Biology subjects

Sun, Y.

Publications and source records attributed to Sun, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Diatoms maintain metabolic activity in deep ocean twilight zones

Phytoplankton are primarily confined to the sunlit epipelagic zone, yet intact algal cells persist in the oceans mesopelagic twilight zone where light is minimal. However, their survival strategies in the deeper ocean remain unknown. Here, we isolate Chaetoceros sp. DS1 from 1000 m depth and reveal its survival mechanisms under prolonged darkness and high pressure, including membrane lipid remodeling and enhanced antioxidant defenses. Importantly, DS1 maintains a latent photosynthetic reserve that activates upon exposure to dim blue light and higher pressure typical of the twilight zone, enabling photosynthesis and nutrient uptake. It exhibits metabolic flexibility by utilizing stored carbon in darkness and assimilating organic carbon under dim light. Global meta-omics data show widespread, transcriptionally active Chaetoceros-like diatoms in the twilight zone, expressing blue-light sensors and protein synthesis genes. These findings identify the ocean twilight zone as a previously overlooked niche for metabolically active phytoplankton, expanding understanding of deep-ocean microbial ecology and carbon cycling.

ecology↗

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗

bioRxiv2026

LIFU-Responsive Nanocomplexes Deliver PDGF-BB mRNA for Plaques Stabilization via Neovascularization Modulation

BackgroundPathological intraplaque neovascularization, vascular leakage, and fibrous cap thinning contribute to vulnerable atherosclerotic plaque rupture. Platelet- derived growth factor-BB (PDGF-BB) has been shown to promote pericyte recruitment, thereby stabilizing the microvascular structure, and to induce phenotypic modulation of vascular smooth muscle cells (VSMCs), which enhances fibrous cap thickness and reinforces plaque stability. Nevertheless, systemic protein delivery is limited by rapid clearance and potential off-target effects. MethodsWe developed PDGF-BB mRNA-loaded lipid nanoparticle-poly(lactic-co- glycolic acid) nanobubble complexes (LNPmRNA@PLGA) and used low-intensity focused ultrasound (LIFU) to enhance plaque-targeted delivery. Cellular uptake, PDGF- BB expression, vascular mural-cell responses, plaque histology, hemodynamics, and proteomic changes were evaluated in vitro and in ApoE-/-Fbn1C1041G+/- mice. ResultsLIFU enhanced nanocomplex uptake and PDGF-BB expression, promoted vascular smooth muscle cell proliferation, migration, and phenotypic switching, and increased pericyte coverage. In vivo, LIFU plus LNPmRNA@PLGA reduced the plaque vulnerability index by 78.2% and the neovascularization area by 67.3% compared with controls, while increasing collagen deposition and improving carotid hemodynamics. ConclusionsLIFU-responsive delivery of PDGF-BB mRNA stabilized vulnerable plaques by promoting neovessel maturation and strengthening the fibrous cap. This strategy provides a spatially controlled framework for therapeutic remodeling of high-risk atherosclerotic plaques. Research Perspective What New Question Does This Study Raise?O_LICan spatially controlled PDGF-BB mRNA delivery simultaneously mature intraplaque neovessels and reinforce the fibrous cap without the systemic effects associated with recombinant PDGF-BB? C_LI What Question Should Be Addressed Next?O_LIFuture studies should define the therapeutic window, durability, and long-term safety of LIFU-triggered PDGF-BB mRNA delivery in large-animal models that more closely reproduce human plaque rupture. C_LI

pharmacology and toxicology↗

bioRxiv2026

Multidimensional variation and population stratification across 8000 complete human centromeres

