Cell systemsPub Date : 2024-08-21Epub Date: 2024-08-13DOI: 10.1016/j.cels.2024.07.003
Levente Varga, Vasile V Moca, Botond Molnár, Laura Perez-Cervera, Mohamed Kotb Selim, Antonio Díaz-Parra, David Moratal, Balázs Péntek, Wolfgang H Sommer, Raul C Mureșan, Santiago Canals, Maria Ercsey-Ravasz
{"title":"Brain dynamics supported by a hierarchy of complex correlation patterns defining a robust functional architecture.","authors":"Levente Varga, Vasile V Moca, Botond Molnár, Laura Perez-Cervera, Mohamed Kotb Selim, Antonio Díaz-Parra, David Moratal, Balázs Péntek, Wolfgang H Sommer, Raul C Mureșan, Santiago Canals, Maria Ercsey-Ravasz","doi":"10.1016/j.cels.2024.07.003","DOIUrl":"10.1016/j.cels.2024.07.003","url":null,"abstract":"<p><p>Functional magnetic resonance imaging (fMRI) provides insights into cognitive processes with significant clinical potential. However, delays in brain region communication and dynamic variations are often overlooked in functional network studies. We demonstrate that networks extracted from fMRI cross-correlation matrices, considering time lags between signals, show remarkable reliability when focusing on statistical distributions of network properties. This reveals a robust brain functional connectivity pattern, featuring a sparse backbone of strong 0-lag correlations and weaker links capturing coordination at various time delays. This dynamic yet stable network architecture is consistent across rats, marmosets, and humans, as well as in electroencephalogram (EEG) data, indicating potential universality in brain dynamics. Second-order properties of the dynamic functional network reveal a remarkably stable hierarchy of functional correlations in both group-level comparisons and test-retest analyses. Validation using alcohol use disorder fMRI data uncovers broader shifts in network properties than previously reported, demonstrating the potential of this method for identifying disease biomarkers.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"770-786.e5"},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141984113","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}
Cell systemsPub Date : 2024-07-17Epub Date: 2024-06-11DOI: 10.1016/j.cels.2024.05.007
Niklas F C Hummel, Kasey Markel, Jordan Stefani, Max V Staller, Patrick M Shih
{"title":"Systematic identification of transcriptional activation domains from non-transcription factor proteins in plants and yeast.","authors":"Niklas F C Hummel, Kasey Markel, Jordan Stefani, Max V Staller, Patrick M Shih","doi":"10.1016/j.cels.2024.05.007","DOIUrl":"10.1016/j.cels.2024.05.007","url":null,"abstract":"<p><p>Transcription factors can promote gene expression through activation domains. Whole-genome screens have systematically mapped activation domains in transcription factors but not in non-transcription factor proteins (e.g., chromatin regulators and coactivators). To fill this knowledge gap, we employed the activation domain predictor PADDLE to analyze the proteomes of Arabidopsis thaliana and Saccharomyces cerevisiae. We screened 18,000 predicted activation domains from >800 non-transcription factor genes in both species, confirming that 89% of candidate proteins contain active fragments. Our work enables the annotation of hundreds of nuclear proteins as putative coactivators, many of which have never been ascribed any function in plants. Analysis of peptide sequence compositions reveals how the distribution of key amino acids dictates activity. Finally, we validated short, \"universal\" activation domains with comparable performance to state-of-the-art activation domains used for genome engineering. Our approach enables the genome-wide discovery and annotation of activation domains that can function across diverse eukaryotes.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"662-672.e4"},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141312522","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}
Cell systemsPub Date : 2024-07-17Epub Date: 2024-07-05DOI: 10.1016/j.cels.2024.06.001
Mengtong Duan, Ishaan Dev, Andrew Lu, Goar Ayrapetyan, Mei Yi You, Mikhail G Shapiro
{"title":"SEMPER: Stoichiometric expression of mRNA polycistrons by eukaryotic ribosomes for compact, ratio-tunable multi-gene expression.","authors":"Mengtong Duan, Ishaan Dev, Andrew Lu, Goar Ayrapetyan, Mei Yi You, Mikhail G Shapiro","doi":"10.1016/j.cels.2024.06.001","DOIUrl":"10.1016/j.cels.2024.06.001","url":null,"abstract":"<p><p>Here, we present a method for expressing multiple open reading frames (ORFs) from single transcripts using the leaky scanning model of translation initiation. In this approach termed \"stoichiometric expression of mRNA polycistrons by eukaryotic ribosomes\" (SEMPER), adjacent ORFs are translated from a single mRNA at tunable ratios determined by their order in the sequence and the strength of their translation initiation sites. We validate this approach by expressing up to three fluorescent proteins from one plasmid in two different cell lines. We then use it to encode a stoichiometrically tuned polycistronic construct encoding gas vesicle acoustic reporter genes that enables efficient formation of the multi-protein complex while minimizing cellular toxicity. We also demonstrate that SEMPER enables polycistronic expression of recombinant monoclonal antibodies from plasmid DNA and of two fluorescent proteins from single mRNAs made through in vitro transcription. Finally, we provide a probabilistic model to elucidate the mechanisms underlying SEMPER. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"597-609.e4"},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11298409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545640","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}
