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CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway. CXCR4 通过 JAK2/STAT3 通路协调 CD8+ T 细胞的毒素编程衰竭表型。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 Epub Date: 2024-09-23 DOI: 10.1016/j.xgen.2024.100659
Canhui Cao, Miaochun Xu, Ye Wei, Ting Peng, Shitong Lin, Xiaojie Liu, Yashi Xu, Tian Chu, Shiyi Liu, Ping Wu, Bai Hu, Wencheng Ding, Li Li, Ding Ma, Peng Wu

Evidence from clinical trials suggests that CXCR4 antagonists enhance immunotherapy effectiveness in several cancers. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. Here, we employed single-cell transcriptomic analysis and identified CXCR4 as a marker gene in T cells, with CD8+PD-1high exhausted T (Tex) cells exhibiting high CXCR4 expression. By blocking CXCR4, the Tex phenotype was attenuated in vivo. Mechanistically, CXCR4-blocking T cells mitigated the Tex phenotype by regulating the JAK2-STAT3 pathway. Single-cell RNA/TCR/ATAC-seq confirmed that Cxcr4-deficient CD8+ T cells epigenetically mitigated the transition from functional to exhausted phenotypes. Notably, clinical sample analysis revealed that CXCR4+CD8+ T cells showed higher expression in patients with a non-complete pathological response. Collectively, these findings demonstrate the mechanism by which CXCR4 orchestrates CD8+ Tex cells and provide a rationale for combining CXCR4 antagonists with immunotherapy in clinical trials.

临床试验的证据表明,CXCR4 拮抗剂可提高多种癌症的免疫治疗效果。然而,CXCR4 促进免疫细胞表型的具体机制尚不完全清楚。在这里,我们采用单细胞转录组分析方法,确定了CXCR4是T细胞的标记基因,CD8+PD-1高衰竭T细胞(Tex)表现出高CXCR4表达。通过阻断 CXCR4,Tex 表型在体内得到了减弱。从机制上讲,阻断 CXCR4 的 T 细胞通过调节 JAK2-STAT3 通路减轻了 Tex 表型。单细胞RNA/TCR/ATAC-seq证实,Cxcr4缺陷的CD8+ T细胞从表观遗传学上缓解了从功能性表型向衰竭表型的转变。值得注意的是,临床样本分析显示,在病理反应不完全的患者中,CXCR4+CD8+ T细胞的表达量更高。总之,这些发现证明了 CXCR4 协调 CD8+ Tex 细胞的机制,并为在临床试验中将 CXCR4 拮抗剂与免疫疗法相结合提供了理论依据。
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引用次数: 0
Identifying compound-protein interactions with knowledge graph embedding of perturbation transcriptomics. 通过扰动转录组学的知识图嵌入识别化合物与蛋白质之间的相互作用。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 Epub Date: 2024-09-19 DOI: 10.1016/j.xgen.2024.100655
Shengkun Ni, Xiangtai Kong, Yingying Zhang, Zhengyang Chen, Zhaokun Wang, Zunyun Fu, Ruifeng Huo, Xiaochu Tong, Ning Qu, Xiaolong Wu, Kun Wang, Wei Zhang, Runze Zhang, Zimei Zhang, Jiangshan Shi, Yitian Wang, Ruirui Yang, Xutong Li, Sulin Zhang, Mingyue Zheng

The emergence of perturbation transcriptomics provides a new perspective for drug discovery, but existing analysis methods suffer from inadequate performance and limited applicability. In this work, we present PertKGE, a method designed to deconvolute compound-protein interactions from perturbation transcriptomics with knowledge graph embedding. By considering multi-level regulatory events within biological systems that share the same semantic context, PertKGE significantly improves deconvoluting accuracy in two critical "cold-start" settings: inferring targets for new compounds and conducting virtual screening for new targets. We further demonstrate the pivotal role of incorporating multi-level regulatory events in alleviating representational biases. Notably, it enables the identification of ectonucleotide pyrophosphatase/phosphodiesterase-1 as the target responsible for the unique anti-tumor immunotherapy effect of tankyrase inhibitor K-756 and the discovery of five novel hits targeting the emerging cancer therapeutic target aldehyde dehydrogenase 1B1 with a remarkable hit rate of 10.2%. These findings highlight the potential of PertKGE to accelerate drug discovery.

