bioRxiv Science⌕ Search

Biology subjects

Lu, Z.

Publications and source records attributed to Lu, Z..

At least 55 records · Page 3Linked to original sources

Epigenome-informed prioritization of bivalent chromatin SNPs enhances genomic prediction robustness: a proof-of-concept study in Pacific white shrimp (Litopenaeus vannamei)

BackgroundGenomic selection (GS) has revolutionized animal breeding, spanning livestock sectors such as pigs and cattle to aquatic species like fish and shrimp. However, its broader application across these industries is often constrained by high genotyping costs and reduced predictive reliability across divergent populations or generations. Developing cost-effective, biologically informed genotyping strategies to overcome these limitations remains a critical goal in animal agriculture. Epigenetic annotations, particularly histone modifications, provide direct functional insights into regulatory elements underlying complex trait variation and represent a promising but underexplored resource for marker prioritization. ResultsHere, using the Pacific white shrimp (Litopenaeus vannamei) as a model organism, we conducted a proof-of-concept study integrating resequencing and phenotypic data from 972 individuals. We generated high-resolution epigenomic maps by profiling four histone marks (H3K4me1, H3K4me3, H3K27me3, and H3K27ac) across multiple embryonic stages and adult muscle tissue using CUT&Tag. These functional annotations were then leveraged to prioritize single nucleotide polymorphism (SNP) subsets for genomic prediction. Among the tested strategies, SNPs located in the muscle-specific bivalent promoter/enhancer (E6) state--characterized by the co-occurrence of active and repressive marks--consistently maximized prediction accuracy under the BayesA model. Notably, even at a moderate density (15k), E6-derived SNPs achieved prediction accuracies exceeding those obtained using substantially larger genome-wide SNP sets. Most importantly, in a challenging cross-population validation using an independent strain, the E6-derived SNP subset significantly improved prediction accuracy by 47.6% (increasing from 0.21 {+/-} 0.05 to 0.31 {+/-} 0.04, p < 0.05) compared to random subsets at equivalent density. ConclusionsThese results demonstrate that epigenetic annotation-guided SNP prioritization provides a biologically informed and cost-effective strategy to enhance genomic prediction accuracy and stability. This framework is broadly transferable across species and offers a practical strategy for designing low-density genotyping panels that reduce costs while maintaining reliable selection outcomes in large-scale breeding programs.

genetics↗

Cell phenotypes in the biomedical literature: a systematic analysis and text mining corpus

The variety of cell phenotypes identified by single-cell technologies is rapidly expanding, yet this knowledge is dispersed across the scientific literature and incompletely represented in structured resources. We present the CellLink corpus, a manually annotated collection of over 22,000 mentions of human and mouse cell populations in recent journal articles, distinguishing specific cell phenotypes, heterogeneous cell populations, and vague cell populations, and linking to Cell Ontology (CL) terms as either exact or related matches, covering nearly half of the terms in the current CL. A systematic analysis reveals lineage-specific patterns in how authors utilize anatomical context, molecular signatures, functional roles, developmental stage, and other attributes in cell naming. We show that fine-tuning transformer-based models on CellLink yields strong performance for named entity recognition, while embedding-based approaches support zero-shot entity linking and distinguishing exact from related matches. We further demonstrate the utility of CellLink to expand and refine the chondrocyte branch of CL.

bioinformatics↗

Identification and characterization of ethR and ethA genes impacting the sensitivity of Mycobacterium abscessus to ethionamide

Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterium with rising global incidence. This pathogen exhibits intrinsic resistance to most antibiotics, presenting a major public health threat. Ethionamide (ETH) requires bioactivation by monooxygenase EthA to form the active ETH-NAD adduct. We previously identified MAB_3513 (NudC) as a phosphohydrolase that confers intrinsic resistance to M. abscessus by hydrolyzing this adduct. However, deletion of nudC results in only partial susceptibility to ETH, indicating the existence of additional resistance mechanisms. This study identified MAB_0984 as the EthR regulator in M. abscessus. Deletion of ethR in a nudC knockout background ({Delta}{Delta}ethR) significantly enhanced ETH-NAD adduct accumulation, leading to hypersusceptibility to ETH. Notably, the {Delta}ethR mutant exhibited higher susceptibility than {Delta}nudC, demonstrating that EthR is a more dominant mediator of ETH resistance than NudC. Furthermore, MAB_0985 (EthA1) and MAB_0103 (EthA2) were identified as the primary EthAs in M. abscessus. Deletion of either gene alone or in combination in the {Delta}nudC reduced adduct formation and increased resistance, while the triple mutant {Delta}{Delta}ethA1{Delta}ethA2 restored wild-type resistance. Using an intergenic region-eGFP reporter system and quantitative reverse transcription-PCR, we demonstrated that EthR confers resistance by specifically suppressing ethA1 expression in M. abscessus. The Mycobacterium tuberculosis EthR inhibitor BDM31343 could boost the efficacy of ETH against M. abscessus by inhibiting EthR. Collectively, this study identified the ethR and ethA genes in M. abscessus for the first time and elucidated their role in mediating resistance to ETH. Therefore, EthR is a promising target for potentiating the efficacy of ETH against M. abscessus. Impact statementMycobacterium abscessus constitutes an escalating global health threat, primarily due to its intrinsic resistance to most antibiotics. This study identifies MAB_0984 (EthR) as a dominant resistance determinant that exerts a more profound impact on ETH susceptibility than the previously characterized NudC. We demonstrate that EthR mediates resistance by specifically repressing the expression of EthA1 (MAB_0985), one of the primary monooxygenases responsible for ETH bioactivation. The EthRMtb inhibitor BDM31343 potentiated the activity of ETH against M. abscessus through inhibition of the EthR. These findings elucidated the mechanism of ETH resistance in M. abscessus, identifying EthR as a promising target for boosting the efficacy of ETH against M. abscessus.

microbiology↗

Multi-Objective Bayesian Optimization for Data-Efficient Bioprocess Development

Process optimization for Chinese hamster ovary (CHO) cell culture remains a challenge in biopharmaceutical development because multiple interacting parameters jointly influence productivity and product quality attributes. Traditional design-of-experiments (DoE) methods, while systematic, become impractically expensive when extended across multiple parameters and clones. To address this challenge, we developed a multi-objective Bayesian Optimization (BO) framework that identifies optimal process conditions efficiently in grouped recommendations, which is well suited for experimental workflows in bioprocess development. The model integrates continuous variables such as pH, DO, temperature, and feed rate with categorical identifiers to enable knowledge transfer across clones and scales, optimizing titer, glycan profile, and charge variants. We validated the framework through in-silico benchmarks on analytic functions, retrospective cross-validation on historical CHO datasets, and forward experimental validation in small-scale bioreactors. Across these tests, our algorithm consistently outperformed Latin Hypercube Sampling (LHS) and Random Search baselines, achieving superior performance under a limited experimental budget. The framework improved titer by up to 37% under single-objective optimization. In the multi-objective setting, it increased titer by 25% while simultaneously reducing overall glycan-profile error by a factor of seven, demonstrating the ability to optimize multiple biologically coupled objectives simultaneously. Through comprehensive in-silico and experimental validation, this study establishes a framework that enables adaptive, AI-guided process development and improves decision-making across multiple objectives, clones, and scales while minimizing experimental runs in process development and optimization workflows.

bioengineering↗

Getting over ANOVA: Estimation graphics for multi-group comparisons

Data analysis in experimental science mainly relies on null-hypothesis significance testing, despite its well-known limitations. A powerful alternative is estimation statistics, which focuses on effect-size quantification. However, current estimation tools struggle with the complex, multi-group comparisons common in biological research. Here we introduce DABEST 2.0, an estimation framework for complex experimental designs, including shared-control, repeated-measures, two-way factorial experiments, and meta-analysis of replicates.

