bioRxiv : the preprint server for biology最新文献

{"title":"scMetaIntegrator: a meta-analysis approach to paired single-cell differential expression analysis.","authors":"Kalani Ratnasiri, Sara N Mach, Catherine A Blish, Purvesh Khatri","doi":"10.1101/2025.06.04.657898","DOIUrl":"10.1101/2025.06.04.657898","url":null,"abstract":"<p><p>Traditional differential gene expression methods are limited for analysis of single cell RNA-sequencing (scRNA-seq) studies that use paired repeated measures and matched cohort designs. Many existing approaches consider cells as independent samples, leading to high false positive rates while ignoring inherent sampling structures. Although pseudobulk methods address this, they ignore intra-sample expression variability and have higher false negatives rates. We propose a novel meta-analysis approach that accounts for biological replicates and cell variability in paired scRNA-seq data. Using both real and synthetic datasets, we show that our method, single-cell MetaIntegrator (https://github.com/Khatri-Lab/scMetaIntegrator), provides robust effect size estimates and reproducible p-values.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277835","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}

{"title":"G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway.","authors":"Esther Liu, Matthew Wright, Andrew O Kearney, Tiffany Caza, Johnson Y Yang, Valerie Garcia, Amal O Dadi, Shuta Ishibe, Navdeep S Chandel, Hanrui Zhang, Edward B Thorp, Jennie Lin","doi":"10.1101/2025.06.06.658371","DOIUrl":"10.1101/2025.06.06.658371","url":null,"abstract":"<p><p>The G1 and G2 variants of the gene encoding Apolipoprotein L1 (<i>APOL1</i>) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 <i>APOL1</i> cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 <i>APOL1</i>. We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor α-difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 <i>APOL1</i> in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277573","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}

{"title":"Primitive Hepatoblasts Driving Early Liver Development.","authors":"Kentaro Iwasawa, Hiroyuki Koike, Hasan Al Reza, Yuka Milton, Keishi Kishimoto, Konrad Thorner, Marissa Granitto, Norikazu Saiki, Connie Santangelo, Kathryn Glaser, Masaki Kimura, Alexander Bondoc, Hee-Wong Lim, Mitsuru Morimoto, Makiko Iwafuchi, James M Wells, Aaron M Zorn, Takanori Takebe","doi":"10.1101/2025.06.08.658502","DOIUrl":"10.1101/2025.06.08.658502","url":null,"abstract":"<p><p>The embryonic development of the liver is initiated by the emergence of hepatoblasts, originating from the ventral foregut endoderm adjacent to the heart. Here, we identify and characterize a previously unrecognized population of early hepatoblasts at the ventroposterior part of the emerging liver bud, traced from <i>Cdx2</i>-positive endoderm progenitors, which we term primitive hepatoblasts. Mouse and human single-cell transcriptomics reveals the expression of both canonical hepatoblast markers <i>TBX3</i>, <i>FGB</i>, and <i>KRT8/18</i> and primitive-specific mesenchymal markers <i>ID3</i>, <i>VIM</i>, and <i>GATA4</i>. Lineage tracing revealed the notable contribution up to 12.6% of LIV2+ hepatoblasts at E11.5 but diminishes in late fetal and postnatal development. Epigenetic and functional perturbation studies further uncover that primitive hepatoblast emergence is primed by WNT-suppression on RA-permissive CDX2+FOXA2+ progenitors. Furthermore, human pluripotent stem cell-derived primitive hepatoblast-like cells secrete pleiotrophin and midkine to amplify hepatoblast populations and develop epithelial-mesenchymal hybrid tissues <i>in vivo</i>. Our results provide a new framework for understanding lineage heterogeneity during early hepatogenesis and offer revised insights into strategies to model normal and abnormal liver development.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277808","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}