扰动转录组学的出现为药物发现提供了新的视角,但现有的分析方法存在性能不足和适用性有限的问题。在这项工作中,我们提出了 PertKGE,这是一种利用知识图嵌入从扰动转录组学中解构化合物与蛋白质相互作用的方法。通过考虑生物系统中具有相同语义背景的多层次调控事件,PertKGE 显著提高了在两个关键的 "冷启动 "环境中解卷的准确性:推断新化合物的靶点和进行新靶点的虚拟筛选。我们进一步证明了纳入多层次调控事件在减轻表征偏差方面的关键作用。值得注意的是,它使我们确定了外切核苷酸焦磷酸酶/磷酸二酯酶-1 是导致坦克酶抑制剂 K-756 产生独特抗肿瘤免疫治疗效果的靶点,并发现了针对新兴癌症治疗靶点醛脱氢酶 1B1 的五个新靶点,命中率高达 10.2%。这些发现凸显了 PertKGE 在加速药物发现方面的潜力。
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引用次数: 0
The hidden costs of aneuploidy: New insights from yeast. 非整倍体的隐性成本:来自酵母的新见解
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100673
Yuerong Wang, Xian Fu, Yue Shen

The molecular mechanisms underlying the paradoxical effects1 of aneuploidy are still not completely understood. In this issue, Rojas et al.2 systematically analyzed the associated costs of aneuploidy and the molecular drivers involved, which revealed that aneuploidy stress is primarily driven by the cumulative effects of genes per chromosome. Notably, gene length was predicted as the most significant indicator of aneuploidy toxicity by machine learning.

非整倍体的悖论效应1 的分子机制仍未完全明了。在本期杂志中,Rojas 等人2 系统分析了非整倍体的相关代价和分子驱动因素,发现非整倍体压力主要由每条染色体上基因的累积效应驱动。值得注意的是,通过机器学习,基因长度被预测为非整倍体毒性的最重要指标。
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引用次数: 0
Unlocking the genetic influence on milk variation and its potential implication for infant health. 揭示基因对牛奶变异的影响及其对婴儿健康的潜在影响。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100676
Claudia Nussbaum, Sarah Kim-Hellmuth

Human milk has long been recognized for its critical role in infant and maternal health. In this issue of Cell Genomics, Johnson et al.1 apply a human genetics and genomics approach to shed light on the complex relationship between maternal genetics, milk variation, and the infant gut microbiome.

母乳对婴儿和产妇健康的重要作用早已得到公认。在本期的《细胞基因组学》(Cell Genomics)杂志上,Johnson 等人1运用人类遗传学和基因组学方法,揭示了母体遗传学、牛奶变异和婴儿肠道微生物组之间的复杂关系。
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引用次数: 0
FUSE: Improving the estimation and imputation of variant impacts in functional screening. FUSE:改进功能筛选中变异影响的估计和估算。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100667
Tian Yu, James D Fife, Vineel Bhat, Ivan Adzhubey, Richard Sherwood, Christopher A Cassa

Deep mutational scanning enables high-throughput functional assessment of genetic variants. While phenotypic measurements from screening assays generally align with clinical outcomes, experimental noise may affect the accuracy of individual variant estimates. We developed the FUSE (functional substitution estimation) pipeline, which leverages measurements collectively within screening assays to improve the estimation of variant impacts. Drawing data from 115 published functional assays, FUSE assesses the mean functional effect per amino acid position and makes estimates for individual allelic variants. It enhances the correlation of variant functional effects from different assay platforms and increases the classification accuracy of missense variants in ClinVar across 29 genes (area under the receiver operating characteristic [ROC] curve [AUC] from 0.83 to 0.90). In UK Biobank patients with rare missense variants in BRCA1, LDLR, or TP53, FUSE improves the classification accuracy of associated phenotypes. FUSE can also impute variant effects for substitutions not experimentally screened. This approach improves accuracy and broadens the utility of data from functional screening.

深度突变扫描可对基因变异进行高通量功能评估。虽然筛查测定的表型测量结果通常与临床结果一致,但实验噪音可能会影响单个变异估计的准确性。我们开发了 FUSE(功能替代估算)管道,利用筛查测定中的集体测量来改进对变异影响的估算。FUSE 从 115 项已发表的功能测定中提取数据,评估每个氨基酸位置的平均功能效应,并对单个等位基因变异进行估计。它增强了来自不同检测平台的变体功能效应的相关性,并提高了ClinVar中29个基因的错义变体分类准确性(接收器操作特征曲线[ROC]下面积[AUC]从0.83提高到0.90)。在 BRCA1、LDLR 或 TP53 中存在罕见错义变异的英国生物库患者中,FUSE 提高了相关表型的分类准确性。FUSE 还能对未经实验筛选的置换进行变异效应推算。这种方法提高了准确性,扩大了功能筛选数据的用途。
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引用次数: 0
Genome-wide association study of maternal plasma metabolites during pregnancy. 孕期母体血浆代谢物的全基因组关联研究。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100657
Siyang Liu, Jilong Yao, Liang Lin, Xianmei Lan, Linlin Wu, Xuelian He, Nannan Kong, Yan Li, Yuqing Deng, Jiansheng Xie, Huanhuan Zhu, Xiaoxia Wu, Zilong Li, Likuan Xiong, Yuan Wang, Jinghui Ren, Xuemei Qiu, Weihua Zhao, Ya Gao, Yuanqing Chen, Fengxia Su, Yun Zhou, Weiqiao Rao, Jing Zhang, Guixue Hou, Liping Huang, Linxuan Li, Xinhong Liu, Chao Nie, Liqiong Luo, Mei Zhao, Zengyou Liu, Fang Chen, Shengmou Lin, Lijian Zhao, Qingmei Fu, Dan Jiang, Ye Yin, Xun Xu, Jian Wang, Huanming Yang, Rong Wang, Jianmin Niu, Fengxiang Wei, Xin Jin, Siqi Liu

