Cell systems最新文献

Iterative deep learning design of human enhancers exploits condensed sequence grammar to achieve cell-type specificity. 人类增强子的迭代深度学习设计利用浓缩序列语法来实现细胞类型特异性。

Cell systems Pub Date : 2025-06-04 DOI: 10.1016/j.cels.2025.101302

Christopher Yin, Sebastian Castillo-Hair, Gun Woo Byeon, Peter Bromley, Wouter Meuleman, Georg Seelig

{"title":"Iterative deep learning design of human enhancers exploits condensed sequence grammar to achieve cell-type specificity.","authors":"Christopher Yin, Sebastian Castillo-Hair, Gun Woo Byeon, Peter Bromley, Wouter Meuleman, Georg Seelig","doi":"10.1016/j.cels.2025.101302","DOIUrl":"10.1016/j.cels.2025.101302","url":null,"abstract":"An important and largely unsolved problem in synthetic biology is how to target gene expression to specific cell types. Here, we apply iterative deep learning to design synthetic enhancers with strong differential activity between two human cell lines. We initially train models on published datasets of enhancer activity and chromatin accessibility and use them to guide the design of synthetic enhancers that maximize predicted specificity. We experimentally validate these sequences, use the measurements to re-optimize the model, and design a second generation of enhancers with improved specificity. Our design methods embed relevant transcription factor binding site (TFBS) motifs with higher frequency than comparable endogenous enhancers while using a more selective motif vocabulary, and we show that enhancer activity is correlated with transcription factor expression at the single-cell level. Finally, we characterize causal features of top enhancers via perturbation experiments and show that enhancers as short as 50 bp can maintain specificity. A record of this paper's transparent peer review process is included in the supplemental information.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101302"},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236143","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

Uncovering the principles coordinating systems-level organelle biogenesis with cellular growth. 揭示系统级细胞器生物发生与细胞生长的协调原理。

Cell systems Pub Date : 2025-06-03 DOI: 10.1016/j.cels.2025.101267

Shixing Wang, Deepthi Kailash, Shankar Mukherji

{"title":"Uncovering the principles coordinating systems-level organelle biogenesis with cellular growth.","authors":"Shixing Wang, Deepthi Kailash, Shankar Mukherji","doi":"10.1016/j.cels.2025.101267","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101267","url":null,"abstract":"A complete framework of eukaryotic cellular growth control must include the growth of its defining hallmarks: organelles. Organelle coordination with cellular growth is opaque without measuring multiple organelles in the same cell with adequate statistics to test theoretical frameworks. Here, we map out the correlation structure of systems-level organelle biogenesis with cellular growth using \"rainbow yeast,\" simultaneously visualizing 6 major metabolically active organelles. Hyperspectral imaging of thousands of rainbow yeast cells revealed that systems-level organelle biogenesis is organized into collective organelle modes activated by changes in nutrient availability. Chemical biological dissection suggests that sensed growth rate and cell size specifically activate these organelle modes. Mathematical modeling and synthetic control of cytoplasmic availability suggest that the organelle mode structure allows growth homeostasis in constant environments and responsiveness to environmental change. This regulatory architecture may underlie how compartmentalization allows cell size and growth rate flexibility to satisfy otherwise incompatible environmental and developmental constraints.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101267"},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251317","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

SPaSE: Spatially resolved pathology scores using optimal transport on spatial transcriptomics data. SPaSE：在空间转录组学数据上使用最佳转运的空间解决病理评分。

Cell systems Pub Date : 2025-06-03 DOI: 10.1016/j.cels.2025.101301

Mohammad Nuwaisir Rahman, Mohammed Abid Abrar, Vikram Rakesh Shaw, James F Martin, M Saifur Rahman, Md Abul Hassan Samee

{"title":"SPaSE: Spatially resolved pathology scores using optimal transport on spatial transcriptomics data.","authors":"Mohammad Nuwaisir Rahman, Mohammed Abid Abrar, Vikram Rakesh Shaw, James F Martin, M Saifur Rahman, Md Abul Hassan Samee","doi":"10.1016/j.cels.2025.101301","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101301","url":null,"abstract":"Pathological events often impact tissue regions in a spatially variable manner, making it challenging to identify therapeutic targets. Spatial transcriptomics (ST) is a powerful technology to map spatially variable molecular mechanisms, yet suitable analytical methods have been lacking. We introduce spatially resolved pathology score (SPaSE), an optimal transport-based algorithm to compare ST data from diseased and control tissues. SPaSE computes a \"pathology score\" for each spot in the diseased sample, quantifying the pathological impact at that spot. In post-myocardial infarction (post-MI) mouse hearts, these scores delineated zones that matched independent expert annotations. Modeling pathology scores from gene expression revealed signatures predictive of varying pathological severity. The scoring model learned from mouse data showed accurate predictions on human post-MI data. We also demonstrated SPaSE's efficacy on additional simulated and real ST data from traumatic brain injury and Duchenne muscular dystrophy mouse models. SPaSE is a useful addition to the existing ST algorithms. A record of this paper's transparent peer review process is included in the supplemental information.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101301"},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251316","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

