Biology subjects

Yang, N.

Publications and source records attributed to Yang, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Systematic Functional Interrogation of Neurodevelopmental Disorder Risk Variants

Neurodevelopmental disorders (NDDs) are highly polygenic, yet the functional consequences of most associated non-coding variants remain unclear. We used a massively parallel reporter assay (MPRA) to test 727 NDD-associated non-coding variants in human neural progenitors, identifying 38 expression-modulating variants (emVars) with regulatory activity. These emVars were predicted to alter transcription factor binding motifs linked to neurodevelopmental signaling and cellular metabolism. We mapped emVars to candidate target genes using expression quantitative trait loci and activity-by-contact (ABC) models. We then used CRISPR droplet sequencing (CROP-seq) in human pluripotent stem cell-derived neurons to identify endogenous target genes and characterize their downstream transcriptional effects. CROP-seq preferentially supported ABC predictions, identified additional regulatory relationships, and revealed convergence on developmentally regulated programs involving neuronal connectivity, synaptic function, and mitochondrial biology. Together, these results connect NDD risk variants to endogenous target genes and shared neurodevelopmental transcriptional programs.

genomics↗

bioRxiv2026

SLC25A28 is a synthetic lethal vulnerability in nucleotide excision repair-deficient cancers

Approximately 10% of bladder, upper urinary tract, and endometrial cancers harbor deleterious somatic alterations in nucleotide excision repair (NER) pathway genes. Although platinum-based chemotherapy is the standard treatment for NER-deficient tumors, its utility is limited by nephrotoxicity, motivating alternative strategies that avoid direct DNA targeting. Here, we employed a genome-wide CRISPR-Cas9 screen to identify synthetic lethal vulnerabilities in NER-deficient cancer cells. An ERCC4-null RT112/84 bladder cancer cell line was generated and validated by Sanger sequencing and Western blotting, and functional NER deficiency was confirmed using a host cell reactivation assay. Parallel screens in ERCC4-deficient and isogenic wild-type cells. nominated SLC25A28 as the top-ranked synthetic lethal candidate in ERCC4-deficient cells, an interaction further supported by DepMap dependency. Clonogenic assays confirmed that loss of SLC25A28 selectively impaired cell viability in cells deficient for ERCC2, ERCC3, ERCC4, or ERCC5 and inducible knockout selectively suppressed ERCC4-deficient xenograft growth in-vivo. Mechanistically, RNA sequencing followed by gene set enrichment analysis revealed enrichment of oxidative stress-related pathways, including cellular responses to reactive oxygen species (ROS) and DNA damage signatures, upon SLC25A28 loss. These transcriptional changes are consistent with increased oxidative stress and DNA damage, placing heightened demand on NER-mediated repair. Direct measurement confirmed increased intracellular ROS. Collectively, our nominates SLC25A28 as a previously unrecognized synthetic lethal vulnerability in NER-deficient cancers and implicate mitochondrial iron homeostasis as a candidate metabolic dependency that may be targeted independently of platinum-based chemotherapy.

cancer biology↗

bioRxiv2026

Spatiotemporal conservation of bacteria in the Trichodesmium microbiome

Trichodesmium is a major nitrogen fixer in the nutrient-limited tropical and subtropical ocean, contributing up to 50% of new nitrogen and driving primary productivity. Trichodesmium filaments often aggregate into colonies that host a diverse consortium of microbes that can influence their activity and physiology; however, it is unclear what factors shape community structure. To address this, we used metagenomics of Trichodesmium colonies collected across the subtropical and tropical Atlantic Ocean to examine how Trichodesmium diversity and abundance shape epibiont community composition. Heterotrophic metagenome-assembled-genomes from Trichodesmium colonies and genes specific to the major Trichodesmium subclades were read mapped against Trichodesmium metagenomes from the North Atlantic, the Western Tropical South Pacific, and the Red Sea. Using this global survey of Trichodesmium subclade distribution patterns and their enriched heterotrophs, we found unique core microbiomes that are specific to Trichodesmium subclades across ocean basins. Genome characteristics of the enriched heterotrophs reveal a genomically small, slow-growing community consistently associates with colonies. Our results suggest that Trichodesmium genotype may influence epibiont community structure, indicating a role for deterministic processes in shaping the microbiome.

