Cell systems最新文献_第2页

Proliferation history and transcription factor levels drive direct conversion to motor neurons. 增殖历史和转录因子水平驱动直接转化为运动神经元。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-13 DOI: 10.1016/j.cels.2025.101205

Nathan B Wang, Brittany A Lende-Dorn, Adam M Beitz, Patrick Han, Honour O Adewumi, Timothy M O'Shea, Kate E Galloway

{"title":"Proliferation history and transcription factor levels drive direct conversion to motor neurons.","authors":"Nathan B Wang, Brittany A Lende-Dorn, Adam M Beitz, Patrick Han, Honour O Adewumi, Timothy M O'Shea, Kate E Galloway","doi":"10.1016/j.cels.2025.101205","DOIUrl":"10.1016/j.cels.2025.101205","url":null,"abstract":"The sparse and stochastic nature of conversion has obscured our understanding of how transcription factors (TFs) drive cells to new identities. To overcome this limit, we develop a tailored, high-efficiency conversion system that increases the direct conversion of fibroblasts to motor neurons 100-fold. By tailoring the cocktail to a minimal set of transcripts, we reduce extrinsic variation, allowing us to examine how proliferation and TFs synergistically drive conversion. We show that cell state-as set by proliferation history-defines how cells interpret the levels of TFs. Controlling for proliferation history and titrating each TF, we find that conversion correlates with levels of the pioneer TF Ngn2. By isolating cells by both their proliferation history and Ngn2 levels, we demonstrate that levels of Ngn2 expression alone are insufficient to predict conversion rates. Rather, proliferation history and TF levels combine to drive direct conversion. Finally, increasing the proliferation rate of adult human fibroblasts generates morphologically mature induced human motor neurons at high rates.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101205"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders. 突触的综合多组学特征揭示了与神经发育障碍相关的RNA加工因子和泛素连接酶。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-06 DOI: 10.1016/j.cels.2025.101204

Yuan Mei, Maya L Gosztyla, Xinzhu Tan, Lara E Dozier, Brent Wilkinson, Justin McKetney, John Lee, Michael Chen, Dorothy Tsai, Hema Kopalle, Marina A Gritsenko, Nicolas Hartel, Nicholas A Graham, Ilse Flores, Stephen K Gilmore-Hall, Shuhao Xu, Charlotte A Marquez, Sophie N Liu, Dylan Fong, Jing Chen, Kate Licon, Derek Hong, Sarah N Wright, Jason F Kreisberg, Alexi Nott, Richard D Smith, Wei-Jun Qian, Danielle L Swaney, Lilia M Iakoucheva, Nevan J Krogan, Gentry N Patrick, Yang Zhou, Guoping Feng, Marcelo P Coba, Gene W Yeo, Trey Ideker

{"title":"Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders.","authors":"Yuan Mei, Maya L Gosztyla, Xinzhu Tan, Lara E Dozier, Brent Wilkinson, Justin McKetney, John Lee, Michael Chen, Dorothy Tsai, Hema Kopalle, Marina A Gritsenko, Nicolas Hartel, Nicholas A Graham, Ilse Flores, Stephen K Gilmore-Hall, Shuhao Xu, Charlotte A Marquez, Sophie N Liu, Dylan Fong, Jing Chen, Kate Licon, Derek Hong, Sarah N Wright, Jason F Kreisberg, Alexi Nott, Richard D Smith, Wei-Jun Qian, Danielle L Swaney, Lilia M Iakoucheva, Nevan J Krogan, Gentry N Patrick, Yang Zhou, Guoping Feng, Marcelo P Coba, Gene W Yeo, Trey Ideker","doi":"10.1016/j.cels.2025.101204","DOIUrl":"10.1016/j.cels.2025.101204","url":null,"abstract":"The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data. This data-driven framework identifies proteins with key molecular features intrinsic to the synapse, including characteristic patterns of biophysical interactions and cross-tissue expression. The multi-omic analysis captures synaptic proteins across developmental stages and experimental systems, including 493 synaptic candidates supported by proteomics. We further investigate three such proteins that are associated with neurodevelopmental disorders-Cullin 3 (CUL3), DEAD-box helicase 3 X-linked (DDX3X), and Y-box binding protein-1 (YBX1)-by mapping their networks of physically interacting synapse proteins or transcripts. Our study demonstrates the potential of an integrated multi-omic approach to more comprehensively resolve the synaptic architecture.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101204"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Minding the synapse: A multi-omic approach reveals hidden regulators of neurodevelopment. 注意突触：一种多组学方法揭示了隐藏的神经发育调节因子。