A systems view of cellular heterogeneity: Unlocking the "wheel of fate". 细胞异质性的系统观点：解开“命运之轮”。

Cell systems Pub Date : 2025-06-02 DOI: 10.1016/j.cels.2025.101300

Hourieh Movasat, Enzo Giacopino, Ali Shahdoost, Yeganeh Dorri Nokoorani, Ali Houshyar Abrbekouh, Yaser Tahamtani, Nika Shakiba

{"title":"A systems view of cellular heterogeneity: Unlocking the \"wheel of fate\".","authors":"Hourieh Movasat, Enzo Giacopino, Ali Shahdoost, Yeganeh Dorri Nokoorani, Ali Houshyar Abrbekouh, Yaser Tahamtani, Nika Shakiba","doi":"10.1016/j.cels.2025.101300","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101300","url":null,"abstract":"Systems biology offers a view of the cell as an input-output device: a biochemical network (or cellular \"processor\") that interprets cues from the microenvironment to drive cell fate. Advancements in single-cell technologies are unlocking the cellular black box, revealing heterogeneity in seemingly homogeneous cell populations. But are these differences technical variability or biology? In this review, we explore this question through a systems biology lens, offering a framework for conceptualizing heterogeneity from the cell's perspective and summarizing systems and synthetic biology tools for capturing heterogeneity. While cellular inputs shape the probability of attaining particular fates, each cell spins a stochastic \"wheel of fate.\" Applying this framework, we explore heterogeneity in two case studies: human pluripotent stem cell (hPSC) culture and beta cell differentiation. Looking forward, we discuss how a systems approach to heterogeneity may enable more predictable outcomes in stem cell research, with broad implications for developmental biology and regenerative medicine.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101300"},"PeriodicalIF":0.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236142","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

Machine-guided dual-objective protein engineering for deimmunization and therapeutic functions. 机器引导的双目标蛋白工程用于脱免疫和治疗功能。

Cell systems Pub Date : 2025-05-23 DOI: 10.1016/j.cels.2025.101299

Eric Wolfsberg, Jean-Sebastien Paul, Josh Tycko, Binbin Chen, Michael C Bassik, Lacramioara Bintu, Ash A Alizadeh, Xiaojing J Gao

{"title":"Machine-guided dual-objective protein engineering for deimmunization and therapeutic functions.","authors":"Eric Wolfsberg, Jean-Sebastien Paul, Josh Tycko, Binbin Chen, Michael C Bassik, Lacramioara Bintu, Ash A Alizadeh, Xiaojing J Gao","doi":"10.1016/j.cels.2025.101299","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101299","url":null,"abstract":"Cell and gene therapies often express nonhuman proteins, which carry a risk of anti-therapy immunogenicity. An emerging consensus is to instead use modified human protein domains, but these domains include nonhuman peptides around mutated residues and at interdomain junctions, which may also be immunogenic. We present a modular workflow to optimize protein function and minimize immunogenicity by using existing machine learning models that predict protein function and peptide-major histocompatibility complex (MHC) presentation. We first applied this workflow to existing transcriptional activation and RNA-binding domains by removing potentially immunogenic MHC II epitopes. We then generated small-molecule-controllable transcription factors with human-derived DNA-binding domains targeting non-genomic DNA sequences. Finally, we established a workflow for creating deimmunized zinc-finger arrays to target arbitrary DNA sequences and upregulated two therapeutically relevant genes, utrophin (UTRN) and sodium voltage-gated channel alpha subunit 1 (SCN1A), using it. Our modular workflow offers a way to potentially make cell and gene therapies safer and more efficacious using state-of-the-art algorithms.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101299"},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227978","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

Statistical modeling and analysis of cell counts from multiplexed imaging data. 统计建模和分析细胞计数从多路复用成像数据。

Cell systems Pub Date : 2025-05-22 DOI: 10.1016/j.cels.2025.101296

Pierre Bost, Ruben Casanova, Uria Mor, Martina Haberecker, Chantal Pauli, Susanne Dettwiler, Bernd Bodenmiller

引用次数: 0

Scalable image-based visualization and alignment of spatial transcriptomics datasets. 可扩展的基于图像的可视化和空间转录组学数据集的对齐。

