Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 703 records · Page 39Linked to original sources

bioRxiv2025

Homozygous kinase-dead Csf1r mutation in outbred mice reveals essential and redundant functions of tissue resident macrophages

The proliferation, differentiation and survival of cells of the macrophage lineage depends on signals from the macrophage colony-stimulating factor receptor (CSF1R). On a C57BL/6J background homozygous kinase-dead Csf1r mutation (Csf1rE631K/E631K - E631Km/m) causes perinatal lethality. Here we demonstrate that E631Km/m mice on a mixed genetic background (C57 x BALB/c F2) are osteopetrotic and growth retarded but viable as adults with no other gross developmental deficits. They lack osteoclasts, microglia and most peripheral tissue resident macrophages and exhibit perturbed hematopoiesis. Although CD169+ tissue resident macrophages in bone marrow are considered an essential component of the hematopoietic niche, CD169 is undetectable in E631Km/m marrow and F4/80+ macrophages are depleted. These changes are associated with expansion of mature and immature granulocytes and reduced B cells, whereas monocytes and stem and progenitor populations are unaffected as a proportion of total cells. Erythropoiesis in bone marrow is maintained in E631Km/m mice, associated with a residual population of CSF1R-independent CD169-ve/F4/80+ macrophages. Nevertheless, splenic extramedullary hematopoiesis in E631Km/m mice indicates a degree of bone marrow insufficiency. Red pulp macrophages are retained but CD169+ marginal metallophil macrophages are absent and CD209b+ (SIGNR1) macrophages are present but disorganized. Circulating white blood cell count is unchanged in E631Km/m mice, but the proportion of neutrophils is greatly increased whilst B cells and monocytes are reduced. This novel model reveals the essential roles of CSF1R-dependent macrophages in hematopoiesis and demonstrates that many developmental and homeostatic functions attributed to murine resident tissue macrophages are redundant and/or specific to inbred mouse strains.

immunology↗

bioRxiv2025

Pluripotent stem cell-derived siTNK cells attack tumors via a synthetic CD8-CD28 TCR complex

Tumor-associated antigen-specific T cell receptor (TCR)-engineered T cells offer a promising strategy for cancer therapy. Natural killer (NK) cells exhibit broad anti-tumor activity with low side effects but lack the capacity to recognize intracellular antigens. Here, we found that the human pluripotent stem cell (hPSC)-derived iNK cells, unlike tissue-isolated NK cells, expressed all four CD3 subunits at the transcriptome level. We introduced a synthetic gene-expressing complex (SCOTR), encoding a tumor antigen- specific TCR, CD8 coreceptor, and CD28 costimulatory molecule, into hPSCs to generate SCOTR-hPSCs. The SCOTR-hPSCs gave rise to abundant synthetic TCR complex-expressing iNK (siTNK) cells via an organoid induction method. These siTNK cells showed HLA-dependent, antigen-specific cytotoxicity against tumor cells and significantly suppressed tumor growth in tumor xenograft animal models, while also preserving universal non-specific tumor-killing activity. Collectively, siTNK cells, as hPSC-derived hybrid cells with dual features of adaptive T and inherent NK cells, offer an artificial cell source for human immunotherapies.

immunology↗

bioRxiv2025

Measure Sodium Transport in Cells with NMR

Sodium ions (Na+) are fundamental to numerous physiological functions, such as maintaining electrolyte balance, enabling nerve impulse transmission, and facilitating muscle contraction. Dysregulation of Na+ transport across cell membranes is implicated in a range of health issues, including metabolic syndromes, neurological conditions, and cardiovascular diseases. However, current methods for assessing cellular Na+ activity often face limitations; they can be invasive or fail to capture dynamic changes. In this study, we introduce a non-invasive 23Na nuclear magnetic resonance (NMR) methodology designed to directly quantify the transport rate of sodium ions in living cells. Our technique integrates relaxation exchange spectroscopy (REXSY) with a multi-site exchange model, enabling the investigation of Na+ transport dynamics on a timescale of sub-seconds. A key advantage is its ability to differentiate between intracellular and extracellular Na+ pools based on the endogenous NMR relaxation difference, thereby avoiding the need for potentially disruptive exogenous reagents. Experiments conducted on human cell lines successfully demonstrated the techniques capacity to distinguish between various physiological states, such as when ion channels are pharmacologically blocked or activated. The resulting measurements of Na+ transport rates and intracellular Na+ fractions show a clear correlation with cellular metabolic activity, offering valuable quantitative markers for monitoring transmembrane ion dynamics in vitro.