Cell systems Pub Date : 2025-04-16 DOI: 10.1016/j.cels.2025.101263

Alicia Ljungdahl, Ryan S Dhindsa

引用次数: 0

SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data. SpaGRN：研究空间解析转录组学数据的空间知情调控路径。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-04-02 DOI: 10.1016/j.cels.2025.101243

Yao Li, Xiaobin Liu, Lidong Guo, Kai Han, Shuangsang Fang, Xinjiang Wan, Dantong Wang, Xun Xu, Ling Jiang, Guangyi Fan, Mengyang Xu

{"title":"SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data.","authors":"Yao Li, Xiaobin Liu, Lidong Guo, Kai Han, Shuangsang Fang, Xinjiang Wan, Dantong Wang, Xun Xu, Ling Jiang, Guangyi Fan, Mengyang Xu","doi":"10.1016/j.cels.2025.101243","DOIUrl":"10.1016/j.cels.2025.101243","url":null,"abstract":"Cells spatially organize into distinct cell types or functional domains through localized gene regulatory networks. However, current spatially resolved transcriptomics analyses fail to integrate spatial constraints and proximal cell influences, limiting the mechanistic understanding of tissue organization. Here, we introduce SpaGRN, a statistical framework that reconstructs cell-type- or functional-domain-specific, dynamic, and spatial regulons by coupling intracellular spatial regulatory causality with extracellular signaling path information. Benchmarking across synthetic and real datasets demonstrates SpaGRN's superior precision over state-of-the-art tools in identifying context-dependent regulons. Applied to diverse spatially resolved transcriptomics platforms (Stereo-seq, STARmap, MERFISH, CosMx, Slide-seq, and 10x Visium), complex cancerous samples, and 3D datasets of developing Drosophila embryos and larvae, SpaGRN not only provides a versatile toolkit for decoding receptor-mediated spatial regulons but also reveals spatiotemporal regulatory mechanisms underlying organogenesis and inflammation.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101243"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Assembly of stool-derived bacterial communities follows "early-bird" resource utilization dynamics. 粪便衍生细菌群落的组装遵循“早起鸟”的资源利用动态。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-28 DOI: 10.1016/j.cels.2025.101240

Andrés Aranda-Díaz, Lisa Willis, Taylor H Nguyen, Po-Yi Ho, Jean Vila, Tani Thomsen, Taylor Chavez, Rose Yan, Feiqiao Brian Yu, Norma Neff, Brian C DeFelice, Alvaro Sanchez, Sylvie Estrela, Kerwyn Casey Huang

{"title":"Assembly of stool-derived bacterial communities follows \"early-bird\" resource utilization dynamics.","authors":"Andrés Aranda-Díaz, Lisa Willis, Taylor H Nguyen, Po-Yi Ho, Jean Vila, Tani Thomsen, Taylor Chavez, Rose Yan, Feiqiao Brian Yu, Norma Neff, Brian C DeFelice, Alvaro Sanchez, Sylvie Estrela, Kerwyn Casey Huang","doi":"10.1016/j.cels.2025.101240","DOIUrl":"10.1016/j.cels.2025.101240","url":null,"abstract":"Diet can impact host health through changes to the gut microbiota, yet we lack mechanistic understanding linking nutrient availability and microbiota composition. Here, we use thousands of microbial communities cultured in vitro from human stool to develop a predictive model of community composition upon addition of single nutrients from central carbon metabolism to a complex medium. Among these communities, membership was largely determined by the donor stool, whereas relative abundances were determined by the supplemental carbon source. The absolute abundance of most taxa was independent of the supplementing nutrient due to the ability of a few organisms to quickly exhaust their niche in the complex medium and then exploit and monopolize the supplemental carbon source. Relative abundances of dominant taxa could be predicted from the nutritional preferences and growth dynamics of species in isolation, and exceptions were consistent with strain-level variation in growth capabilities. Our study reveals that assembly of this community of gut commensals can be explained by nutrient utilization dynamics that provide a predictive framework for manipulating community composition through nutritional perturbations.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101240"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion. 紧凑的转录因子盒式磁带通过直接转化产生功能性的、可移植的运动神经元。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-13 DOI: 10.1016/j.cels.2025.101206