microbiology↗

bioRxiv2026

The cellular and genetic basis of inflorescence divergence between maize and teosinte

The domestication of maize from teosinte involved dramatic remodeling of the ear, yet the cellular and genetic bases of this transformation remain unclear. Here, we generate a single-nucleus and spatial transcriptome atlas of developing maize and teosinte ears. Comparative analysis reveals divergence in cob-associated cell types, with enhanced cytokinin signaling and reduced growth-inhibitory signals collectively driving cob thickening and enlargement in maize. We further demonstrate that domestication expanded the spatial expression domain of key transcription factors in maize meristem cells, enhancing the potential for increasing kernel number. Additionally, we verified a major domestication gene, ZmSPD1, in which two nonsynonymous SNPs differentiate maize from teosinte and alter jasmonic acid (JA) levels in the ear, thereby suppressing spikelet abortion to effectively double kernel production. These findings provide a cell-resolved mechanistic framework for how cob architecture and kernel number were shaped during maize domestication, offering new insights into the formation of key agronomic traits.

plant biology↗

bioRxiv2026

DPCGS: a computational framework for linking GWAS to single-cell transcriptomics in complex traits and diseases

Complex traits and diseases arise from the interplay between genetic variation and cellular heterogeneity, making it essential to understand how genetic risk manifests at the cellular level. However, connecting genome-wide association studies (GWAS) to specific cell populations remains challenging due to cellular complexity and the prevalence of noncoding variants. Here, we present DPCGS, a computational framework that systematically integrates GWAS summary statistics with single-cell RNA-sequencing (scRNA-seq) data to identify trait-associated cell subpopulations, genes, and regulatory programs. Unlike existing approaches that primarily evaluate pathway enrichment or cell-type-level associations, DPCGS quantifies the enrichment of genetically prioritized genes within individual cells through a statistically calibrated gene-set scoring strategy, enabling high-resolution mapping of genetic risk to cellular states. Benchmarking across simulated and diverse human single-cell datasets demonstrates that DPCGS achieves superior accuracy, sensitivity, and robustness compared with existing methods, including scDRS and scPagwas. Applying DPCGS to Alzheimers disease and asthma reveals disease-associated cellular populations and uncovers potential molecular drivers, including CD74, FOS, and AP-1 family regulatory programs, providing insights into disease-specific immune and cellular mechanisms. By bridging genetic discoveries from GWAS with functional interpretation at single-cell resolution, DPCGS establishes a generalizable framework for dissecting the cellular architecture of complex traits and diseases. This approach enables systematic discovery of disease-relevant cell subpopulations, regulatory networks, and potential therapeutic targets, offering broad applications in human genetics, single-cell biology, and precision medicine.

bioinformatics↗

bioRxiv2026

IgGM2: An All-Atom Foundation Model for Adaptive Immune Receptor Design

Accurate immune receptor design requires modeling the coupled variation of aminoacid sequence, full-atom conformation, and target-binding geometry across antibodies, nanobodies, and T-cell receptors (TCRs). Existing methods often address only part of this problem, either by separating structure generation from sequence design, relying on fixed-backbone inverse folding, or focusing on a single receptor class. We introduce IgGM2, a unified all-atom generative framework for immune receptor structure prediction and CDR sequence-structure co-design. IgGM2 follows a structure-to-design strategy: it first learns how immune receptors are positioned around fixed target structures, and then transfers this target-conditioned structural prior to CDR design. Unlike modular design pipelines, IgGM2 jointly generates CDR residue identities and full-atom receptor structures, allowing frame-work geometry to adapt to designed CDRs without separate inverse folding or external sidechain packing. Unlike continuous residue encodings based on virtualatom geometry, IgGM2 keeps sequence prediction explicit while using atom14 placeholders only for full-atom representation. On structure prediction benchmarks, IgGM2 better captures receptor-target spatial relationships than AlphaFold3 on FoldBench and achieves strong performance on TCR-pMHC modeling. On sequence design benchmarks, IgGM2 achieves competitive amino-acid recovery and improves Rosetta-based interface preference metrics, suggesting more favorable generated binding interfaces. These results support IgGM2 as a unified all-atom framework for adaptive immune receptor structure prediction and design.