cell biology↗

bioRxiv2025

Multi-omic mapping of Drosophila protein secretomes reveals tissue-specific origins and inter-organ trafficking

Secreted proteins regulate many aspects of animal biology and are attractive targets for biomarkers and therapeutics. However, comprehensively identifying the "secretome", along with their tissues of origin, remains extremely challenging. To address this, we employed multiple omics methods to define a tissue-secretome map of 535 blood plasma proteins derived from specific cell-types and organs in Drosophila melanogaster. This map was enabled by methodological improvements including a collection of transgenic flies to label endogenous secreted proteins in 10 major tissue types, large-scale blood isolation, whole animal snRNA-seq, and a collection of 40 knock-in strains. Using this map, we discover surprising findings about circulating proteins: most originate from specific tissues including unusual sources (e.g. glia), many are uncharacterized, and some are shed ectodomains of transmembrane proteins. In addition, in vivo experiments revealed circulating proteins with remarkably tissue-specific expression, as well as proteins that are deposited in a different tissue from where they are synthesized, suggesting potential inter-organ functions. Our secretome map will serve as a resource to investigate blood protein function, discover novel tissue-tissue communication signals, and mine for homologues of human biomarkers.

genomics↗

bioRxiv2025

Temporal foundation model unveils ancient HepatitisB virus evolution

Since ancient hepatitis B virus (HBV) sequencing data are scarce and incomplete, the evolutionary dynamics of HBV have long remained enigmatic. This data gap hinders a comprehensive understanding of HBV genetic variations, evolutionary trajectories, and host interactions in different historical periods, preventing insight into its long-standing co-evolutionary relationship with humans. In this study, we developed a sequence-based generative foundational model, ViraChron (Viral Chronology Foundation Model), that integrates multi-scale temporal information to compensate for the lack of ancient HBV data. We confirmed the robustness of our model through sequence identity, phylogenetic, and recombination analyses. ViraChron enabled the identification of fixed mutations specific to HBV genotype A, demonstrating that HBV acquires survival advantages through mutations that are ultimately fixed by natural selection. Our model outperforms the original baseline in terms of sequence completion, achieving significantly higher accuracy. The model significantly reduced data acquisition time from 80 hours to 5.4 minutes per HBV genome, providing reliable, high-quality data for 7 new HBV genomes from specific archeological sites. ViraChron overcomes previous limitations, obtaining high-quality genomic data from samples over ten thousand years old, thereby facilitating a systematic understanding of viral evolution and its biological characteristics.