bioinformatics↗

The histone code of love: epigenetics of maturation of gonads in the human blood fluke Schistosoma mansoni

Schistosoma mansoni is a parasitic flatworm that has two, genetically determined, sexes. We used aggregated data of 8 posttranslational histone modifications (ChIP-Seq), chromatin accessibility (ATAC-Seq), transcription (RNA-Seq) and genome feature annotations to decipher the histone code of genes involved in the differentiation of schistosome gonads (i.e. female ovaries and male testes). We show schistosome gonads express at least two classes of protein coding genes: H3K4me3-positive genes that display canonical features of eukaryotic protein-coding genes such as peaks of H3K4me3 at the transcription start sites (TSS) and increases in histone acetylation marks towards the transcription end site (TES), but also a non-canonical H3K9/27me3 plateau just upstream of the TSS. H3K4me3 enrichment at the TSS is highly predictive for transcription strength in these genes compared to a second class of protein coding genes (H3K4me3-negative genes) that do not display this pattern and is characterised by absence of the investigated histone marks at TSS and TES. This is indicative of the existence of hitherto unknown, potentially schistosome-specific histone marks in these genes. The absence of H3K4me3 at the TSS is not associated with inducible or stable gene expression in the gonads. Instead, gene ontology analysis indicates that H3K4me3-positive genes are related to functions which typically govern processes such as metabolism or signal transduction while H3K4me3-negative genes are dedicated to cell communication or immune responses. Second, individual histone modifications and their combinations are associated with functional features of the schistosome genome, known as "chromatin colours". In H3K4me3-positive genes, there is clear co-linearity of 3 colours, which strongly suggests a functional role for histone modifications in the control of transcription pre-initiation, promotor release, and transcription termination. Third, there are striking chromatin structure changes during maturation of the gonads in all genomic features including protein-coding and non-protein coding genes as well as repetitive sequences. The nature of these changes is different in both sexes. H3K36me3 and H3K9me3, as well as H3K23ac and H3K9ac show the strongest variations. Last, we show that pharmacological inhibition of histone demethylation activity by IOX1 leads to a concentration-dependent separation ("divorce") of schistosome couples confirming the importance of H3K36/H3K9 methylation for pairing maintenance and indicating histone demethylases as a potential drug target family. Collectively, our findings offer unprecedented insights into histone codes and chromatin dynamics governing the reproductive development of S. mansoni gonads.

developmental biology↗

Single-cell and spatial transcriptomics unveils key regulators governing cell differentiation for Schistosoma sexual development

Schistosomiasis remains a major global health challenge, primarily due to the large number of egg production by sexually mature parasites. However, the cellular basis and regulatory programs governing sexual development and egg production are poorly characterized. Here, we constructed a dynamic single-cell atlas of Schistosoma japonicum (S. japonicum) covering key development stages of sexual maturation and egg production, and integrated it for the first time with spatial transcriptomics to map tissue-resolved cellular niches. Through bioinformatic analysis and experimental validation, we identified several critical cell populations and regulatory networks that drive parasite development and egg laying. By mapping de novo identified transcription factors (TFs) onto these atlases, we generated a comprehensive spatiotemporal expression profile of TFs and define the regulatory programs of several tissue-specific TFs including Zfp, Fbp3, and Lim. Integrated re-clustering further revealed and validated key regulators of germline stem-cell differentiation in S. japonicum. Finally, comparative analyses with S. mansoni single-cell datasets revealed both conserved and species-divergent cellular plasticity, providing unprecedented insights into their distinct biological traits. Collectively, our comprehensive study establishes a foundational resource for understanding schistosome biology, deciphers regulatory programs underlying cell differentiation and pathogenicity, and accelerates the identification of key molecules involved in sexual development against schistosomiasis.