bioinformatics↗

bioRxiv2026

The gut microbiota-derived metabolite queuosine regulates neuronal development and network function through tRNA modification

Queuosine (Q) modification is a hypermodified nucleoside derived from guanine on tRNAs that enhances the decoding of codons and equilibrates translational speed. Q is biosynthesized in bacteria, and eukaryotes salvage Q and the nucleobase queuine from the diet and the gut microbiome. In animals, Q deficiency causes impaired proteostasis, mitochondrial dysfunction, and neurological phenotypes, possibly due to the longevity and high metabolic demand of neurons. Yet, how Q affects isolated neurons has not been explored yet. Here, primary rat cortical neurons were cultured in Q-free synthetic medium to directly modulate Q modification levels independently of genetic perturbation, enabling assessment of its effects on neuronal development, survival, morphology, synaptic organization, and activity. Importantly, we found that the presence of Q modification facilitated neuronal arborization, decreased inhibitory synaptic density, and increased the frequency of spontaneous calcium transients, showing that tRNA Q modification enhances neuronal structural maturation and synaptic activity. Thus, the fine-tuning of neuronal translation programs by Q-tRNAs is required for proper network development and may influence neuronal resilience and synaptic function.

neuroscience↗

bioRxiv2026

Diverse root fungal endophytes mediate plant access to soil nutrients

Plant roots are broadly colonized by endophytic fungi with saprotrophic capabilities, but our understanding of whether they function in ways that are beneficial or detrimental to the host remains limited to model organisms. We hypothesized that endophytic fungi broadly affect plant access to soil nutrients, particularly organic forms that are typically not directly available to the plant. To address this, we paired 41 fungal endophytes with switchgrass (Panicum virgatum L.) and provided either inorganic or organic forms of nitrogen (N) and phosphorus (P). We evaluated how the fungi affected plant tissue N and P as well as plant growth. We also examined if these outcomes could be predicted from fungal phylogenetic relationships, in vitro traits of the fungi, or characteristics of the habitat from which fungi were isolated. There was substantial variation in both plant N (0.05-0.63%) and P (0.02-0.10%) acquisition that depended on the interaction of fungus and nutrient treatment. More fungi were beneficial for plant N than for P and shoot nutrients generally increased more than root nutrients from fungal associations. However, fungal effects on plant nutrients were not predicted by fungal traits, habitat traits, or fungal phylogenetic relationships. This unpredictability highlights a key challenge for incorporating endophytes into nutrient management strategies. Improving our ability to predict endophyte impacts on host nutrient acquisition will require identifying the mechanisms underlying observed beneficial effects and scaling up to realistic, diverse root microbial communities.

ecology↗

bioRxiv2026

Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver

ObjectivesPrior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. MethodsMice with or without hepatocyte cyclin D1 (D1fl/fl or D1{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. ResultsCyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. ConclusionsCyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging. HighlightsO_LICyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression. C_LIO_LIAcute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1. C_LIO_LIHepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation. C_LIO_LICyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans. C_LI

physiology↗

bioRxiv2026

Benchmarking Static Gene Regulatory Network Reconstruction and Dynamic Transition Probing in Single-Cell Foundation Models.

Single-cell foundation models may encode gene regulatory information, but it remains unclear which model components capture this signal and how it compares with conventional inference methods. Here, we introduce a unified benchmark that evaluates gene regulatory network (GRN) reconstruction from six single-cell foundation models and three classical baselines across six datasets and four reference network types. We disentangle three sources of regulatory signal within each model--pretrained token embeddings, final-layer hidden states, and attention-derived scores. Under a strict zero-shot setting, scGPT token-embedding similarity outperforms classical baselines on STRING and ChIP-seq references, recovers core transcription factors, and best preserves reference network topology. Moreover, static GRNs cannot test whether learned gene-gene relationships are predictive of expression dynamics, we therefore introduce dynamic transition probing, which iteratively applies a models reconstruction head to drive early-cell profiles toward late-cell states without temporal supervision. We find pretrained models capture meaningful developmental transitions, with scFoundation showing the strongest overall performance. Together, our results show that single-cell foundation models encode transferable regulatory and dynamical priors, but how well these priors can be recovered depends on model architecture, pretraining design, and extraction strategy.

