Proceedings of the National Academy of Sciences of the United States of America最新文献

Joint disruption of Ret and Ednrb transcription shifts cell fate trajectories in the enteric nervous system in Hirschsprung disease. 先天性巨结肠疾病中Ret和Ednrb转录的联合中断改变了肠神经系统中细胞的命运轨迹。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2507062122

Ryan D Fine, Rebecca Chubaryov, Mingzhou Fu, Gabriel Grullon, Aravinda Chakravarti

{"title":"Joint disruption of Ret and Ednrb transcription shifts cell fate trajectories in the enteric nervous system in Hirschsprung disease.","authors":"Ryan D Fine, Rebecca Chubaryov, Mingzhou Fu, Gabriel Grullon, Aravinda Chakravarti","doi":"10.1073/pnas.2507062122","DOIUrl":"10.1073/pnas.2507062122","url":null,"abstract":"Despite extensive genetic heterogeneity, 72% of pathogenic alleles for Hirschsprung disease (HSCR) arise from coding and regulatory variants in genes of the RET and EDNRB gene regulatory network (GRN) in the enteric nervous system (ENS). To elucidate the mechanisms leading to enteric neuronal loss from these genetic defects, we generated four strains of mice carrying reduced function alleles at Ret or Ednrb or both, along with their wild-type alleles. ENS tissue- and single-cell gene expression profiling of the developing and postnatal gastrointestinal tract in these five mouse models revealed three major insights: i) Ret and Ednrb deficiency, rather than complete loss, is sufficient to induce HSCR, ii) Ret and Ednrb demonstrate strong trans interactions, and iii) disruption of this interaction leads to cellular fate changes to compensate for neuronal loss. Critically, we show the combined reduction of signaling of these two receptors below a threshold in enteric neural crest-derived cells (ENCDCs) leads to a molecular tipping point at which otherwise lesser cellular defects result in aganglionosis. This study of targeted mouse models of a multifactorial disorder reveals how increasing dosage of genetic defects within a GRN leads to quantifiably increasing dysregulation from genotype to gene expression to cellular identity to function. Importantly, our studies establish that aganglionosis results only with severely reduced gene expression at both receptor genes and their consequent disruption of normal and compensatory cell fate trajectories.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2507062122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling. 突变型p53通过甲羟戊酸通路依赖的Rho/ROCK信号通路调控复杂三维环境下癌细胞的侵袭。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2424904122

Asja Guzman, Tatsuya Kawase, Alexander J Devanny, Gizem Efe, Raúl Navaridas, Karen Yu, Kausik Regunath, Iris G Mercer, Rachel C Avard, Rafaela Muniz de Queiroz, Anil K Rustgi, Laura J Kaufman, Carol Prives

{"title":"Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.","authors":"Asja Guzman, Tatsuya Kawase, Alexander J Devanny, Gizem Efe, Raúl Navaridas, Karen Yu, Kausik Regunath, Iris G Mercer, Rachel C Avard, Rafaela Muniz de Queiroz, Anil K Rustgi, Laura J Kaufman, Carol Prives","doi":"10.1073/pnas.2424904122","DOIUrl":"https://doi.org/10.1073/pnas.2424904122","url":null,"abstract":"Certain TP53 mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) reorganization via increasing mevalonate pathway-dependent RhoA localization to the membrane. In line with this, RhoA-dependent proinvasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell-ECM interactions. Together our findings link mutant p53 metabolic GOF activity with a context-dependent invasive cellular phenotype.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2424904122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors. 连接蛋白调控多能造血干细胞和祖细胞的髓系和淋巴系分化。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2509412122

Kutay Karatepe, Bruna Mafra de Faria, Jian Zhang, Xinyue Chen, Hugo Pinto, Dmitry Fyodorov, Esen Sefik, Michael A Willcockson, Richard A Flavell, Arthur I Skoultchi, Shangqin Guo