microbiology↗

eTRex Reveals Oncogenic Transcriptional Regulatory Programs Across Human Cancers

Transcriptional regulators (TRs) are essential proteins that regulate gene transcription, and their dysregulation defines the oncogenic transcriptional regulatory programs that drive tumor-specific gene expression. Existing pan-cancer resources summarize these programs by aggregating signals across individual datasets, neglecting the context-specific features that capture the diversity of transcriptional regulation underlying cancer heterogeneity. By developing a variational Bayesian hierarchical model named eTRex (epigenomics-based Transcriptional Regulator explorer) and applying it to 4,819 cancer-related ATAC-seq datasets, we provide a comprehensive pan-cancer atlas of functional TR profiles that preserve the context-specific features of each dataset. This study reveals both common regulators across diverse malignancies and those with highly specific roles. We extensively validated these findings using independent CRISPR/Cas9 screening, mutation, and transcriptomic datasets. Collectively, this pan-cancer atlas of functional TR profiles represents a comprehensive, biologically interpretable resource for uncovering transcriptional regulatory programs, identifying biomarkers, prioritizing therapeutic targets in oncology, and is freely accessible through an interactive web portal.

bioinformatics↗

Aerobic Exercise Preserves Capillary Oxygen Homeostasis and Neurovascular Function in a Mouse Model of Alzheimer's Disease

Age-related cerebrovascular dysfunction is increasingly recognized as a critical contributor to cognitive decline and Alzheimers disease (AD) progression. Aerobic physical activity (PA) and other modifiable lifestyle interventions can substantially reduce the likelihood of dementia; however, their ability to mitigate cerebrovascular alterations remains poorly defined. PA reportedly improves systemic vascular health and cognitive function in aging humans, but its impact on cerebrovascular function during aging and amyloid {beta} (A{beta}) pathology is unclear. Here, we longitudinally quantified microvascular oxygen tension and stimulus-evoked oxygen dynamics in awake APP/PS1dE9 mice and wild-type littermates using two-photon phosphorescence lifetime microscopy. Routine aerobic PA initiated in early adulthood preserved basal arteriolar, capillary, and venular oxygenation, prevented age-dependent increases in microvascular heterogeneity, and mitigated excessive oxygen extraction in preclinical AD mice. While amyloid pathology impaired stimulus-evoked oxygen responses across vascular compartments, PA selectively enhanced capillary dilation and accelerated hyperemic kinetics without altering vascular density or architecture. Notably, sedentary AD mice developed lower, widely-dispersed distributions in capillary oxygenation, hallmarks of malignant microvascular dysfunction, which were largely absent in physically active animals. These findings demonstrate that routine aerobic PA preserves basal capillary oxygenation and stimulus-evoked hyperemia during aging and A{beta}, supporting a capillary-centric mechanism through which exercise confers neurovascular resilience in preclinical AD.

neuroscience↗

Parthenogenote-Derived Brain Unveils the Critical Role of Paternal Genome in Neural Development

Genomic imprinting, an epigenetic mechanism that governs parent-of-origin-specific gene expression, is essential for mammalian development, yet its role in late-stage development remains unclear due to the lethality of parthenogenetic (Pg) embryos. Here, we establish cell replacement with parthenogenote-derived cells (CReP), a blastocyst complementation strategy that enables survival and tissue-specific contribution of Pg-derived cells. Brain-targeted CReP showed that Pg-derived cells can participate in neural development but fail to maintain neuronal-glial balance due to aberrant activation of Notch signaling caused by the loss of the paternally expressed gene Dlk1. Restoration of Dlk1 normalized Notch activity and rescued neuronal differentiation. These findings reveal a critical role of the paternal genome, through Dlk1-mediated regulation of Notch signaling, in ensuring neural stem cell expansion and balanced cell fate decisions. The CReP model provides a powerful platform for investigating genomic imprinting and parental genome contributions in development and disease.