Cell systemsPub Date : 2024-07-17Epub Date: 2024-07-08DOI: 10.1016/j.cels.2024.06.004
Catherine M Porter, Grace C Qian, Samuel H Grindel, Alex J Hughes
{"title":"Highly parallel production of designer organoids by mosaic patterning of progenitors.","authors":"Catherine M Porter, Grace C Qian, Samuel H Grindel, Alex J Hughes","doi":"10.1016/j.cels.2024.06.004","DOIUrl":"10.1016/j.cels.2024.06.004","url":null,"abstract":"<p><p>Organoids derived from human stem cells are a promising approach for disease modeling, regenerative medicine, and fundamental research. However, organoid variability and limited control over morphological outcomes remain as challenges. One open question is the extent to which engineering control over culture conditions can guide organoids to specific compositions. Here, we extend a DNA \"velcro\" cell patterning approach, precisely controlling the number and ratio of human induced pluripotent stem cell-derived progenitors contributing to nephron progenitor (NP) organoids and mosaic NP/ureteric bud (UB) tip cell organoids within arrays of microwells. We demonstrate long-term control over organoid size and morphology, decoupled from geometric constraints. We then show emergent trends in organoid tissue proportions that depend on initial progenitor cell composition. These include higher nephron and stromal cell representation in mosaic NP/UB organoids vs. NP-only organoids and a \"goldilocks\" initial cell ratio in mosaic organoids that optimizes the formation of proximal tubule structures.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"649-661.e9"},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565354","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}
Cell systemsPub Date : 2024-07-17Epub Date: 2024-07-08DOI: 10.1016/j.cels.2024.06.003
Jeremy Philippe Moore, Keita Kamino, Rafaela Kottou, Thomas S Shimizu, Thierry Emonet
{"title":"Signal integration and adaptive sensory diversity tuning in Escherichia coli chemotaxis.","authors":"Jeremy Philippe Moore, Keita Kamino, Rafaela Kottou, Thomas S Shimizu, Thierry Emonet","doi":"10.1016/j.cels.2024.06.003","DOIUrl":"10.1016/j.cels.2024.06.003","url":null,"abstract":"<p><p>In uncertain environments, phenotypic diversity can be advantageous for survival. However, as the environmental uncertainty decreases, the relative advantage of having diverse phenotypes decreases. Here, we show how populations of E. coli integrate multiple chemical signals to adjust sensory diversity in response to changes in the prevalence of each ligand in the environment. Measuring kinase activity in single cells, we quantified the sensitivity distribution to various chemoattractants in different mixtures of background stimuli. We found that when ligands bind uncompetitively, the population tunes sensory diversity to each signal independently, decreasing diversity when the signal's ambient concentration increases. However, among competitive ligands, the population can only decrease sensory diversity one ligand at a time. Mathematical modeling suggests that sensory diversity tuning benefits E. coli populations by modulating how many cells are committed to tracking each signal proportionally as their prevalence changes.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"628-638.e8"},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565355","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}
Cell systemsPub Date : 2024-07-17Epub Date: 2024-07-08DOI: 10.1016/j.cels.2024.06.002
Jose M G Vilar, Leonor Saiz
{"title":"The unreasonable effectiveness of equilibrium gene regulation through the cell cycle.","authors":"Jose M G Vilar, Leonor Saiz","doi":"10.1016/j.cels.2024.06.002","DOIUrl":"10.1016/j.cels.2024.06.002","url":null,"abstract":"<p><p>Systems like the prototypical lac operon can reliably hold repression of transcription upon DNA replication across cell cycles with just 10 repressor molecules per cell and behave as if they were at equilibrium. The origin of this phenomenology is still an unresolved question. Here, we develop a general theory to analyze strong perturbations in quasi-equilibrium systems and use it to quantify the effects of DNA replication in gene regulation. We find a scaling law linking actual with predicted equilibrium transcription via a single kinetic parameter. We show that even the lac operon functions beyond the physical limits of naive regulation through compensatory mechanisms that suppress non-equilibrium effects. Synthetic systems without adjuvant activators, such as the cAMP receptor protein (CRP), lack this reliability. Our results provide a rationale for the function of CRP, beyond just being a tunable activator, as a mitigator of cell cycle perturbations.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"639-648.e2"},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565370","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}
Cell systemsPub Date : 2024-06-19Epub Date: 2024-05-25DOI: 10.1016/j.cels.2024.05.003
Thomas R Mumford, Diarmid Rae, Emily Brackhahn, Abbas Idris, David Gonzalez-Martinez, Ayush Aditya Pal, Michael C Chung, Juan Guan, Elizabeth Rhoades, Lukasz J Bugaj
{"title":"Simple visualization of submicroscopic protein clusters with a phase-separation-based fluorescent reporter.","authors":"Thomas R Mumford, Diarmid Rae, Emily Brackhahn, Abbas Idris, David Gonzalez-Martinez, Ayush Aditya Pal, Michael C Chung, Juan Guan, Elizabeth Rhoades, Lukasz J Bugaj","doi":"10.1016/j.cels.2024.05.003","DOIUrl":"10.1016/j.cels.2024.05.003","url":null,"abstract":"","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"593"},"PeriodicalIF":0.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156043","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}
