024-10-01 DOI: 10.1038/s41421-024-00713-9

Yuehua Liu, Xiaoqian Nie, Xingyun Yao, Huafeng Shou, Yang Yuan, Yun Ge, Xiangmin Tong, Hsiang-Ying Lee, Xiaofei Gao

{"title":"Developing an erythrocyte‒MHC-I conjugate for cancer treatment.","authors":"Yuehua Liu, Xiaoqian Nie, Xingyun Yao, Huafeng Shou, Yang Yuan, Yun Ge, Xiangmin Tong, Hsiang-Ying Lee, Xiaofei Gao","doi":"10.1038/s41421-024-00713-9","DOIUrl":"10.1038/s41421-024-00713-9","url":null,"abstract":"Mature erythrocytes are known to lack major histocompatibility complex (MHC) proteins. However, the presence of MHC molecules on erythrocytes has been occasionally reported, though without a defined function. In this study, we designed erythrocyte conjugated solely with a fusion protein consisting of an antigenic peptide linked to MHC class I (MHC-I) protein, termed MHC-I‒Ery. The modified erythrocyte, decorated with the peptide derived from human papillomavirus (HPV) 16 oncoprotein E6/E7, effectively activated antigen-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from HPV16+ cervical cancer patients. Additionally, MHC-I‒Ery monotherapy was shown to inhibit antigen-positive tumor growth in mice. This treatment immediately activated CD8+ T cells and reduced suppressive myeloid cells in the spleen, leading to systemic anti-tumor activity. Safety and tolerability evaluations of MHC-I‒Ery in non-human primates further supported its clinical potential. Our results first demonstrated that erythrocytes equipped solely with antigen peptide‒MHC-I complexes can robustly stimulate the immune system, suggesting a novel and promising approach for advancing cancer immunotherapy.","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"99"},"PeriodicalIF":13.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342290","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}

引用次数: 0

Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development. 人类胚胎在早期发育过程中存在复杂的嵌合现象，非整倍体细胞广泛存在。

IF 13 1区生物学

Cell Discovery Pub Date : 2024-09-24 DOI: 10.1038/s41421-024-00719-3

Fan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan, Jie Qiao

{"title":"Human embryos harbor complex mosaicism with broad presence of aneuploid cells during early development.","authors":"Fan Zhai, Siming Kong, Shi Song, Qianying Guo, Ling Ding, Jiaqi Zhang, Nan Wang, Ying Kuo, Shuo Guan, Peng Yuan, Liying Yan, Zhiqiang Yan, Jie Qiao","doi":"10.1038/s41421-024-00719-3","DOIUrl":"10.1038/s41421-024-00719-3","url":null,"abstract":"Pre-implantation genetic testing for aneuploidy (PGT-A) is used in approximately half of in vitro fertilization cycles. Given the limited understanding of the genetics of human embryos, the current use of PGT-A is based on biologically uncertain assumptions and unvalidated guidelines, leading to the possibility of disposing of embryos with pregnancy potential. We isolated and sequenced all single cells (1133) from in vitro cultured 20 human blastocysts. We found that all blastocysts exhibited mosaicism with mitotic-induced aneuploid cells and showed an ~25% aneuploidy rate per embryo. Moreover, 70% (14/20) of blastocysts contained 'chromosome-complementary' cells, suggesting genetic mosaicism is underestimated in routine PGT-A. Additionally, the analysis of 20,945 single cells from day 8-14 embryos (in vitro cultured) and embryonic/fetal organs showed that 97% of the analyzed embryos/organs were mosaic. Over 96% of their aneuploid cells harbored ≤ 2 chromosome errors. Our findings have revealed a high prevalence of mosaicism in human embryos.","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"98"},"PeriodicalIF":13.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307180","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}

引用次数: 0

Epigenetic editing alleviates Angelman syndrome phenotype in mice by unsilencing paternal Ube3a 表观遗传编辑通过解除父系 Ube3a 的沉默减轻小鼠的安杰曼综合征表型