developmental biology↗

A New Paradigm of Transcriptional Regulation by the SufR-Like Iron-Sulfur Transcription Factors

SufR is an iron-sulfur ([4Fe-4S]) cluster-containing transcription factor belonging to an uncharacterized domain family (COG2345). It has been shown to negatively regulate the sulfur utilization factor (SUF) Fe-S biogenesis system in several Gram-negative and Gram-positive bacteria including Cyanobacteria, Mycobacteria and Streptomyces. The structural basis for its DNA recognition and transcriptional regulation by the SufR-like proteins remains enigmatic. In this study, we present the cryo-EM structure of Mycobacterium tuberculosis SufR bound to its promoter, revealing a new domain architecture. Our structural, biochemical and molecular analyses show that SufR possesses an unusual [4Fe-4S] cluster coordination environment in the sensory domain and recognizes its promoter via a dual-module mechanism using both the AT-hook and the helix-turn-helix (HTH) DNA-binding motif in the DNA-binding domain. This DNA recognition strategy differs from a canonical winged HTH transcription factor. Moreover, our bioinformatic analysis and structural modeling suggest that SufR and SufR-like proteins in the COG2345 family represent a large, previously uncharacterized family of transcription factors widely distributed across bacteria and archaea. Together, these findings establish SufR-like proteins as a new model for transcriptional regulation by Fe-S transcription factors in prokaryotes and uncover the underappreciated evolutionary versatility of AT-hooks.

biochemistry↗

MRMhub: one-stop solution for automated processing of large-scale targeted metabolomics data

Data processing and quality control are essential for complex targeted mass spectrometry (MS) assays in large-scale metabolomics studies. However, existing software solutions have significant gaps in robustness and scalability. We report MRMhub, a one-stop solution for streamlined processing of large-scale targeted MS data. MRMhub consists of a novel peak integration engine with unique algorithmic design to address the scalability challenge and a comprehensive collection of post-acquisition data processing and analytical quality control tools. The ensemble facilitates rapid and consistent processing of complex chromatograms, quantification, drift and batch correction, quality assessment and control, feature filtering, and data/workflow sharing and reporting. MRMhub can process data from highly complex assays in population-scale studies within minutes, with full digital footprints warranting reproducibility and traceability. We demonstrate its performance using two large-scale lipidomics data sets. We distribute the source code and data sets freely for community development.

bioinformatics↗

MisTIC: Missegmented Transcript Inference Correction for Improved Spatial Transcriptomics Analysis

Imaging-based spatially resolved transcriptomics (SRT) technologies, such as 10X Xenium, MERSCOPE, and CosMx, have revolutionized our ability to study gene expression within the spatial context of tissues at single-cell resolution. The acquisition of such data relies heavily on cell segmentation algorithms, which often produce imperfect boundaries, leading to transcript misassignment. These misassignments can significantly affect downstream analyses, including cell type identification, differential expression analysis, cell-cell communication, and RNA localization. We present MisTIC (Missegmented Transcript Inference Correction), a variational Bayesian model designed to correct transcript misassignment errors without requiring resegmentation. In benchmarking analyses using synthetic data with simulated transcript misassignment, MisTIC demonstrated high sensitivity and specificity in removing misassigned transcripts. In real data applications, MisTIC effectively enhances cell type identification, reduces ambiguity in differential expression analysis, and improves the detection of cell-cell communication. Furthermore, RNA localization analysis based on data corrected by MisTIC revealed that, in T cells located near cancer-associated fibroblasts compared to those farther away, genes involved in T cell activation, inflammation, and cytotoxicity were depleted from cytoplasmic regions despite not being differentially expressed between the two T cell subsets. In conclusion, MisTIC is a powerful tool for correcting transcript misassignment in SRT data. It not only improves the accuracy of routine analyses but also enables novel investigations that provide deeper insights into the dynamics of gene expression.