Metabolites are key indicators of health and therapeutic targets, but their genetic underpinnings during pregnancy-a critical period for human reproduction-are largely unexplored. Using genetic data from non-invasive prenatal testing, we performed a genome-wide association study on 84 metabolites, including 37 amino acids, 24 elements, 13 hormones, and 10 vitamins, involving 34,394 pregnant Chinese women, with sample sizes ranging from 6,394 to 13,392 for specific metabolites. We identified 53 metabolite-gene associations, 23 of which are novel. Significant differences in genetic effects between pregnant and non-pregnant women were observed for 16.7%-100% of these associations, indicating gene-environment interactions. Additionally, 50.94% of genetic associations exhibited pleiotropy among metabolites and between six metabolites and eight pregnancy phenotypes. Mendelian randomization revealed potential causal relationships between seven maternal metabolites and 15 human traits and diseases. These findings provide new insights into the genetic basis of maternal plasma metabolites during pregnancy.

代谢物是健康的关键指标和治疗靶点,但它们在孕期--人类生殖的关键时期--的遗传基础在很大程度上尚未被探索。利用无创产前检测的基因数据,我们对包括 37 种氨基酸、24 种元素、13 种激素和 10 种维生素在内的 84 种代谢物进行了全基因组关联研究,涉及 34,394 名中国孕妇,特定代谢物的样本量从 6,394 到 13,392 不等。我们发现了 53 种代谢物与基因的关联,其中 23 种是新发现的。在这些关联中,16.7%-100% 的遗传效应在孕妇和非孕妇之间存在显著差异,这表明基因与环境之间存在相互作用。此外,50.94%的基因关联在代谢物之间以及六种代谢物与八种妊娠表型之间表现出多效性。孟德尔随机化揭示了7种母体代谢物与15种人类特征和疾病之间的潜在因果关系。这些发现为研究孕期母体血浆代谢物的遗传基础提供了新的视角。
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引用次数: 0
Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types. 在四种人类细胞类型中,稳定而强大的Xi和Y转录组在体内和体外驱动细胞类型特异的常染色体和Xa反应。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-09-11 Epub Date: 2024-08-06 DOI: 10.1016/j.xgen.2024.100628
Laura V Blanton, Adrianna K San Roman, Geryl Wood, Ashley Buscetta, Nicole Banks, Helen Skaletsky, Alexander K Godfrey, Thao T Pham, Jennifer F Hughes, Laura G Brown, Paul Kruszka, Angela E Lin, Daniel L Kastner, Maximilian Muenke, David C Page

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (∼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.

最近对人类性染色体非整倍体的体外研究表明,Xi("非活性 "X)和 Y 染色体可广泛调节常染色体和 Xa("活性 "X)基因的表达。我们在体内检验了这些发现。对具有一至三条 X 染色体和零至两条 Y 染色体的个体的 CD4+ T 细胞和单核细胞进行线性建模,发现有 82 个性染色体基因和 344 个常染色体基因的表达在体内随 Xi 和/或 Y 的剂量发生显著变化。性染色体表达的变化在体内和体外都非常稳定;常染色体对Xi和/或Y剂量的反应在很大程度上具有细胞类型特异性(比性染色体反应的变化大2.6倍)。性染色体转录因子 ZFX 和 ZFY 的靶标在体内和体外均占这些常染色体反应的很大一部分。我们的结论是,人类的 Xi 和 Y 转录组具有惊人的稳健性和稳定性,但它们以细胞类型特异性的方式调节常染色体基因和 Xa 基因。
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引用次数: 0
ONCOLINER: A new solution for monitoring, improving, and harmonizing somatic variant calling across genomic oncology centers. ONCOLINER:用于监测、改进和协调各基因组肿瘤中心体细胞变异调用的新解决方案。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-09-11 Epub Date: 2024-08-30 DOI: 10.1016/j.xgen.2024.100639
Rodrigo Martín, Nicolás Gaitán, Frédéric Jarlier, Lars Feuerbach, Henri de Soyres, Marc Arbonés, Tom Gutman, Montserrat Puiggròs, Alvaro Ferriz, Asier Gonzalez, Lucía Estelles, Ivo Gut, Salvador Capella-Gutierrez, Lincoln D Stein, Benedikt Brors, Romina Royo, Philippe Hupé, David Torrents