paleontology↗

bioRxiv2025

Context-dependent regulatory variants in Alzheimer's disease

Noncoding genetic variants underlie many complex diseases, yet identifying and interpreting their functional impacts remains challenging. Late-onset Alzheimers disease (LOAD), a polygenic neurodegenerative disorder, exemplifies this challenge. The disease is strongly associated with noncoding variation, including common variants enriched in microglial enhancers and rare variants nominated at loci implicated in neurodevelopment and synaptic function. These variants may perturb regulatory sequences by disrupting transcription factor (TF) motifs or altering local regulatory sequence context, with potential consequences for gene expression and chromatin accessibility. However, assessing their impact is complicated by the context-dependent functions of regulatory sequences, underscoring the need to systematically examine variant effects across diverse tissues, cell types, and cellular states. Here, we combined in vitro and in vivo massively parallel reporter assays (MPRAs) with interpretable machine-learning models to systematically characterize common and rare variants across myeloid and neuron-enriched neural contexts. Parallel profiling of variants in four immune states in vitro and three mouse brain regions in vivo revealed that individual variants can differentially and even oppositely modulate reporter activity across cellular contexts, while a subset showed immune-state-dependent effects. Within the assayed candidate set, the relative effect sizes of common and rare variants reversed between contexts, with common variants showing larger effects in THP-1 macrophages and rare variants in brain tissue. Interpretable sequence-to-function models prioritized context-biased variants and generated motif-level hypotheses, including predicted transcription-factor motif disruption and subtler changes in local motif context. To probe endogenous consequences at a prioritized locus, we used CRISPR interference to perturb a rare-variant-containing enhancer at the SEC63-OSTM1 locus, revealing metabolic and biosynthetic transcriptional programs resembling those induced by SEC63 promoter perturbation, together with a stimulation-specific interferon response. These findings show that LOAD-associated noncoding variants exhibit context-dependent effects on reporter activity and predicted chromatin accessibility, and provide a framework for linking genetic association to regulatory activity, sequence grammar and endogenous transcriptional state.

genomics↗

bioRxiv2025

BrainBeacon: A Cross-Species Foundation Model for Single-cell Resolved Brain Spatial Transcriptomics

The brains functional complexity emerges from spatiotemporal heterogeneity in molecular, cellular, and circuit organization, shaped by evolution, aging, and disease. Single-cell spatial transcriptomics provides a transformative framework to decode this complexity, resolving cell-type-specific expression patterns, region-specific regulation, evolutionary divergence, and disease-associated disruptions. Despite recent advances in spatial transcriptomics, a unified foundation model capturing cross-species, whole-brain cellular architecture remains lacking. Here, we introduce BrainBeacon, the first cross-species foundation model for whole-brain spatial transcriptomics. Trained on 133 million spatially resolved cells covering a total area of 210194 mm2 from human, macaque, marmoset and mouse brains profiled across five major platforms, BrainBeacon integrates gene expression rankings, spatial cellular organization, and evolutionarily conserved genetic relationships into a unified transformer-based architecture. A two-stage training strategy captures both intra-cellular transcriptional dependencies and inter-cellular spatial interactions, yielding biologically grounded and interpretable representations of brain structure. Subsequently, BrainBeacon enables cross-species alignment of brain cell types and anatomical regions, facilitating integrative analyses of conserved and divergent cellular architectures. Moreover, it uncovers spatial regulatory mechanisms of aging by predicting bidirectional perturbation responses between cells and their local niche. Together, BrainBeacon serves as a foundational cross-species model for whole-brain spatial transcriptomics, enabling virtual brain atlas construction, systematic in silico perturbation studies, and mechanistic insights into brain disease pathogenesis.

bioinformatics↗

bioRxiv2025

Deciphering the Nrf2/ARE Mechanism: GanCaoXieXin Decoction Combats Oxidative Stress in Ulcerative Colitis Pathogenesis

BackgroundGanCaoXieXin (GCXX) decoction, a classic prescription, has shown clinical efficacy in treating ulcerative colitis (UC). However, its mechanism remains incompletely understood. ObjectiveThis study aims to explore how GCXX modulates the Nrf2/ARE signaling pathway to mitigate oxidative stress (OS)-induced damage and thereby ameliorate UC. Materials and methodsNetwork pharmacology and bioinformatics analyses identified key targets of GCXX in UC treatment. Ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-MS/MS) analyzed GCXXs effective compounds. A 2.5% Dextran Sulfate Sodium Salt (DSS)-induced UC mouse model was used. Immunohistochemistry (IHC) assessed tight junction proteins. Enzyme-linked immunosorbent assay (ELISA) measured intestinal permeability and oxidative stress markers. Western blot (WB) analyzed Nrf2/ARE signaling proteins. In 800mol/L H2O2-induced oxidative stress (OS) state HT-29 cells, cell viability, apoptosis, oxidative stress indicators, and apoptosis-related proteins were evaluated. Immunofluorescence (IF) detected Nrf2/ARE signaling axis proteins. ResultsThe results of network pharmacology and bioinformatics analysis revealed that GCXX could intervene in UC by regulating OS-related pathways. GCXX contained antioxidant components like quercetin, berberine, and baicalin. In vivo, GCXX alleviated mucosal damage, reduced intestinal permeability, downregulated MDA, upregulated SOD, suppressed Keap1, and promoted tight junction and Nrf2/ARE pathway proteins. In vitro, GCXX increased cell survival, improved antioxidant capacity, reduced MDA and apoptosis in OS state cells. Immunofluorescence confirmed Nrf2/ARE pathway as crucial in GCXXs protective effects. ConclusionsGCXX elevates the expression level of Nrf2, HO-1 and NQO1, thus reducing entercell OS-induced damage, intestinal cell apoptosis, alleviating UC intestinal mucosal damaget.