Human centromeres are indispensable for the faithful segregation of chromosomes during cell division, yet their highly repetitive nature has historically precluded comprehensive characterization, leaving fundamental questions about their sequence diversity, evolution trajectories and function dynamics unresolved. Here, we generated 6,312 complete human centromere sequences from 320 phased genome assemblies in Asian Pan-Genome project phase 1. By integrating the assemblies from the Human Pangenome Reference Consortium (HPRC) and Human Genome Structural Variation Consortium (HGSVC), we constructed a multidimensional genetic variation map encompassing over 8,000 gapless centromeres. Centromeric satellite arrays account for 4.19% to 6.01% of the whole genome, with substantial variations in size and architecture across chromosomes. Using a refined alpha satellite clustering approach that captures global diversity, we identified 195 higher-order repeat (HOR) arrays, 56.4% of which are absent from the T2T-CHM13 reference genome. Extensive structural variations across multiple dimensions exhibit population stratification, including centromeric haplotypes (CenHaps), ultra-large pericentric inversions spanning up to 36.6 Mbp, and inter-chromosomal HOR sharing that reflects sequence exchange among chromosomes. Integrating CENP-A CUT&Tag experiments and long-read-based DNA methylation profiles, we demonstrate that 16.8% of centromeres harbor multiple potential kinetochore assembly sites, and CenHap-specific local HOR homogenization is associated with kinetochore positioning. Despite global suppression of recombination at centromeres, we observed asymmetric linkage disequilibrium flanking centromeres and an ancient recombination event within the centromere of chromosome 19. Furthermore, contrary to the prevailing assumption of high mutation rates in centromeres, our estimates based on stringent orthology reveal no significantly higher single-base substitution rates for centromeres relative to flanking pericentromeric regions with substantial variations across chromosomes, despite extraordinary structural plasticity. Collectively, these multi-scale centromeric variations provide a global view of human centromere diversity and population stratification, fundamentally redefine centromere evolution through a dual-track model balancing structural innovation with mutational constraint, and establish an essential resource for investigating centromere biology and a baseline reference for diagnosing centromere-associated disorders.

genomics↗

bioRxiv2026

Deciphering complete archaic introgression sequences in modern human genomes

Genetic introgression from archaic hominins has profoundly reshaped the genetic diversity and adaptive potential of modern humans, yet the full catalog of introgressed sequences, particularly those residing in structurally complex regions has remained elusive. Here, we present ASMaid (ASseMbly-based archaic introgression detector), a Hidden Markov Model-based framework that leverages haplotype-resolved pangenome assemblies to identify archaic-derived sequences with unprecedented completeness. By integrating both single-nucleotide genotype and structural variation (SV) signals, ASMaid captures significantly more intact archaic segments than conventional reference-based approaches. Applying ASMaid to a global panel of 610 phased human genome assemblies, we show that non-African individuals carry approximately 79.8 Mbp of Neanderthal and 8.3 Mbp of Denisovan sequences, representing substantial increases over previous estimates, respectively. Notably, we detected several centromere-spanning archaic segments, including EAS-specific calls on chromosomes 5 and 7. Our assembly-based approach uncovered 1,701 archaic-derived SVs, revealing a previously overlooked layer of archaic functional legacy. High-frequency introgressed loci are enriched in pathways associated with metabolism, immunity, and nervous system (e.g. CTNNA2 linked to early-onset schizophrenia risk), underscoring the fundamental role of introgression in modulating modern human traits. Notably, we identified dozens of loci potentially facilitating local adaptation, such as PRDM16 involved in adipocyte differentiation and cold tolerance, and CSGALNACT2 associated with chondroitin sulfate synthesis. Furthermore, our analysis delineates three distinct Denisovan introgression pulses in Eastern Eurasian genomes, in which the first two pulses are shared across East Eurasian and Oceanian populations, while the third remain primarily exclusive in East Asians. Reflecting these complex introgression events, 31 Denisovan-derived segments, including the TBX15-WARS2 locus, are inferred to have been introduced via at least two events. This comprehensive map of archaic introgression provides a fundamental resource for understanding how ancient gene flow continuously shapes human phenotypic diversity and adaptation.

evolutionary biology↗

bioRxiv2026

Uhrf1 loss disrupts Ctcf-associated chromatin organization during early mouse embryogenesis