{"title":"Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors.","authors":"Kutay Karatepe, Bruna Mafra de Faria, Jian Zhang, Xinyue Chen, Hugo Pinto, Dmitry Fyodorov, Esen Sefik, Michael A Willcockson, Richard A Flavell, Arthur I Skoultchi, Shangqin Guo","doi":"10.1073/pnas.2509412122","DOIUrl":"https://doi.org/10.1073/pnas.2509412122","url":null,"abstract":"Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here, we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. Linker histones package nucleosomes and compact chromatin. HSPCs expressing a doxycycline (dox)-inducible H1.0 transgene favor the lymphoid fate, display strengthened nucleosome organization, and reduced chromatin accessibility at subsets of genomic regions. The genomic regions showing reduced chromatin accessibility host many known marker genes of myeloid-biased HSCs. The transcription factor Hlf is located in one of the most differentially closed regions, whose chromatin accessibility and gene expression are reduced in H1.0high HSPCs. Failure to reduce Hlf expression in multipotential HSPCs abrogates the H1.0-endowed lymphoid potential. Furthermore, HSPCs display aspartyl protease-dependent H1.0 decreases, especially in response to interferon alpha (IFNα). Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work elucidates a molecular scenario of how myeloid bias arises and uncovers a point of intervention for correcting myeloid skewed hematopoiesis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2509412122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimal disk packing of chloroplasts in plant cells. 植物细胞中叶绿体的最佳圆盘包装。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-22 DOI: 10.1073/pnas.2511696122

Nico Schramma, Eric R Weeks, Maziyar Jalaal

引用次数: 0

Hierarchical self-assembly for high-yield addressable complexity at fixed conditions. 固定条件下高成品率可寻址复杂度的分层自组装。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-22 DOI: 10.1073/pnas.2500245122

Miranda Holmes-Cerfon, Matthieu Wyart

{"title":"Hierarchical self-assembly for high-yield addressable complexity at fixed conditions.","authors":"Miranda Holmes-Cerfon, Matthieu Wyart","doi":"10.1073/pnas.2500245122","DOIUrl":"https://doi.org/10.1073/pnas.2500245122","url":null,"abstract":"There is evidence that the self-assembly of complex molecular systems often proceeds hierarchically, by first building subunits that later assemble in larger entities, in a process that can repeat multiple times. Yet, our understanding of this phenomenon and its performance is limited. Here, we introduce a simple model for hierarchical addressable self-assembly, where interactions between particles can be optimized to maximize the fraction of a well-formed target structure, or yield. We find that a hierarchical strategy leads to an impressive yield up to at least five generations of the hierarchy and does not require a cycle of temperatures as used in previous methods. High yield is obtained when the microscopic interaction decreases with the scale of units considered, such that the total interaction between intermediate structures remains identical at all scales. We provide thermodynamic and dynamical arguments constraining the interaction strengths where this strategy is effective. Overall, our work characterizes an alternative strategy for addressable self-assembly at a fixed temperature, and provides insight into the mechanisms sustaining hierarchical assembly in biological systems.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2500245122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis. HEIP1在哺乳动物减数分裂过程中协调前交叉蛋白活性。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2515747122

Arnaud De Muyt, Sunkyung Lee, Sushil Khanal, Laurine Dal Toe, Céline Adam, Raphael Mercier, Valérie Borde, Neil Hunter, Thomas Robert

{"title":"HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis.","authors":"Arnaud De Muyt, Sunkyung Lee, Sushil Khanal, Laurine Dal Toe, Céline Adam, Raphael Mercier, Valérie Borde, Neil Hunter, Thomas Robert","doi":"10.1073/pnas.2515747122","DOIUrl":"10.1073/pnas.2515747122","url":null,"abstract":"Meiotic crossovers (COs) are needed to produce genetically balanced gametes. In mammals, CO formation is mediated by a conserved set of pro-CO proteins via mechanisms that remain unclear. Here, we characterize a mammalian pro-CO factor HEIP1. In mouse HEIP1 is essential for crossover and fertility of both sexes. HEIP1 promotes crossover by orchestrating the recruitment of other pro-CO proteins, including the MutSγ complex (MSH4-MSH5) and E3 ligases (HEI10, RNF212, and RNF212B), that are required to mature CO sites and recruit the CO-specific resolution complex MutLγ. Moreover, HEIP1 directly interacts with HEI10, suggesting a direct role in controlling the recruitment of pro-CO E3 ligases. During early stages of meiotic prophase I, HEIP1 interacts with the chromosome axes, independently of recombination, before relocalizing to the central region of the synaptonemal complex. We propose that HEIP1 is a conserved master regulator of CO proteins that controls different CO maturation steps.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2515747122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteolytically activated antibacterial toxins inhibit the growth of diverse gram-positive bacteria. 蛋白水解激活的抗菌毒素抑制多种革兰氏阳性细菌的生长。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2505807122