pharmacology and toxicology↗

bioRxiv2025

Structural basis of DNA N6-adenine methylation in eukaryotes

As a transcription-associated epigenetic mark abundantly present in many unicellular eukaryotes, DNA N6-adenine methylation (6mA) is maintained by the AMT1 complex. However, the structure-function relationship of the AMT1 complex remains to be fully elucidated. Here, we employ AlphaFold3 (AF3) for de novo structural modeling of the AMT1 complex, complemented by molecular dynamics simulations. Functional relevance of key structural features, especially those of the AMT1 ternary complex with the double-stranded DNA (dsDNA) substrate and the cofactor, are validated by extensive mutagenesis, both in vivo and in vitro. Our analysis reveals the structural basis for DNA substrate recognition, base flipping, and catalysis in this prototypical eukaryotic DNA 6mA-methyltransferase. It also allows us to delineate the reaction pathway for processive methylation involving translocation of the AMT1 complex along the dsDNA. As the active site is conserved across the MT-A70 family of eukaryotic N6-adenine methyltransferases, the structural insight will facilitate rational design of specific inhibitors.

molecular biology↗

bioRxiv2025

Gut Microbiota Succession and Metabolic Pathway Remodeling in the Progression of Type 2 Diabetes Mellitus in Adult Rats

BackgroundEmerging evidence highlights the complex interplay between gut microbiota and type 2 diabetes mellitus (T2D); however, the temporal trajectory of microbial community succession and the concomitant shifts in associated metabolic pathways across the disease lifecycle remain poorly characterized. In this study, we conducted a multi-dimensional analysis of gut microbiota composition and functional pathways in rats, spanning the continuum from health, through the T2D pathological state, to post-intervention recovery phases. ResultsHealthy aged rats exhibited significantly greater gut microbial diversity compared to both younger healthy cohorts and T2D rats. In the absence of intervention, progressive T2D development led to a sustained decline in microbial diversity that persisted until death. Notably, {beta}-tocotrienol ({beta}-T3), metformin hydrochloride (MET) and healthy dietary interventions not only improved fasting blood glucose (FPG) levels in T2D mice but also restored their gut microbial diversity and metabolic functions. At the phylum level, the ratio of p Bacteroidota to p Firmicutes exhibited an age-dependent increase in healthy rats but displayed a progressive decline in T2D rats. Notably, species-specific expansions were observed across both healthy and pathological states. For example, s Bacteroides_acidifaciens (B. acidifaciens) showed a significant expansion in early T2D stage disease, while s Anaerostipes_hadrus became the dominant species in advanced-stage T2D. Among intervention groups, s Phascolarctobacterium_faecium was enriched in the {beta}-tocotrienol ({beta}-T3) group; the abundance of s Escherichia_coli (E. coli) increased dramatically in the deceased rats. Gut metabolites also exhibited distinct characteristics across different physiological stages. In young rats, the metabolite profile was characterized by lower abundances of most metabolites, which stabilized with age accompanied by upregulation of select molecules in older rats. Notably, during T2D progression, the metabolite profile displayed a largely opposite pattern compared to healthy controls. Importantly, dietary interventions including healthy food, {beta}-T3, MET partially restored metabolic homeostasis in T2D rats. Further analysis revealed that key differential metabolites across groups were enriched in bile acids (BAs), amino acids, benzene and its substituted derivatives, and organic acids with their derivatives. Specifically, amino acid metabolism was more active in healthy rats, whereas BA and benzene derivative metabolism were upregulated in T2D. Key microbial species driving these shifts included s Lactobacillus_johnsonii, s Lactobacillus_reuteri, and B. acidifaciens, which exhibited positive correlations with BAs and select amino acids. The B. acidifaciens