UHRF1 is a chromatin-binding protein essential for maintaining DNA methylation and histone modification states, yet its integrated role in vivo remains incompletely understood. To define its function, we generated conditional Uhrf1 knockout embryonic stem cells (ESCs) and embryos. Uhrf1-/- ESCs exhibited near-complete loss of 5mC and 5hmC but maintained pluripotency, whereas Uhrf1-null embryos developed normally until E8.5 and then failed to develop further by E9.5, phenocopying Dnmt1 loss. Single-cell multi-omic (ME-seq) profiling of E8.5 embryos revealed impaired lineage stabilization, widespread hypomethylation, and disrupted chromatin architecture. Uhrf1 loss was associated with altered CTCF-associated chromatin signal, broad remodeling of chromatin contacts, altered cis-regulatory relationships, and reduced predicted BMP-related ligand-receptor communication, particularly within neural crest populations. These findings identify Uhrf1 as a central regulator that tightly couples DNA methylation maintenance to 3D genome organization during gastrulation, thereby, directing early lineage specification and positioning Uhrf1 as a pivotal mediator of epigenetic information transfer during early embryogenesis. HighlightsO_LIUhrf1 knockout ESCs show global loss of 5mC/5hmC but maintain pluripotency. C_LIO_LIUhrf1-null embryos develop normally until E8.5 but die by E9.5 with severe defects. C_LIO_LISingle-cell multi-omics revealed disrupted chromatin, transcription, and lineage stability upon knockout. C_LIO_LILoss of Uhrf1 alters CTCF-associated chromatin signal, predicted BMP-related communication, and cis-regulatory relationships. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/738670v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@15bf31dorg.highwire.dtl.DTLVardef@1b601ecorg.highwire.dtl.DTLVardef@386018org.highwire.dtl.DTLVardef@12ce99f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2026

Coronavirus papain-like protease antagonizes innate immunity by cleaving Importin α1 to disrupt nuclear transport

The Importin family, as key mediators of nucleocytoplasmic transport, represents a common target for viral immune evasion. However, whether coronaviruses directly manipulate Importin to disrupt nuclear trafficking and suppress antiviral immunity has remained unclear. In this study, we identify a previously unrecognized mechanism by which coronaviruses from all four genera subvert host innate immunity through the proteolytic inactivation of Importin 1, a key mediator of nuclear import of cargo proteins. We demonstrate that the membrane-associated papain-like protease (PLpro-TM) directly cleaves Importin 1 at specific glycine residues, G129 for PEDV and IBV PLpro, and G119 for MHV and PDCoV PLpro, thereby disrupting its nuclear import function. This cleavage impairs the nuclear translocation of multiple transcription factors (IRF3, STAT1, STAT2, and p65) and suppresses the expression of downstream antiviral genes, including IFN-{beta} and IFN-stimulated genes (ISGs). Importantly, cleavage-resistant mutants of Importin 1 (G129A or G119A) restore nuclear import capability and rescue IFN-{beta} signaling. Consequently, they exert a more potent inhibitory effect on viral replication than the wild-type Importin 1, fulfilling an antiviral role. Our work establishes PLpro-TM-mediated cleavage of Importin 1 as a conserved immune evasion strategy across coronaviruses and highlights this interaction as a potential target for broad-spectrum antiviral intervention. Author summaryThe nuclear transport of transcription factors is a critical checkpoint for the initiation of innate antiviral immunity. Here, we identify the PLpro-TM protein as a pan-coronavirus antagonist of nucleocytoplasmic trafficking and innate immune response. We demonstrate that PLpro-TM from four distinct coronavirus genera directly cleaves Importin 1 at specific glycine residues, thereby disabling its ability to mediate the nuclear import of key transcription factors and subsequent transcription of anti-viral genes. This work reveals a previously unrecognized, evolutionarily conserved immune evasion strategy shared across , {beta}, {gamma}, and {delta} coronaviruses. By uncovering the proteolytic inactivation of Importin 1 targeting by PLpro-TM, our findings not only resolve a long-standing question about how coronaviruses disrupt nuclear trafficking, but also establish PLpro-TM and Importin 1 as promising targets for the development of broad-spectrum antiviral therapeutics against current and emerging coronaviruses.

microbiology↗

bioRxiv2026

A Deep Learning Framework for Biomarker Segmentation and Classification in Traumatic Brain Injury