systems biology↗

bioRxiv2026

Depth-dependent eDNA abundances across ecosystems inform deep-sea sampling strategies

Environmental DNA (eDNA) surveys are increasingly used to assess marine biodiversity and inform deep-sea environmental decision-making, including mineral resource management and fisheries oversight. Yet standard low-volume protocols inherited from coastal work may be inadequate at depth, and recent findings indicate that depth- and productivity-aware sampling, often requiring high-volume in situ filtration, is needed, but no quantitative framework links depth and ecosystem context to defensible filtration volume targets. We compiled 841 eDNA samples from eight expeditions across the North Atlantic, Wider Caribbean, and Pacific (surface to 4000 m) to quantify how recoverable eDNA scales with depth and surface productivity, and to derive depth- and productivity-aware sampling targets. Total eDNA concentration declined with depth as a power law, with attenuation exponents (b) modulated by surface productivity: most gradual in eutrophic waters (b = 0.67), intermediate in mesotrophic (b = 0.90), and steepest in oligotrophic systems (b = 1.25); volume-weighted models explained 66 to 88% of the variance. At a fixed extract-concentration target, required filtration volumes diverged ~7-fold between oligotrophic and eutrophic systems at 200 m and ~38-fold at 4000 m. Conventional Niskin sampling therefore undersamples deep-sea biodiversity, particularly in mid- to low-productivity systems. Among laboratory parameters, the assay-specific extract-concentration target exerted greater leverage on required volume than extraction efficiency or elution volume. Volume-aware sampling paired with optimized recovery should be routine in deep-sea eDNA surveys.

ecology↗

bioRxiv2026

Two Novel Genes, Stb23 and Stb24, Conferring Multi-stage Resistance to Zymoseptoria tritici: Rapid Deployment in Marker-Assisted Wheat Breeding

The fungal pathogen Zymoseptoria tritici poses a major global threat to wheat production, causing severe yield losses and necessitating intensive and costly fungicide applications. The increasing demand for durable genetic resistance has intensified interest in quantitative resistance loci, particularly those exhibiting multi-stage resistance (MSR), which suppress pathogen development continuously throughout the wheat life cycle. Many previously effective resistance genes are now showing declining efficacy, underscoring the urgent need for novel and long-lasting sources of resistance. In this study, we report the identification and genetic mapping of two quantitative resistance loci that address this need. The first locus, designated Stb23, is a major QTL on chromosome 1DS, with LOD scores exceeding 9 and explaining 6-36% of phenotypic variation at the seedling stage and 2-16% at the adult-plant stage. The second locus, designated Stb24, is a major QTL on chromosome 3DL, with LOD scores of approximately 10 and accounting for 11-30% of seedling-stage variation and 9-23% of adult-plant variation. Furthermore, two tightly linked KASP markers-snp_1D1217527 for Stb23 and snp_3D1077880 for Stb24-were developed and validated across three popular Australian bread wheat cultivars, providing practical tools for deploying these loci in breeding programs targeting improved resistance to Z. tritici. Key messageTwo significant major-effect resistance loci on chromosomes 1DS (proposed as Stb23) and 3DL (proposed as Stb24) were identified and characterized. Two tightly linked KASP markers with these loci were also discovered and validated for molecular-assisted breeding programs.

genetics↗

bioRxiv2026

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

cancer biology↗

bioRxiv2026

ISPpu10 is a structure-gated bridge RNA recombinase that drives safe, large-scale genomic plasticity