bioinformatics↗

Influenza A infection accelerates disease-associated microglia formation during physiological aging

Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test the hypothesis that non-neuroinvasive influenza A virus (IAV) pneumonia results in transcriptional responses in brain microglia that drive premature expansion of DAM. Using bulk and single-cell RNA-sequencing, metabolomics, and spatial transcriptomics, we profiled neuroimmune populations in young, middle-aged, and old male mice during IAV infection and recovery. We observed an increased abundance of DAM, interferon-responsive microglia (IRM), CD4+ T cells, and CD8+ T cells in white matter regions beginning in middle age and persisting in old animals, irrespective of IAV infection. DAM exhibited a metabolic shift toward aerobic glycolysis with disrupted TCA cycling, citrulline depletion, and an elevated itaconate/-ketoglutarate ratio. Spatial transcriptomic profiling of the human middle frontal gyrus (MFG) in normal agers, SuperAgers, and patients with dementia revealed an analogous accumulation of DAM and CD8+ T cells in white matter. IAV pneumonia induced a transient immunosenescent-like response in microglia, marked by glucocorticoid-responsive gene expression and Ccnd3 upregulation. In response to IAV pneumonia, DAM expanded in middle-aged mice, whereas old mice were elevated at baseline and were largely unaffected by IAV infection. The age-related expansion of DAM was unaffected by pharmacological depletion and repopulation of microglia with a CSF1R antagonist or genetic gain or loss of function of the phagocytic receptor MERTK, suggesting the DAM phenotype is driven by the CNS microenvironment, rather than cell-intrinsic mechanisms. Our findings suggest that IAV pneumonia induces an acute immunosenescence response in microglia and accelerates the age-dependent expansion of DAM in white matter.

neuroscience↗

A global atlas of deep-sea cold seep viruses uncovers extensive genomic novelty, pervasive viral dark matter, and biotechnological potential

Cold seeps are globally distributed deep-sea ecosystems harboring diverse chemosynthetic microbial communities, yet their viral components remain poorly understood. Here, we establish the Global Cold Seep Virome, a comprehensive catalog of 191,937 species-level viral operational taxonomic units (vOTUs) and 2.44 million viral protein clusters reconstructed from 314 metagenomes spanning 18 cold seep sites worldwide. Most vOTUs are distinct from those in existing environmental viromes, suggesting that cold seeps harbor a largely unexplored viral reservoir. Host prediction suggests diverse viral associations with key prokaryotes, including anaerobic methanotrophic archaea. Protein annotation reveals that these viruses encode widespread uncharacterized proteins and viral hallmark proteins with divergent physicochemical properties, potentially contributing to their ecological adaptability. We also identify putative auxiliary metabolic genes, anti-defense genes, and lysins, and experimentally validate representative anti-defense proteins and lysins with strong activities. This resource expands current knowledge of deep-sea viral diversity and provides a foundation for studying virus-host interactions, testing biogeochemical hypotheses, and exploring biotechnological potential in cold seep ecosystems.

microbiology↗

A dataset of differentiable biologically-derived single neuron models

Biological neural networks contain diverse cell types with heterogeneous electrophysiological properties. Artificial neural networks (ANNs) model computational aspects of biology but use homogeneous neurons, limiting realism. A key obstacle to building bio-inspired ANNs is the absence of a database of neuron models that both fit biological data and remain differentiable for gradient-based learning. We present such a database: over 1,000 differentiable single-neuron firing-rate models with accompanying PyTorch code for integration with machine learning. The models belong to the linear-nonlinear (LN) class, which, for ease of reference, we term Generalized Firing Rate (GFR) neurons. Each GFR neuron uses input and firing-rate history filters across multiple timescales, followed by a nonlinearity to generate firing rates. Models are fit to patch-clamp recordings from mouse and human central nervous system slices. Parameter clustering reflects electrophysiological diversity and partially aligns with transgenic lines. This resource will enable development of bio-inspired ANNs built from biologically grounded, differentiable single-neuron models. HighlightsO_LIResource of over 1,000 differentiable single-neuron models fit to mouse and human patch-clamp recordings C_LIO_LIOpen source PyTorch code and reproducible pipelines support model fitting, evaluation, and network integration C_LIO_LIFitted model parameters capture electrophysiological diversity, with parameter clusters partially aligning to inhibitory/excitatory types and Cre driver lines C_LI