could be a biomarker of T2D and glycoursodeoxycholic acid, sohyodeoxycholic acid, beta-muricholic acid and allocholic acid were the key BAs to regulate glycometabolism of the host. ConclusionsDuring the T2D stage, both gut microbiota composition and metabolic profiles exhibited distinct characteristics compared to those of healthy age-matched older rats. Notably, {beta}-T3 and MET interventions not only facilitated the recovery of gut microbial diversity and metabolite levels in T2D mice but also promoted the proliferation of specific dominant species, each intervention favoring distinct taxa. In this context, B. acidifaciens emerged as a dominant bacterial species in T2D, exerting regulatory effects on glycometabolism through BA and amino acid metabolic pathways. Collectively, these findings advance our understanding of T2D pathophysiology and highlight the potential of probiotic-based therapies for its management. ImportanceThe T2D is a kind of chronic disease and the gut microbiota shows a continuously slow succession from some microbial populations to other ones in the disease progress. Uncovering the rule of change in gut bacteria from healthy rats to T2D ones and the recovering capacity of gut microbiota through interventions of healthy food, {beta}-T3 and antidiabetic drug are beneficial to understand the real regulation mechanism of gut bacteria in T2D progress. Then the results lay the foundation of developing probiotics and researching new metabolic therapeutic target of gut microorganisms. In addition, to research the metabolic regulation mechanism of gut bacteria, using multi-omics including microbiomics and metabonomics is an effective way.

microbiology↗

bioRxiv2025

An artificially selected cytokinin-pathway transcription factor balances soybean yield and pathogen resistance

Soybean contributes to sustainable food and feed production, but some modern varieties favor yield at the cost of disease resistance. Using a bottom-up approach, we demonstrate that the RR2b transcription factor activates cytokinin signaling for plant growth and reproductive fitness but represses disease-resistance and root-nodulation pathways. RR2b was artificially selected during domestication and improvement, and its expression levels correlate with ATT repeat polymorphisms in its promoter. Most wild soybeans and landraces have either more or less ATT repeats: more lead to weak RR2b expression with lower yield and enhanced resistance to soybean bacterial blight, and fewer cause strong RR2b expression, higher yield but reduced disease resistance. Elite cultivars instead balance yield and defense via moderate RR2b expression and several ATT repeats. This confers contrasting RR2b functionality across haplotypes in response to contrasting selection pressures and offers insights into decoupling trade-offs between yield and disease resistance to enhance crop productivity.

genetics↗

bioRxiv2025

The evolution of high-order genome architecture revealed from 1,000 species

Spatial genome organization plays a crucial regulatory role, but its evolution remains unknown. Leveraging Hi-C data from 1,025 species, we trace the evolutionary trajectories of 3D genome, through two higher-order architectures, global folding (spatial organization of karyotype) and checkerboard (chromatin compartments). Early life forms, including prokaryotes and unicellular eukaryotes, mostly display random configurations. Through the evolution of plants, global folding became the prominent architecture with eudicots and remained dominant. Animals, however, progressively developed stronger checkerboard throughout vertebrate and invertebrate evolution, and even during early embryogenesis, suggesting a conserved gene co-regulation mechanism. In contrast, plants prefer linear gene clusters over checkerboard. Both strategies of gene arrangement reinforce the biological principle structure determines function: divergent evolutionary paths converge on architectural solutions to meet the greater regulatory demands.

evolutionary biology↗

bioRxiv2025

GatorST: A Versatile Contrastive Meta-Learning Framework for Spatial Transcriptomic Data Analysis