Nathan B Wang, Honour O Adewumi, Brittany A Lende-Dorn, Adam M Beitz, Timothy M O'Shea, Kate E Galloway

{"title":"Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion.","authors":"Nathan B Wang, Honour O Adewumi, Brittany A Lende-Dorn, Adam M Beitz, Timothy M O'Shea, Kate E Galloway","doi":"10.1016/j.cels.2025.101206","DOIUrl":"10.1016/j.cels.2025.101206","url":null,"abstract":"Direct conversion generates patient-specific, disease-relevant cell types, such as neurons, that are rare, limited, or difficult to isolate from common and easily accessible cells, such as skin cells. However, low rates of direct conversion and complex protocols limit scalability and, thus, the potential of cell-fate conversion for biomedical applications. Here, we optimize the conversion protocol by examining process parameters, including transcript design; delivery via adeno-associated virus (AAV), retrovirus, and lentivirus; cell seeding density; and the impact of media conditions. Thus, we report a compact, portable conversion process that boosts proliferation and increases direct conversion of mouse fibroblasts to induced motor neurons (iMNs) to achieve high conversion rates of above 1,000%, corresponding to more than ten motor neurons yielded per cell seeded, which we achieve through expansion. Our optimized, direct conversion process generates functional motor neurons at scales relevant for cell therapies (>107 cells) that graft with the mouse central nervous system. High-efficiency, compact, direct conversion systems will support scaling to patient-specific, neural cell therapies.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101206"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Probing enzyme-dependent pseudouridylation using direct RNA sequencing to assess epitranscriptome plasticity in a neuronal cell line. 利用直接RNA测序探测酶依赖性假尿嘧啶化以评估神经细胞系的表转录组可塑性。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-20 DOI: 10.1016/j.cels.2025.101238

Oleksandra Fanari, Sepideh Tavakoli, Yuchen Qiu, Amr Makhamreh, Keqing Nian, Stuart Akeson, Michele Meseonznik, Caroline A McCormick, Dylan Bloch, Howard Gamper, Miten Jain, Ya-Ming Hou, Meni Wanunu, Sara H Rouhanifard

{"title":"Probing enzyme-dependent pseudouridylation using direct RNA sequencing to assess epitranscriptome plasticity in a neuronal cell line.","authors":"Oleksandra Fanari, Sepideh Tavakoli, Yuchen Qiu, Amr Makhamreh, Keqing Nian, Stuart Akeson, Michele Meseonznik, Caroline A McCormick, Dylan Bloch, Howard Gamper, Miten Jain, Ya-Ming Hou, Meni Wanunu, Sara H Rouhanifard","doi":"10.1016/j.cels.2025.101238","DOIUrl":"10.1016/j.cels.2025.101238","url":null,"abstract":"Chemical modifications in mRNAs, such as pseudouridine (psi), can control gene expression. Yet, we know little about how they are regulated, especially in neurons. We applied nanopore direct RNA sequencing to investigate psi dynamics in SH-SY5Y cells in response to two perturbations that model a natural and unnatural cellular state: retinoic-acid-mediated differentiation (healthy) and exposure to the neurotoxicant lead (unhealthy). We discovered that the expression of some psi writers changes significantly in response to physiological conditions. We also found that globally, lead-treated cells have more psi sites but lower relative occupancy than untreated cells and differentiated cells. Examples of highly plastic sites were accompanied by constant expression for psi writers, suggesting trans-regulation. Many positions were static throughout all three cellular states, suggestive of a \"housekeeping\" function. This study enables investigations into mechanisms that control psi modifications in neurons and their possible protective effects in response to cellular stress.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101238"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Explainable modeling of single-cell perturbation data using attention and sparse dictionary learning. 利用注意力和稀疏字典学习对单细胞扰动数据进行可解释建模