Cell systems Pub Date : 2025-05-21 Epub Date: 2025-04-22 DOI: 10.1016/j.cels.2025.101264

Stephan Preibisch, Michael Innerberger, Daniel León-Periñán, Nikos Karaiskos, Nikolaus Rajewsky

引用次数: 0

Decoding the role of the arginine dihydrolase pathway in shaping human gut community assembly and health-relevant metabolites. 解码精氨酸二水解酶途径在塑造人类肠道群落组装和健康相关代谢物中的作用。

Cell systems Pub Date : 2025-05-21 Epub Date: 2025-05-07 DOI: 10.1016/j.cels.2025.101292

Yiyi Liu, Yu-Yu Cheng, Jaron Thompson, Zhichao Zhou, Eugenio I Vivas, Matthew F Warren, Julie M DuClos, Karthik Anantharaman, Federico E Rey, Ophelia S Venturelli

{"title":"Decoding the role of the arginine dihydrolase pathway in shaping human gut community assembly and health-relevant metabolites.","authors":"Yiyi Liu, Yu-Yu Cheng, Jaron Thompson, Zhichao Zhou, Eugenio I Vivas, Matthew F Warren, Julie M DuClos, Karthik Anantharaman, Federico E Rey, Ophelia S Venturelli","doi":"10.1016/j.cels.2025.101292","DOIUrl":"10.1016/j.cels.2025.101292","url":null,"abstract":"The arginine dihydrolase pathway (arc operon) provides a metabolic niche by transforming arginine into metabolic byproducts. We investigate the role of the arc operon in probiotic Escherichia coli Nissle 1917 on human gut community assembly and health-relevant metabolite profiles. By stabilizing environmental pH, the arc operon reduces variability in community composition in response to pH perturbations and frequently enhances butyrate production in synthetic communities. We use a tailored machine learning model for microbiomes to predict community assembly in response to variation in initial media pH and arc operon activity. This model uncovers the pH- and arc operon-dependent interactions shaping community assembly. Human gut species display altered colonization dynamics in response to the arc operon in the murine gut. In sum, our framework to quantify the contribution of a specific pathway to microbial community assembly and metabolite production can reveal new engineering strategies. A record of this paper's transparent peer review process is included in the supplemental information.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101292"},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065398","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

What is the current bottleneck in mapping molecular interaction networks? 绘制分子相互作用网络的当前瓶颈是什么？

Cell systems Pub Date : 2025-05-21 DOI: 10.1016/j.cels.2025.101295

Michael A Skinnider, Katja Luck, M Shahid Mukhtar, Martin Garrido-Rodriguez, Julio Saez-Rodriguez, Jolanda van Leeuwen, Pedro Beltrao, Anne-Ruxandra Carvunis, Mikko Taipale, Andrew Emili, Martha L Bulyk, Nevan J Krogan

引用次数: 0

Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence. 基于文库的CAR信号单细胞分析揭示了体内持久性的驱动因素。

Cell systems Pub Date : 2025-05-21 Epub Date: 2025-04-10 DOI: 10.1016/j.cels.2025.101260

Caleb R Perez, Andrea Garmilla, Avlant Nilsson, Hratch M Baghdassarian, Khloe S Gordon, Louise G Lima, Blake E Smith, Marcela V Maus, Douglas A Lauffenburger, Michael E Birnbaum

{"title":"Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence.","authors":"Caleb R Perez, Andrea Garmilla, Avlant Nilsson, Hratch M Baghdassarian, Khloe S Gordon, Louise G Lima, Blake E Smith, Marcela V Maus, Douglas A Lauffenburger, Michael E Birnbaum","doi":"10.1016/j.cels.2025.101260","DOIUrl":"10.1016/j.cels.2025.101260","url":null,"abstract":"The anti-tumor function of engineered T cells expressing chimeric antigen receptors (CARs) is dependent on signals transduced through intracellular signaling domains (ICDs). Different ICDs are known to drive distinct phenotypes, but systematic investigations into how ICD architectures direct T cell function-particularly at the molecular level-are lacking. Here, we use single-cell sequencing to map diverse signaling inputs to transcriptional outputs, focusing on a defined library of clinically relevant ICD architectures. Informed by these observations, we functionally characterize transcriptionally distinct ICD variants across various contexts to build comprehensive maps from ICD composition to phenotypic output. We identify a unique tonic signaling signature associated with a subset of ICD architectures that drives durable in vivo persistence and efficacy in liquid, but not solid, tumors. Our findings work toward decoding CAR signaling design principles, with implications for the rational design of next-generation ICD architectures optimized for in vivo function.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101260"},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058812","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