{"title":"Biliverdin Reductase A is a major determinant of neuroprotective Nrf2 signaling.","authors":"Chirag Vasavda, Ruchita Kothari, Navneet Ammal Kaidery, Suwarna Chakraborty, Sunil Jamuna Tripathi, Ryan S Dhindsa, Samaneh Saberi, Julia E Lefler, Priyanka Kothari, Kalyani Chaubey, Adele M Snowman, Michael C Ostrowski, Eugenio Barone, Lakshminarayan M Iyer, L Aravind, Sudarshana M Sharma, Andrew A Pieper, Bobby Thomas, Solomon H Snyder, Bindu D Paul","doi":"10.1101/2025.06.04.657936","DOIUrl":"https://doi.org/10.1101/2025.06.04.657936","url":null,"abstract":"<p><p>Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a novel non-enzymatic role for BVRA in redox regulation. We show that BVRA directly interacts with nuclear factor erythroid-derived factor-like 2 (Nrf2), the master regulator of redox homeostasis, to modulate target signaling pathways. ChIP-seq and RNA-seq analyses reveal that this interaction coordinates the expression of neuroprotective genes that are typically dysregulated in Alzheimer's disease and other neurodegenerative conditions. Thus, this previously unknown BVRA-Nrf2 axis controls an essential pathway of redox signaling in neuroprotection. Our findings establish BVRA as a dual-function integrator of antioxidant defenses in both the lipophilic and hydrophilic subcellular compartments, bridging these two distinct and critical cellular protection mechanisms in the brain. This advancement in understanding the endogenous antioxidant system of the brain positions the BVRA-Nrf2 axis as a promising therapeutic target for neurodegenerative disease.</p><p><strong>Significance statement: </strong>We show a non-canonical role for biliverdin reductase A (BVRA), classically known as the biosynthetic enzyme for bilirubin, in nonenzymatic modulation of antioxidant neuroprotective nuclear factor erythroid-derived factor-like 2 (Nrf2) signaling in the brain. Both BVRA and Nrf2 signaling are compromised in neurodegenerative diseases such as Alzheimer's disease, and the BVRA-Nrf2 axis offers a new direction for developing neuroprotective therapies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277430","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}

{"title":"Nociceptin/Orphanin FQ receptor agonism attenuates behavioral and neural responses to conditioned aversive stimuli.","authors":"Kwang-Hyun Hur, Diego A Pizzagalli, Jessi Stover, Kenroy Cayetano, Stephen J Kohut","doi":"10.1101/2025.06.05.658049","DOIUrl":"https://doi.org/10.1101/2025.06.05.658049","url":null,"abstract":"<p><p>The nociceptin/orphanin FQ peptide (NOP) receptor has emerged as a promising anxiolytic target, as its activation has been shown to reduce anxiety-related behaviors in rodents. However, the mechanisms underlying these effects are not well understood. Here, we investigated the effects of the selective NOP receptor agonist SCH-221510 (SCH; 0.01-0.1 mg/kg, IM) on behavioral and neural responses to aversive stimuli in squirrel monkeys (n=3). Subjects underwent Pavlovian fear conditioning, wherein a visual conditioned stimulus (CS) was paired with the presentation of an aversive stimulus. Event-related fMRI was conducted in awake subjects to evaluate CS-evoked neural responses. Behavioral and neural responses to the CS were assessed across three experimental phases: pre-conditioning (Pre-C), post-conditioning (Post-C), and Post-C with SCH administration. In behavioral assessments, CS presentation during Post-C elicited a robust suppression of ongoing operant responding, which was absent during Pre-C and significantly attenuated by SCH treatment (0.1 mg/kg). Functional magnetic resonance imaging (fMRI) results revealed that, relative to Pre-C, CS presentation during Post-C was associated with increased BOLD activity in brain regions previously implicated in fear processing (e.g., amygdala), expression and regulation (e.g., prefrontal cortex; PFC), as well as sensory integration. Critically, SCH (0.1 mg/kg) administration significantly attenuated CS-induced neural activation in these regions. Furthermore, resting-state functional connectivity analysis revealed that SCH administration decreased connectivity between the PFC and the amygdala, while enhancing connectivity among subregions of the PFC. Collectively, these findings suggest that NOP receptor agonism may attenuate conditioned responses to aversive stimuli by modulating functional interactions within the PFC-amygdala circuit.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277696","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}