IntroductionRecent advances in spatial transcriptomics (ST) technologies have revolutionized our understanding of cellular functions by providing gene expression profiles with rich spatial context. Effectively learning spatial representations is crucial for downstream analyses and requires robust integration of spatial information with transcriptomic data. While existing methods have shown promise, they often fail to adequately capture both local (neighbor-level) and global (tissue-wide) spatial contexts. Moreover, they tend to rely heavily on augmentation strategies, which can introduce noise and instability. ObjectivesThis study aims to introduce and demonstrate a novel, versatile framework called GatorST, which explicitly combines graph-based modeling with advanced learning strategies to generate spatially informed representations of ST data. GatorST is designed to improve various downstream tasks, including identification of spatial domains, gene expression imputation, batch effect removal, and trajectory inference. MethodsGatorST constructs a spot-spot graph by connecting each node to its k nearest spatial neighbors and extracts two-hop neighborhood subgraphs to capture local context. At the global level, gene expression profiles are clustered using soft K-means to generate pseudo-labels, which serve as weak supervision signals within a contrastive learning framework. This process encourages the alignment of embeddings with shared pseudo-labels while separating those with different labels. GatorST further adopts an episodic training strategy inspired by meta-learning, wherein each episode consists of a support set for contrastive optimization and a disjoint query set for embedding classification, guided by the pseudo-labeled data. This design enables the model to classify unseen samples based on learned embeddings, thereby enhancing its generalization to new spatial contexts. ResultsComprehensive comparisons with fifteen state-of-the-art methods across fourteen spatial transcriptomics datasets demonstrate that GatorST consistently achieves superior performance in identifying spatial domains, imputing gene expressions, and removing batch effects. The results showcase the versatility and strong generalization capabilities of GatorST across diverse tissue types and experimental settings. ConclusionGatorST effectively integrates spatial topology and global gene expression through graph-based modeling, pseudo-labeling, and contrastive meta-learning. This framework generates biologically meaningful representations and significantly improves key downstream tasks, including spatial domain identification, gene expression imputation, batch effect removal, and trajectory inference.

bioinformatics↗

bioRxiv2025

Cholinergic Signaling Modulates Intestinal Pathophysiology in a Drosophila Model of Cystic Fibrosis

Cystic fibrosis (CF) is a monogenic genetic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride/bicarbonate channel, which is expressed in certain epithelial cells. Current therapies focus on restoring CFTR function, but many gut-related pathologies persist, highlighting the need for complementary treatments to improve the quality of life of people with CF. In this study, we use Drosophila melanogaster as a model to investigate the gut-specific effects of Cftr loss. We demonstrate that enterocyte specific knockdown of Cftr in flies recapitulates several CF pathologies, including reduced intestinal motility, nutrient malabsorption, and decreased energy stores. Using single-nuclei RNA sequencing (snRNA-seq), we identify significant transcriptional changes in the CF model gut, including the upregulation of acetylcholine esterase (Ace, human AChE), which leads to reduced cholinergic signaling. Cholinergic signaling has been shown to affect CFTR function but this is the first time CFTR loss of function has been shown to alter cholinergic signaling. Functional assays confirm that cholinergic sensitivity is diminished in CF guts. Furthermore, restoring cholinergic signaling via Ace knockdown rescues multiple CF-associated phenotypes. Additionally, we identify the transcription factor Fork head (Fkh), the Drosophila homolog of human FOXA1/FOXA2, which is known to be a positive regulator of Cftr transcription in the intestine, as a positive regulator of Ace expression in CF guts. This study establishes the Drosophila gut as a powerful model to investigate CF pathogenesis, genetic modifiers, and identifies Ace and fkh as genetic modifiers. This work also suggests that enhancing cholinergic signaling may represent a viable therapeutic strategy for gastrointestinal manifestations of CF. Author SummaryCystic fibrosis (CF) is a genetic disease that causes complications in multiple organ systems, including the lungs and gastrointestinal tract. While recent therapies have greatly improved life span and respiratory outcomes in people with CF (pwCF), they continue to report significant gastrointestinal symptoms that impact their quality of life. Therefore, there is a need to better understand the progression of CF in the gut and identify gut specific therapeutic targets to improve patient quality of life. In this study we use Drosophila to model gut specific complications of CF. We show our model recapitulates many CF clinical presentations in the gut demonstrating our model may be clinically relevant. Furthermore, we identify acetylcholine esterase (Ace) as a gene that is increased in our CF model guts that is important for the development of CF pathologies. We additionally, perform a screen to identify a transcriptional regulator of Ace, whose genetic manipulation also regulates CF phenotypes. Our findings not only identify a potential target to alleviate GI symptoms in patients with CF, but also validate the Drosophila gut as a robust model for studying CF pathogenesis, genetic modifiers, and screening therapeutics.