Jake Colautti, Stephen R Garrett, John C Whitney

{"title":"Proteolytically activated antibacterial toxins inhibit the growth of diverse gram-positive bacteria.","authors":"Jake Colautti, Stephen R Garrett, John C Whitney","doi":"10.1073/pnas.2505807122","DOIUrl":"10.1073/pnas.2505807122","url":null,"abstract":"Many species of bacteria produce small-molecule antibiotics that enter and kill a wide range of competitor microbes. However, diffusible antibacterial proteins (ABPs) that share this broad-spectrum activity are not known to exist. Here, we report a family of proteins widespread in gram-positive bacteria that display potent antibacterial activity against a diverse range of target organisms. Upon entering susceptible cells, these ABPs enzymatically degrade essential cellular components including DNA, transfer ribonucleic acid (tRNA), and ribosomal ribonucleic acid (rRNA). Unlike previously characterized bactericidal proteins, which require a specific cell surface receptor and therefore display a narrow spectrum of activity, we find that ABPs act in a receptor-independent manner and consequently kill bacteria spanning multiple phyla. Target cell entry by ABPs requires proteolytic activation by a cognate, coexported serine protease, and the liberated toxin component of the cleaved ABP is driven across the target cell membrane by the proton motive force. By examining representative ABPs from diverse pathogenic, commensal, and environmental bacteria, we show that broad-spectrum antibacterial activity is a conserved property of this protein family. Collectively, our work demonstrates that secreted proteins can act as broad-spectrum antibiotics, suggesting that ABPs represent one of potentially many such families produced in nature.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2505807122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Full interhemispheric integration sustained by a fraction of posterior callosal fibers. 由一小部分后胼胝体纤维维持的半球间完整整合。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2520190122

Tyler Santander, Selin Bekir, Theresa Paul, Jessica M Simonson, Valerie M Wiemer, Henri Etel Skinner, Johanna L Hopf, Anna Rada, Friedrich G Woermann, Thilo Kalbhenn, Barry Giesbrecht, Christian G Bien, Olaf Sporns, Michael S Gazzaniga, Lukas J Volz, Michael B Miller

{"title":"Full interhemispheric integration sustained by a fraction of posterior callosal fibers.","authors":"Tyler Santander, Selin Bekir, Theresa Paul, Jessica M Simonson, Valerie M Wiemer, Henri Etel Skinner, Johanna L Hopf, Anna Rada, Friedrich G Woermann, Thilo Kalbhenn, Barry Giesbrecht, Christian G Bien, Olaf Sporns, Michael S Gazzaniga, Lukas J Volz, Michael B Miller","doi":"10.1073/pnas.2520190122","DOIUrl":"https://doi.org/10.1073/pnas.2520190122","url":null,"abstract":"The dynamic integration of the lateralized and specialized capacities of the two cerebral hemispheres constitutes a hallmark feature of human brain function. This interhemispheric exchange of information critically depends upon the corpus callosum. Classical anatomical descriptions of callosal organization outline a topographic gradient from front to back, such that specific transcallosal fibers support distinct aspects of integrated brain function. Here, we present a challenge to this conventional model. Using neuroimaging data obtained from a new cohort of adult corpus callosotomy patients, we leverage modern network neuroscience techniques to show that full interhemispheric integration can be achieved via a small proportion of posterior callosal fibers. Partial callosotomy patients with spared callosal fibers retained widespread patterns of interhemispheric functional connectivity and showed no signs of behavioral disconnection, even with only 1 cm of the splenium intact. Conversely, only complete callosotomy patients demonstrated sweeping disruptions of interhemispheric network architectures, aligning with disconnection syndromes long-thought to reflect diminished information propagation and communication across the brain. These findings motivate an evolving mechanistic understanding of synchronized interhemispheric neural activity for large-scale human brain function and behavior.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2520190122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Foot placement control underlies stable locomotion across species. 脚的位置控制是跨物种稳定运动的基础。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2413958122