{"title":"A human <i>ex vivo</i> model of radiation-induced skin injury reveals p53-driven DNA damage signaling and recapitulates a TGFβ fibrotic response.","authors":"Caroline Dodson, Sophie M Bilik, Gabrielle DiBartolomeo, Hannah Pachalis, Lindsey Siegfried, Jordan A K Johnson, Seth R Thaller, Irena Pastar, Marjana Tomic-Canic, Anthony J Griswold, Rivka C Stone","doi":"10.1101/2025.06.04.657901","DOIUrl":"10.1101/2025.06.04.657901","url":null,"abstract":"<p><p>Radiation-induced skin injury is a poorly understood complication affecting cancer patients who undergo radiotherapy, with no current therapies able to prevent or halt its progression to debilitating radiation-induced skin fibrosis (RISF). Addressing the need for clinically relevant human models, this study developed and characterized a human <i>ex vivo</i> skin model that recapitulates the temporal molecular processes of cutaneous radiation injury, as demonstrated through bulk RNA-sequencing and tissue validation studies. Human skin explants subjected to ionizing radiation demonstrated rapid induction of DNA double-strand breaks, followed by a robust, p53-driven transcriptional program involving genes related to cell cycle arrest, apoptosis, and senescence. Over time, the irradiated skin exhibited increasing activation of pro-fibrotic pathways, notably epithelial-mesenchymal transition and <i>TGFβ1</i>-mediated signaling. This resulted in upregulation of classic fibrosis markers such as <i>COL1A1</i>, <i>FN1</i>, and increased collagen thickness. Importantly, regulators of the p53 axis, MDM2 and miR-34a, was observed, implicating these factors as potential therapeutic targets to modulate the balance between repair of radiation injury and pathologic fibrosis. Transcriptome analysis of irradiated and non-irradiated breast skin from post-mastectomy patients showed notable concordance of p53 and pro-fibrotic gene signatures comparable to the <i>ex vivo</i> model, underscoring its translational relevance. This work provides a platform for identifying early biomarkers and testing therapeutic strategies to prevent or mitigate cutaneous radiation toxicities, including RISF, beginning with elucidating the dynamic interplay between the p53-mediated DNA damage response and the onset of fibrosis following radiation. Ultimately, this work aims to improve long-term skin health and quality of life for cancer patients.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277261","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}

{"title":"Characterization of a Novel Cell Wall-Associated Nucleotidase of <i>Enterococcus faecalis</i> that Degrades Extracellular c-di-AMP.","authors":"Adriana G Morales Rivera, Anju Bala, Leila G Casella, Debra N Brunson, Aria Patel, Elsa Wongso, Ana L Flores-Mireles, José A Lemos","doi":"10.1101/2025.06.08.658492","DOIUrl":"10.1101/2025.06.08.658492","url":null,"abstract":"<p><p><i>Enterococcus faecalis</i> is a prolific opportunistic pathogen responsible for a range of life-threatening infections for which treatment options are increasingly limited due to the high prevalence of multidrug-resistant isolates. Cyclic di-AMP has emerged as an essential bacterial signaling molecule due to its impact on physiological processes, including osmotic adaptation, cell wall homeostasis, antibiotic tolerance, and virulence. In addition, c-di-AMP is a potent pathogen-associated molecular pattern (PAMP) molecule recognized by the host immune system to trigger protective responses. In previous work, we identified and characterized the enzymes responsible for the synthesis and degradation of intracellular c-di-AMP in <i>E. faecalis</i>, demonstrating that maintaining c-di-AMP homeostasis is vital for bacterial fitness and virulence. In addition to the intracellular enzymes that regulate c-di-AMP levels, a limited number of bacteria encode surface-associated nucleotidases capable of cleaving extracellular c-di-AMP, potentially facilitating immune evasion. Here, we characterize a novel and unique cell wall-anchored phosphodiesterase, termed EecP (<i>E. faecalis</i> extracellular c-di-AMP phosphodiesterase), which features duplicated catalytic domains and specifically degrades extracellular c-di-AMP. Deletion of <i>eecP</i> (Δ<i>eecP</i>) resulted in a marked accumulation of extracellular c-di-AMP. Although the Δ<i>eecP</i> strain exhibited comparable growth and behavior to the parent strain <i>in vitro</i>, it displayed increased susceptibility to killing by phagocytic cells. Using two murine infection models, we show that the impact of <i>eecP</i> deletion and the consequent buildup of extracellular c-di-AMP on <i>E. faecalis</i> pathogenesis may be site-specific. Notably, disseminated infection was more severe in mice infected with the Δ<i>eecP</i> strain, suggesting that extracellular c-di-AMP influences infection outcomes, likely through modulation of host immune responses.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277353","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}