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-04-04 DOI: 10.1016/j.cels.2025.101245

Yang Xu, Stephen Fleming, Matthew Tegtmeyer, Steven A McCarroll, Mehrtash Babadi

{"title":"Explainable modeling of single-cell perturbation data using attention and sparse dictionary learning.","authors":"Yang Xu, Stephen Fleming, Matthew Tegtmeyer, Steven A McCarroll, Mehrtash Babadi","doi":"10.1016/j.cels.2025.101245","DOIUrl":"10.1016/j.cels.2025.101245","url":null,"abstract":"Single-cell transcriptomics, in conjunction with genetic and compound perturbations, offers a robust approach for exploring cellular behaviors in diverse contexts. Such experiments allow uncovering cell-state-specific responses to perturbations and unraveling the intricate molecular mechanisms governing cellular behavior. However, prevailing computational methods predominantly focus on predicting average cellular responses, disregarding inherent response heterogeneity associated with cell state diversity and model explainability. In this study, we present CellCap, a deep generative model designed for the end-to-end analysis of single-cell perturbation experiments. CellCap employs sparse dictionary learning in a latent space to deconstruct cell-state-specific perturbation responses into a set of transcriptional response programs and utilizes an attention mechanism to capture correspondence between cell state and perturbation response. We thoroughly evaluate CellCap's interpretability using multiple simulated scenarios as well as two real single-cell perturbation datasets. Our results demonstrate that CellCap successfully uncovers the relationship between cell state and perturbation response, unveiling insights overlooked in previous analyses.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101245"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs. 对同一细胞中染色质可及性和基因表达的联合分析揭示了癌症特异性调控程序。

Cell systems Pub Date : 2025-04-15 DOI: 10.1016/j.cels.2025.101266

Lei Tang, Jinsong Zhang, Yanqiu Shao, Yifan Wei, Yuzhe Li, Kang Tian, Xiang Yan, Changjiang Feng, Qiangfeng Cliff Zhang

{"title":"Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs.","authors":"Lei Tang, Jinsong Zhang, Yanqiu Shao, Yifan Wei, Yuzhe Li, Kang Tian, Xiang Yan, Changjiang Feng, Qiangfeng Cliff Zhang","doi":"10.1016/j.cels.2025.101266","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101266","url":null,"abstract":"Biological analyses conducted at the single-cell scale have revealed profound impacts of heterogeneity and plasticity of chromatin states and gene expression on physiology and cancer. Here, we developed Parallel-seq, a technology for simultaneously measuring chromatin accessibility and gene expression in the same single cells. By combining combinatorial cell indexing and droplet overloading, Parallel-seq generates high-quality data in an ultra-high-throughput fashion and at a cost two orders of magnitude lower than alternative technologies (10× Multiome and ISSAAC-seq). We applied Parallel-seq to 40 lung tumor and tumor-adjacent clinical samples and obtained over 200,000 high-quality joint scATAC-and-scRNA profiles. Leveraging this large dataset, we characterized copy-number variations (CNVs) and extrachromosomal circular DNA (eccDNA) heterogeneity in tumor cells, predicted hundreds of thousands of cell-type-specific regulatory events, and identified enhancer mutations affecting tumor progression. Our analyses highlight Parallel-seq's power in investigating epigenetic and genetic factors driving cancer development at the cell-type-specific level and its utility for revealing vulnerable therapeutic targets.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101266"},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolutionary paths that link orthogonal pairs of binding proteins. 连接正交结合蛋白对的进化路径。

Cell systems Pub Date : 2025-04-10 DOI: 10.1016/j.cels.2025.101262

Ziv Avizemer, Carlos Martí-Gómez, Shlomo Yakir Hoch, David M McCandlish, Sarel J Fleishman

引用次数: 0