The characterization of somatic genomic variation associated with the biology of tumors is fundamental for cancer research and personalized medicine, as it guides the reliability and impact of cancer studies and genomic-based decisions in clinical oncology. However, the quality and scope of tumor genome analysis across cancer research centers and hospitals are currently highly heterogeneous, limiting the consistency of tumor diagnoses across hospitals and the possibilities of data sharing and data integration across studies. With the aim of providing users with actionable and personalized recommendations for the overall enhancement and harmonization of somatic variant identification across research and clinical environments, we have developed ONCOLINER. Using specifically designed mosaic and tumorized genomes for the analysis of recall and precision across somatic SNVs, insertions or deletions (indels), and structural variants (SVs), we demonstrate that ONCOLINER is capable of improving and harmonizing genome analysis across three state-of-the-art variant discovery pipelines in genomic oncology.

描述与肿瘤生物学相关的体细胞基因组变异是癌症研究和个性化医疗的基础,因为它指导着癌症研究的可靠性和影响,以及临床肿瘤学中基于基因组的决策。然而,目前各癌症研究中心和医院的肿瘤基因组分析在质量和范围上存在很大差异,这限制了各医院肿瘤诊断的一致性以及各研究之间数据共享和数据整合的可能性。为了向用户提供可操作的个性化建议,全面提高和统一跨研究和临床环境的体细胞变异识别能力,我们开发了 ONCOLINER。利用专门设计的镶嵌基因组和肿瘤基因组分析体细胞 SNV、插入或缺失(indels)和结构变异(SVs)的召回率和精确度,我们证明了 ONCOLINER 能够改进和协调基因组肿瘤学中三种最先进的变异发现管道的基因组分析。
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引用次数: 0
Ribosomes unraveled: The path from variant to impact. 解开核糖体:从变异到影响的路径
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-09-11 DOI: 10.1016/j.xgen.2024.100658
Paxton Kostos, Anna Galligos, Jennifer L Gerton

In this issue of Cell Genomics, Rothschild et al.1 reveal how ribosomal RNA diversity impacts ribosome structure and its implications for health and disease. Their innovative methodologies uncover distinct ribosome subtypes with significant structural variations and expression patterns. This work reveals connections to tissue-specific biology and cancer, positing new research avenues.

在本期《细胞基因组学》(Cell Genomics)杂志上,Rothschild 等人1揭示了核糖体 RNA 多样性如何影响核糖体结构及其对健康和疾病的影响。他们的创新方法发现了具有显著结构变化和表达模式的不同核糖体亚型。这项工作揭示了与组织特异性生物学和癌症的联系,提出了新的研究途径。
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引用次数: 0
ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling. 通过 BDNF/NGFR 信号传导,ABCA7 依赖性诱导神经肽 Y 是阿尔茨海默病突触复原力所必需的。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-09-11 Epub Date: 2024-08-30 DOI: 10.1016/j.xgen.2024.100642
Hüseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min, Xue Wang, Yiyi Ma, Ni Wang, Inyoung Jeong, Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak, Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenersen, Joseph S Reddy, Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi, Andrew F Teich, Takahisa Kanekiyo, Giuseppe Tosto, Badri N Vardarajan, Özkan İş, Nilüfer Ertekin-Taner, Richard Mayeux, Caghan Kizil

Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.

阿尔茨海默病(AD)相关基因ABCA7的基因变异会增加AD风险,但其与病因的功能相关性尚不清楚。我们生成了 CRISPR-Cas9 介导的 abca7 基因敲除斑马鱼,以探索 ABCA7 在 AD 中的作用。杂合子abca7+/-敲除结合Aβ42毒性的单细胞转录组学发现,ABCA7对神经肽Y(NPY)、脑源性神经营养因子(BDNF)和神经生长因子受体(NGFR)的表达至关重要,而这些表达对突触完整性、星形胶质细胞增殖和小胶质细胞的流行至关重要。NPY诱导受损会降低BDNF和突触密度,而异位NPY可以挽救这两种情况。在暴露于 Aβ42 的诱导多能干细胞衍生的人类神经元中,ABCA7-/-抑制 NPY。临床数据显示,AD 中 NPY 的减少与 Braak 分期的升高、与 AD 相关的 NPY 基因变异以及与 ABCA7 变异相关的 NPY、NGFR 和 BDNF 启动子的表观遗传学变化有关。因此,ABCA7依赖的NPY信号通过BDNF-NGFR维持突触的完整性,它的受损会降低大脑的恢复能力,从而增加AD的风险。
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引用次数: 0
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Cell genomics
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