neuroscience↗

Adaptive Partial Conjunction Hypothesis: Identifying Pleiotropy Across Heterogeneous Effect Units

Pleiotropy arises when a single SNP, gene, or locus affects multiple traits, and in many applications the key scientific question is which specific subset of traits shares a non-null effect. We introduce the Adaptive Partial Conjunction Hypothesis (APCH), an empirical Bayes framework that uses summary statistics to test, for each effect unit, which subsets of features are jointly non-null while controlling the false discovery rate for subset selection. APCH combines adaptive shrinkage priors with a hierarchical model that accounts for correlation among effect estimates and computes local false discovery rates for all candidate subsets. A top-down search over subset size then selects at most one maximally informative jointly significant subset per effect unit. In simulations, APCH maintained well-calibrated FDR and, in most settings, achieved higher power than both empirical Bayes methods that learn across effects and subset-based procedures that test each effect unit separately. It remained reliable with heterogeneous effect sizes, correlated estimation errors across features, and sparse jointly significant patterns. We apply APCH to GWAS summary statistics for five type 2 diabetes-related traits and identify co-occurring trait subsets that go beyond what single-trait genome-wide scans reveal. In particular, APCH brings in traits that fall short of genome-wide significance on their own but repeatedly appear in the same jointly significant subsets, revealing stable cross-trait co-association patterns and sharpening our overall picture of how loci act across these traits. More broadly, APCH is directly applicable to other multi-feature settings, such as multi-tissue or multi-omic association analyses, using only summary statistics.

genetics↗

Oxygen-adaptive plasticity of Asgard archaea dependent on terminal oxidase and globin

The oxygenation of ancient Earth is thought to have driven eukaryogenesis, beginning with the endosymbiosis of an aerobic alphaproteobacterium (proto-mitochondria) with an archaeal host. Given that the archaeal host likely evolved from within Asgard archaea (phylum Promethearchaeota), the metabolic traits of Asgard archaea could provide key insights into eukaryotic origins. Although Asgard archaea cultured to date are obligate anaerobes, their genomes encode oxygen-adaptive proteins, suggesting they might be oxygen-tolerant. Here, we demonstrate that some Asgard archaea, in particular, Hodarchaeales, the closest known relatives of eukaryotes, and Kariarchaeaceae, exhibit oxygen adaptation mediated by terminal oxidase and globin. Phylogenetic analysis reveals long-term vertical evolution of terminal oxidases in Asgard archaea, suggesting ancient adaptation to molecular oxygen. By contrast, globin was likely acquired by Asgard archaea via horizontal gene transfer from facultative aerobic Chloroflexales bacteria. Heterologous expression of the Asgard globin enhances aerobic growth of Haloarchaea and Escherichia coli in the presence of terminal oxidase-dependent electron transfer chain, suggesting that Asgard growth benefits from ambient oxygen. The Asgard globin gene is embedded in an oxygen-sensitive bidirectional promoter region, with one promoter driving oxygen-induced globin expression, and the other anaerobically activating expression of two enzymes, PdxS and PdxT, involved in a pyridoxal 5-phosphate biosynthesis. The Asgard globin and promoter region exhibit high functional robustness across archaea and bacteria, and could contribute to the symbiosis between the Asgard and aerobic bacterial partners. These findings highlight the oxygen-adaptive plasticity of Asgard archaea and its potential contribution to eukaryogenesis.

evolutionary biology↗