{"title":"Tissue module discovery in single-cell-resolution spatial transcriptomics data via cell-cell interaction-aware cell embedding.","authors":"Yuzhe Li, Jinsong Zhang, Xin Gao, Qiangfeng Cliff Zhang","doi":"10.1016/j.cels.2024.05.001","DOIUrl":"10.1016/j.cels.2024.05.001","url":null,"abstract":"<p><p>Computational methods are desired for single-cell-resolution spatial transcriptomics (ST) data analysis to uncover spatial organization principles for how individual cells exert tissue-specific functions. Here, we present ST data analysis via interaction-aware cell embedding (SPACE), a deep-learning method for cell-type identification and tissue module discovery from single-cell-resolution ST data by learning a cell representation that captures its gene expression profile and interactions with its spatial neighbors. SPACE identified spatially informed cell subtypes defined by their special spatial distribution patterns and distinct proximal-interacting cell types. SPACE also automatically discovered \"cell communities\"-tissue modules with discernible boundaries and a uniform spatial distribution of constituent cell types. For each cell community, SPACE outputs a characteristic proximal cell-cell interaction network associated with physiological processes, which can be used to refine ligand-receptor-based intercellular signaling analyses. We envision that SPACE can be used in large-scale ST projects to understand how proximal cell-cell interactions contribute to emergent biological functions within cell communities. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"578-592.e7"},"PeriodicalIF":0.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186041","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}
Cell systemsPub Date : 2024-06-19Epub Date: 2024-06-05DOI: 10.1016/j.cels.2024.05.002
Apeksha Singh, Supriya Sen, Michael Iter, Adewunmi Adelaja, Stefanie Luecke, Xiaolu Guo, Alexander Hoffmann
{"title":"Stimulus-response signaling dynamics characterize macrophage polarization states.","authors":"Apeksha Singh, Supriya Sen, Michael Iter, Adewunmi Adelaja, Stefanie Luecke, Xiaolu Guo, Alexander Hoffmann","doi":"10.1016/j.cels.2024.05.002","DOIUrl":"10.1016/j.cels.2024.05.002","url":null,"abstract":"<p><p>The functional state of cells is dependent on their microenvironmental context. Prior studies described how polarizing cytokines alter macrophage transcriptomes and epigenomes. Here, we characterized the functional responses of 6 differentially polarized macrophage populations by measuring the dynamics of transcription factor nuclear factor κB (NF-κB) in response to 8 stimuli. The resulting dataset of single-cell NF-κB trajectories was analyzed by three approaches: (1) machine learning on time-series data revealed losses of stimulus distinguishability with polarization, reflecting canalized effector functions. (2) Informative trajectory features driving stimulus distinguishability (\"signaling codons\") were identified and used for mapping a cell state landscape that could then locate macrophages conditioned by an unrelated condition. (3) Kinetic parameters, inferred using a mechanistic NF-κB network model, provided an alternative mapping of cell states and correctly predicted biochemical findings. Together, this work demonstrates that a single analyte's dynamic trajectories may distinguish the functional states of single cells and molecular network states underlying them. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"563-577.e6"},"PeriodicalIF":0.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11226196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285663","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}
Cell systemsPub Date : 2024-06-19Epub Date: 2024-06-10DOI: 10.1016/j.cels.2024.05.005
David Bradley, Chantal Garand, Hugo Belda, Isabelle Gagnon-Arsenault, Moritz Treeck, Sabine Elowe, Christian R Landry
{"title":"The substrate quality of CK2 target sites has a determinant role on their function and evolution.","authors":"David Bradley, Chantal Garand, Hugo Belda, Isabelle Gagnon-Arsenault, Moritz Treeck, Sabine Elowe, Christian R Landry","doi":"10.1016/j.cels.2024.05.005","DOIUrl":"10.1016/j.cels.2024.05.005","url":null,"abstract":"<p><p>Most biological processes are regulated by signaling modules that bind to short linear motifs. For protein kinases, substrates may have full or only partial matches to the kinase recognition motif, a property known as \"substrate quality.\" However, it is not clear whether differences in substrate quality represent neutral variation or if they have functional consequences. We examine this question for the kinase CK2, which has many fundamental functions. We show that optimal CK2 sites are phosphorylated at maximal stoichiometries and found in many conditions, whereas minimal substrates are more weakly phosphorylated and have regulatory functions. Optimal CK2 sites tend to be more conserved, and substrate quality is often tuned by selection. For intermediate sites, increases or decreases in substrate quality may be deleterious, as we demonstrate for a CK2 substrate at the kinetochore. The results together suggest a strong role for substrate quality in phosphosite function and evolution. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"544-562.e8"},"PeriodicalIF":0.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141307628","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}