{"title":"Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.","authors":"Vaibhav Vemuganti, Jea Woo Kang, Qijun Zhang, Ruben Aquino-Martinez, Sandra Harding, Joseph Lawrence Harpt, Yuetiva Deming, Sterling Johnson, Sanjay Asthana, Henrik Zetterberg, Kaj Blennow, Corinne D Engelman, Tyler K Ulland, Fredrik Bäckhed, Barbara B Bendlin, Federico E Rey","doi":"10.1101/2025.06.08.657719","DOIUrl":"10.1101/2025.06.08.657719","url":null,"abstract":"<p><p>The gut microbiome modulates metabolic, immune, and neurological functions and has been implicated in Alzheimer's disease (AD), though the specific mechanisms remain poorly defined. The bacterial metabolite imidazole propionate (ImP) has been previously associated with several AD comorbidities, such as type 2 diabetes and cardiovascular disease. Here, we show that elevated plasma ImP levels are associated with lower cognitive scores and AD biomarkers in a cohort of >1,100 cognitively unimpaired individuals. Metagenomic profiling identified gut bacteria encoding putative orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Chronic ImP administration to mice activated neurodegenerative pathways, worsened AD-like neuropathology, and increased blood-brain barrier (BBB) permeability. Complementary <i>in vitro</i> studies showed that ImP compromised the integrity of human brain endothelial cells. Collectively, these findings implicate ImP in AD progression via both neurodegenerative and cerebrovascular mechanisms, identifying it as a potential target for early intervention.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277613","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}

{"title":"Membrane phosphoinositides allosterically tune β-arrestin dynamics to facilitate GPCR core engagement.","authors":"John Janetzko, Jonathan Deutsch, Yuqi Shi, Dirk H Siepe, Matthieu Masureel, Weijing Liu, Rosa Viner, Asuka Inoue, Brian K Kobilka, Rabindra V Shivnaraine","doi":"10.1101/2025.06.06.658200","DOIUrl":"10.1101/2025.06.06.658200","url":null,"abstract":"<p><p>Arrestin proteins bind active G protein-coupled receptors (GPCRs) through coordinated protein-protein, protein-phosphate, and protein-lipid interactions to attenuate G protein signaling and promote GPCR internalization and trafficking. While there are hundreds of diverse GPCRs, only two β-arrestin isoforms (βarrs) must recognize and engage this wide range of receptors with varied phosphorylation patterns. Traditional models suggest that βarr activation requires displacement of its autoinhibitory C-tail by a phosphorylated GPCR C-terminus; however, this paradigm fails to explain how minimally phosphorylated GPCRs still complex with βarrs. Using single-molecule Förster resonance energy transfer imaging and hydrogen-deuterium exchange mass spectrometry, we observe basal dynamics in which the βarr1 C-tail spontaneously releases from the N-domain, transiently adopting an active conformation that can facilitate binding of the phosphorylated GPCR C-terminus. We further demonstrate the importance of an intermediate state of βarr1 arising from spontaneous C-tail release stabilized by the membrane phosphoinositide PI(4,5)P₂. Both PI(4,5)P₂ and mutations in the proximal or middle regions of the C-tail shift βarr1 towards a partially released state, revealing an allosteric connection that informs a refined model for βarr activation. In this model, membrane engagement conformationally primes βarrs prior to receptor binding, thereby explaining how βarrs are recruited by diverse GPCRs, even those with limited C-terminal phosphorylation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277717","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}

{"title":"Transposon-plasmid nesting enables fast response to fluctuating environments.","authors":"Yuanchi Ha, Rohan Maddamsetti, Xiaoli Chen, Emrah Şimşek, Dongheon Lee, Hyein Son, Charlotte Lee, Edo Kussell, Lingchong You","doi":"10.1101/2025.06.04.657954","DOIUrl":"10.1101/2025.06.04.657954","url":null,"abstract":"<p><p>Mobile genetic elements (MGEs) play a critical role in shaping the response and evolution of microbial populations and communities. Despite distinct maintenance mechanisms, different types of MGEs can form nested structures. Using bioinformatics analysis of 14,338 plasmids in the NCBI RefSeq database, we found transposons to be widespread and significantly enriched on plasmids relative to chromosomes, highlighting the prevalence of transposon-plasmid nesting. We hypothesized that this nested structure provides unique adaptive advantages by combining transposition-driven genetic mobility with plasmid-mediated copy number amplification. Using engineered transposon systems, we demonstrated that nesting enables rapid and tunable responses of transposon-encoded genes in fluctuating environments. Specifically, transposition maintains a reservoir of the encoded genes, while plasmid copy number fluctuations further amplify the dynamic range of gene dosage, thus enhancing the response speed and stability of transposon-encoded traits. Our findings demonstrate an adaptive benefit of transposon-plasmid nesting and provide insights into their ecological persistence and evolutionary success.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277935","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}