IF 33.5 1区生物学

Cell Discovery Pub Date : 2024-09-17 DOI: 10.1038/s41421-024-00727-3

Yajing Liu, Sensen Lou, Jinhui Li, Yuanhua Liu, Shisheng Huang, Yu Wei, Jikai Liu, Ruimin Lv, Junjie Tang, Zhixin Shen, Yidi Sun, Xingxu Huang, Zhiqi Xiong, Hui Yang, Changyang Zhou

引用次数: 0

Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer 以 SNRNP200 诱导的剪接失调为靶点，为糖代谢三阴性乳腺癌提供免疫疗法机会

IF 33.5 1区生物学

Cell Discovery Pub Date : 2024-09-17 DOI: 10.1038/s41421-024-00715-7

Wenxiao Yang, Luo Hong, Linwei Guo, Yunjin Wang, Xiangchen Han, Boyue Han, Zheng Xing, Guoliang Zhang, Hongxia Zhou, Chao Chen, Hong Ling, Zhimin Shao, Xin Hu

{"title":"Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer","authors":"Wenxiao Yang, Luo Hong, Linwei Guo, Yunjin Wang, Xiangchen Han, Boyue Han, Zheng Xing, Guoliang Zhang, Hongxia Zhou, Chao Chen, Hong Ling, Zhimin Shao, Xin Hu","doi":"10.1038/s41421-024-00715-7","DOIUrl":"https://doi.org/10.1038/s41421-024-00715-7","url":null,"abstract":"Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"16 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255888","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

Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control 精氨酸-eIF5A 轴对通过翻译控制激活肌肉干细胞至关重要

IF 33.5 1区生物学

Cell Discovery Pub Date : 2024-09-10 DOI: 10.1038/s41421-024-00712-w

Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li

{"title":"Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control","authors":"Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li","doi":"10.1038/s41421-024-00712-w","DOIUrl":"https://doi.org/10.1038/s41421-024-00712-w","url":null,"abstract":"Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"400 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180176","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

A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity 条件蛋白质扩散模型可生成具有更强活性的人工可编程内切酶序列

IF 33.5 1区生物学

Cell Discovery Pub Date : 2024-09-10 DOI: 10.1038/s41421-024-00728-2

Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong

{"title":"A conditional protein diffusion model generates artificial programmable endonuclease sequences with enhanced activity","authors":"Bingxin Zhou, Lirong Zheng, Banghao Wu, Kai Yi, Bozitao Zhong, Yang Tan, Qian Liu, Pietro Liò, Liang Hong","doi":"10.1038/s41421-024-00728-2","DOIUrl":"https://doi.org/10.1038/s41421-024-00728-2","url":null,"abstract":"Deep learning-based methods for generating functional proteins address the growing need for novel biocatalysts, allowing for precise tailoring of functionalities to meet specific requirements. This advancement leads to the development of highly efficient and specialized proteins with diverse applications across scientific, technological, and biomedical fields. This study establishes a pipeline for protein sequence generation with a conditional protein diffusion model, namely CPDiffusion, to create diverse sequences of proteins with enhanced functions. CPDiffusion accommodates protein-specific conditions, such as secondary structures and highly conserved amino acids. Without relying on extensive training data, CPDiffusion effectively captures highly conserved residues and sequence features for specific protein families. We applied CPDiffusion to generate artificial sequences of Argonaute (Ago) proteins based on the backbone structures of wild-type (WT) Kurthia massiliensis Ago (KmAgo) and Pyrococcus furiosus Ago (PfAgo), which are complex multi-domain programmable endonucleases. The generated sequences deviate by up to nearly 400 amino acids from their WT templates. Experimental tests demonstrated that the majority of the generated proteins for both KmAgo and PfAgo show unambiguous activity in DNA cleavage, with many of them exhibiting superior activity as compared to the WT. These findings underscore CPDiffusion’s remarkable success rate in generating novel sequences for proteins with complex structures and functions in a single step, leading to enhanced activity. This approach facilitates the design of enzymes with multi-domain molecular structures and intricate functions through in silico generation and screening, all accomplished without the need for supervision from labeled data.","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"77 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180175","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