Antoine De Comite, Nidhi Seethapathi

{"title":"Foot placement control underlies stable locomotion across species.","authors":"Antoine De Comite, Nidhi Seethapathi","doi":"10.1073/pnas.2413958122","DOIUrl":"10.1073/pnas.2413958122","url":null,"abstract":"Animals navigate their environment stably without inefficient course corrections despite unavoidable errors. In humans, this stability is achieved by modulating the placement of the foot on each step such that recent errors are corrected. However, it is unknown whether animals with diverse nervous systems and body mechanics use such foot placement control; foot trajectories of many-legged animals are considered to be stereotypical velocity-driven patterns, as opposed to error-driven. Here, we put forth a unified \"feedforward-feedback\" control structure for stable locomotion that combines velocity-driven and body state error-driven foot placement. We provide empirical support for this control structure across flies, mice, and humans by mining their natural locomotor variability, finding that a competing control structure with purely velocity-driven foot placement is not supported by the data. This work finds shared behavioral signatures of foot placement control in flies, mice, and humans. We find that key characteristics of these signatures, such as their urgency and centralization, vary with neuromechanical embodiment across species. For example, more inherently stable multilegged animals exhibit less urgent control with a lower control magnitude and a slower correction timescale compared to humans. Furthermore, many-legged animals display modular, direction-, and leg-specific control signatures, whereas humans exhibit common signatures across both legs. Overall, our findings provide insight into stable locomotion across species, revealing how species with diverse neuromechanics achieve a shared functional goal: foot placement control.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2413958122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disrupted developmental signaling induces novel transcriptional states. 中断的发育信号诱导新的转录状态。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-28 Epub Date: 2025-10-21 DOI: 10.1073/pnas.2418351122

Aleena L Patel, Vanessa Gonzalez, Triveni Menon, Stanislav Y Shvartsman, Rebecca D Burdine, Maria Avdeeva

{"title":"Disrupted developmental signaling induces novel transcriptional states.","authors":"Aleena L Patel, Vanessa Gonzalez, Triveni Menon, Stanislav Y Shvartsman, Rebecca D Burdine, Maria Avdeeva","doi":"10.1073/pnas.2418351122","DOIUrl":"10.1073/pnas.2418351122","url":null,"abstract":"Signaling pathways induce stereotyped transcriptional changes as stem cells progress into mature cell types during embryogenesis. Signaling perturbations are necessary to discover which genes are responsive or insensitive to pathway activity. However, gene regulation is additionally dependent on cell state-specific factors like chromatin modifications or transcription factor binding. Thus, transcriptional profiles need to be assayed in single cells to identify potentially multiple, distinct perturbation responses among heterogeneous cell states in an embryo. In perturbation studies, comparing heterogeneous transcriptional states among experimental conditions often requires samples to be collected over multiple independent experiments, which can introduce confounding batch effects. We present Design-Aware Integration of Single Cell ExpEriments (DAISEE), a new algorithm that models perturbation responses in single-cell datasets collected according to complex experimental designs. We demonstrate that DAISEE improves upon a previously available integrative nonnegative matrix factorization framework, more efficiently separating perturbation responses from confounding variation. We use DAISEE to integrate newly collected single-cell RNA sequencing datasets from 5-h-old zebrafish embryos expressing optimized photoswitchable MEK (psMEK), which globally activates the extracellular signal-regulated kinase (ERK), a signaling molecule involved in many cell specification events. psMEK drives some cells that are normally not exposed to ERK signals toward other wild type states and induces novel states expressing early-acting endothelial genes. Overactive signaling is therefore capable of producing unexpected gene expression states in developing embryos.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 43","pages":"e2418351122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0