genetics↗

bioRxiv2025

Interwoven DNA-MOF crystals for multi-millennial data storage

DNA has emerged as a promising medium for high-density and energy-efficient data storage, providing a promising solution to capacity constraints and energy demands resulting from the exponential growth of data. Long-term stable storage of DNA data in ambient conditions is a critical requirement for its practical application. Whereas strategies have been proposed to protect DNA from environmental degradation, they are often at the expense of data storage density. Here, we propose a strategy via interweaving metal-organic framework (MOF) and DNA to synthesize DNA-MOF crystal (DNA-MOF), a high-density and long-lifespan DNA-based information material. The uniform distribution of DNA molecules within the crystalline frameworks enables a high loading capacity of up to 30 wt%, corresponding to a theoretical information density of 106.6 exabytes/g. The crystal structure of MOF-DNA demonstrates efficient resistance to environmental damage such as heat, ultraviolet radiation, DNase, etc., achieving an estimated archival half-life over 24,000 years at 9.4 {degrees}C. The interwoven DNA-MOF crystals establish a material foundation for the reliable operation of DNA storage systems in open-field deployment and provide a new pathway toward sustainable long-term management of massive data.

biochemistry↗

bioRxiv2025

NANOME: A Nextflow pipeline for haplotype-aware allele-specific consensus DNA methylation detection by nanopore long-read sequencing

Nanopore long-read sequencing has expanded the capacity of long-range, single-base, and single-molecule DNA-methylation (DNAme) detection and haplotype-aware allele-specific epigenetic phasing. Previously, we benchmarked and ranked the robustness of seven computational tools for DNAme detection using nanopore sequencing. The top performers were Megalodon, Nanopolish, DeepSignal and Guppy. However, these algorithms exhibit lower performance at regions with discordant non-singleton DNAme patterns compared to genome-wide regions. Furthermore, long-read sequencing analysis of mammalian genomes requires higher computational resources than next-generation sequencing. To address these issues, we developed a NANOpore Methylation (NANOME) a consensus DNAme predictive model using XGBoost, which integrates the output of Megalodon, Nanopolish, and Deepsignal for analyzing data obtained using Oxford Nanopore Technologies (ONT). NANOME enhanced DNAme detection precision (mean square error) at single-base resolution by 11% and improved accuracy (F1-score) at single-molecule resolution by 2.4% for human B-lymphocyte European cell lines (NA12878). The consensus model also detected [~]200,000 more CpGs than all three tools. Combing variant calling and long-read phasing, NANOME can detect haplotype-aware allele-specific DNAme in known imprinting controls in resolved and previously unresolved regions. We conducted haplotype-aware methylation detection on the T2T genome for dataset NA12878, revealing significant variations in differentially methylated region (DMR) density between gap and non-gap regions. Overall, NANOME represents a significant step forward in DNAme detection and long-range epigenetic phasing, offering a robust and accessible tool for researchers studying the epigenome.

bioinformatics↗

bioRxiv2025

Bromodomain protein IBD1 bridges histone acetylation and H2A.Z deposition to fine-tune transcription and prevent hyperactivation in Tetrahymena thermophila