IS110 elements employ bridge RNA to direct target site recognition, yet whether additional layers of specificity exist beyond RNA-DNA base pairing is unknown. Here we identified ISPpu10, an IS110 element in Pseudomonas putida that is associated with >100-kb segmental amplifications during adaptive laboratory evolution. All insertions mapped to multiple identical copies of a single conserved intergenic sequence harboring a GC-rich 5' extension that forms a stem-loop. Systematic mismatch and compensatory substitution scanning revealed a sequence-structure dual-match logic: base pairing between the bridge RNA and target DNA serves as an RNA-guided match, whereas the target-encoded stem-loop provides an additional specificity determinant. Transplanting this stem-loop into Escherichia coli targets improved on-target integration and reduced genome-wide off-target insertion, establishing the stem-loop as a portable structural gate. These findings reveal a structural recognition layer beyond base-pairing, suggesting how bacteria reconcile transposition with genome integrity and offering a strategy for precise genome editing.

microbiology↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2026

PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis

Metastasis remains the leading cause of cancer mortality, yet effective therapies are limited. While therapeutic responses are influenced by organ-specific immune microenvironments, strategies to pharmacologically modulate these niches remain poorly defined. Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrate that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state. Integrated single-cell/spatial transcriptomics and functional assays reveal that AC484 promotes AM accumulation within metastatic lesions, elevates their IFN{gamma} production and responsiveness, and enhances their tumor-killing activity. Depletion of AMs diminishes the anti-metastatic efficacy of AC484. Mechanistically, inhibiting PTPN1/2 by AC484 amplifies IFN{gamma}-STAT1 signaling in AMs, while disrupting this pathway impairs their tumor control capability. These findings delineate a distinct innate immune axis where PTPN1/2 acts as a molecular "brake" on AM activation, suggesting that pharmacologically unleashing tissue-resident macrophages offers a therapeutic strategy to overcome metastatic progression, particularly in microenvironments where adaptive immunity is insufficient. SignificanceAMs are potent anti-metastatic immune effectors functionally constrained by PTPN1/2. Pharmacologically inhibiting PTPN1/2 amplifies their IFN{gamma}-STAT1 signaling and tumoricidal activity, establishing a strategy to reactivate tissue-resident immunity against metastasis.

immunology↗

bioRxiv2026

Early microglial priming in Alzheimer's disease revealed by ME-seq

Epigenetic modifications, particularly DNA methylation, change dynamically with aging and are implicated in Alzheimers Disease (AD), yet how methylation interfaces with transcriptional and chromatin regulation at single-cell resolution remains poorly understood. Progress has been limited by a lack of scalable technologies capable of jointly profiling these regulatory layers. Here, we present ME-seq, a highly scalable technologies capable of simultaneously profiling DNA methylation, gene expression, and chromatin accessibility, while achieving a 100-fold reduction in cost. We generated over 400,000 single-nucleus trimodal profiles from the aging and AD mouse brain across ages, producing the first such atlas of neurodegeneration. We found AD progression triggers pronounced, disease-specific shifts in cellular composition, characterized by accelerated epigenetic aging and the expansion of disease-associated microglia (DAM). Integrative analyses, including aging clocks, revealed that DNA methylation acts as an early priming layer preceding transcriptional activation with IRF1 identified as a methylation-sensitive transcription factor serving as a gatekeeper for DAM activation. Our results establish ME-seq as a transformative tool for large-scale epigenomic dissection, revealing DNA methylation as a primary coordinator of cell-state transitions in the aging brain. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/702946v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@67435dorg.highwire.dtl.DTLVardef@177c22aorg.highwire.dtl.DTLVardef@16c6fd9org.highwire.dtl.DTLVardef@231b92_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

XomicsDB: a database of paired multi-omics datasets for systems biology

Life science research is primarily driven by data integration on the basis of theoretical development. Broad applications of multiomics (xomics) data calls for efficient integration of xomics data to infer cellular operation and regulation. To that end, it is urgently needed good-quality xomics data should be curated and shared for the community. Here we present XomicsDB, a database curating paired xomics datasets at both bulk and single-cell levels in model organisms. It contains 183 datasets from 13 model organisms, with a total of seven xomics data types. Users can download these datasets individually or in a batch from the ftp server provided. Users can also upload their paired xomics datasets for sharing. Incoporation of xomics data intom GSMs are demonstrated in model organisms Escherichia coli and human. Future efforts will be on collecting more single-cell xomics data and curating non-model oragnisms. The XomicsDB can be found at: http://xomicsdb.com.

systems biology↗