Eukaryotic gene expression is dynamically regulated through the interplay between histone modifications and chromatin remodeling, yet how these processes are coordinated remains incompletely understood. Here, we identify IBD1 as a critical adaptor that bridges histone acetylation and SWR-mediated H2A.Z deposition. We demonstrate that the bromodomain of IBD1 recognizes histone acetylation, specifically H3K9/14 di-acetylation to recruit the SWR complex subunit ARP6, ensuring precise H2A.Z incorporation into chromatin. Genetic disruption of IBD1, either by deletion or bromodomain mutation, attenuates H2A.Z occupancy at target loci, confirming its essential role in H2A.Z deposition. Strikingly, perturbation of the histone acetylation-IBD1-H2A.Z axis triggers transcriptional hyperactivation, revealing a dual function of H2A.Z in sustaining basal transcription while preventing aberrant gene induction. This defines a novel regulatory paradigm in which IBD1 couples acetyl-mark decoding to SWR-dependent H2A.Z deposition, establishing transcriptional homeostasis. Our findings resolve a central ambiguity by demonstrating that H2A.Z acts as a repressive buffer in highly acetylated regions, counterbalancing the inherent activation potential of acetylation. This study provides a framework for investigating H2A.Z functions and reveals new perspectives on how chromatin modifications and histone variants interplay in transcriptional regulation.

genetics↗

bioRxiv2025

Microbial Tryptophan Metabolism Activates Host Lysosomal Activity to Facilitate Lipid Breakdown and Ameliorate Hepatic Steatosis

Lysosomes are central to lipid metabolism, yet how gut microbiota-derived metabolites regulate lysosomal function to influence host lipid homeostasis remains unknown. Here, we identify an evolutionarily conserved mechanism in which bacterial tryptophan metabolism activates lysosomal activity to promote lipid breakdown. By developing a lysosomal-responsive lipid reporter in C. elegans to screen for bacterial metabolic states that modulate host lipid storage, we discover that E. coli tryptophan catabolism via tryptophanase TnaA induces lysosomal lipid chaperone LBP-8, driving lipid mobilization. Moreover, tryptophan metabolites enhanced lysosomal acidification and degradation capacity, while genetic disruption of lysosomal regulators reversed these effects. Strikingly, bacterial tryptophan metabolism further promoted mitochondrial {beta}-oxidation through lysosomal lipase activity. This pathway was conserved in mammalian hepatocytes, where E. coli-derived tryptophan metabolites enhance lysosomal function and reduce lipid accumulation. In high-fat diet mice, restoring gut bacterial tryptophan metabolism alleviated hepatic steatosis. Our work uncovers microbiota-regulated lysosomal activation as a critical axis in lipid homeostasis, highlighting its potential as a therapeutic target for metabolic disorders linked to lysosomal dysfunction. SignificanceWe uncover a conserved mechanism by which microbial tryptophan metabolism enhances lysosomal function to maintain host lipid homeostasis. Specifically, we demonstrate that bacterial tryptophan catabolism--via the enzyme TnaA--promotes lysosomal acidification, proteolytic capacity, and structural remodeling in C. elegans, driving lipid breakdown through the lysosomal chaperone LBP-8. This activation boosts mitochondrial {beta}-oxidation and reduces lipid storage. Importantly, the same pathway operates in mammalian hepatocytes and in a high-fat diet mouse model, where restoring bacterial tryptophan metabolism markedly alleviates hepatic steatosis. Our findings bridge microbial metabolism and lysosomal dynamics, offering fresh insights into host-microbe crosstalk and metabolic regulation. HighlightsTnaA-mediated bacterial tryptophan catabolism promotes lipid mobilization via lysosomal chaperone. Bacterial tryptophan metabolites boost lysosomal function, lipid breakdown, and mitochondrial {beta}-oxidation. Conserved microbiota-lysosome-lipid axis from worms to mammalian liver. Restoring gut bacterial tryptophan metabolism alleviates hepatic steatosis in high-fat diet mice.

cell biology↗