Traumatic brain injury (TBI) triggers widespread biomarker activation, including astrocytic markers such as glial fibrillary acidic protein (GFAP) and microglia markers such as ionized calcium-binding adapter molecule 1 (IBA1). Quantifying and analyzing these biomarkers are critical for understanding injury impact; however, current methods are labor-intensive and time-consuming. In this study, we propose an automated deep learning framework for dual-biomarker segmentation and TBI classification using GFAP and IBA1 immunofluorescent images. Four U-Net variants: Baseline U-Net, U-Net++, MANet, and LinkNet were trained for segmentation. Three classification models, ResNet50, Swin_T, and MaxViT, were trained to distinguish TBI from control images under single- and dual-biomarker conditions. The baseline U-Net achieved the highest segmentation Dice score for GFAP (0.9259), while the U-Net++ achieved the highest Dice score for IBA1 (0.9676). Trained segmentation models demonstrated significantly better performance compared to QuPath alternatives. While GFAP alone supported high classification accuracy, IBA1 alone was less effective. Multimodal fusion of GFAP and IBA1 significantly improved classification performance across all models, with Swin_T achieving the highest overall accuracy (0.9489), and ResNet50 achieving the highest F1-score (0.9499). These findings demonstrate that integrating complementary biomarkers enhances automated TBI classification, and deep learning offers a robust alternative to manual analysis for immunofluorescent brain injury imaging. This framework is scalable to additional biomarkers and injury models, offering a reproducible approach to accelerate biomarker research.

neuroscience↗

bioRxiv2026

Partial epithelial-to-mesenchymal transition mediates profound gap closure through growth and fluidization

Epithelial gap closure is essential for maintaining tissue integrity during development and wound healing. Previous studies have shown that closure of small gaps is driven by actomyosin purse-string contraction and traction forces generated at the gap edge. Here, we show that millimeter-scale circular gap closure in mouse epicardial (MEC1) monolayers is driven primarily by growth-mediated compressive stresses. Compared with MDCK monolayers, MEC1 cells close gaps more rapidly with reduced undulation near gap edge through coordinated tissue-wide extension-contraction. The collective closing dynamics can be modulated by partial epithelial-mesenchymal transition induction and Rho kinase inhibition. By integrating tissue and cell kinematic analyses, traction-force mapping, and a continuum framework that decomposes tissue strain rates into growth-, elastic-, and fluidity-related contributions, we reveal that growth-generated compression drives inward tissue flow, while elastic cell elongation and fluid-like tissue remodeling through cell-cell intercalation act synergistically to accommodate deformation and promote robust collective gap closure.

biophysics↗

bioRxiv2026

LARP4 is a B cell-specific metabolic checkpoint for plasma cell differentiation and a therapeutic target in systemic lupus erythematosus

RNA-binding protein LARP4 plays an important role in T cell activation and differentiation, but its role in B cell biology and the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. This study found that LARP4 was specifically highly expressed in B cells of SLE patients and was positively correlated with disease activity. By constructing T cell-specific and B cell-specific conditional knockout mice, we found that deletion of LARP4 in B cells, but not in T cells, significantly alleviated pristane-induced and Bm12-induced lupus nephritis. Further analysis showed that LARP4 deletion selectively inhibited B cell differentiation into plasma cells, but did not affect germinal center B cell formation. Integrated transcriptomic and metabolomics analyses revealed that this effect is due to reduced phosphatidic acid synthesis and decreased mTORC1 activity caused by mitochondrial oxidative phosphorylation dysfunction. Furthermore, we used LIPEP, a LARP4 inhibitory peptide that effectively mimicked the therapeutic effects of LARP4 gene knockout in the MRL/lpr spontaneous lupus model and outperformed cyclophosphamide in reducing glomerular immune complex deposition and improving extrarenal dermatitis. These results indicates that LARP4 is a key metabolic checkpoint regulating B cell differentiation into Plasma cells and suggest that it may be a potential therapeutic target for SLE.

immunology↗

bioRxiv2026

Lineage recording reveals hijacked hepatic progenitor states as a common origin of HCC and ICC

HighlightsCERAMIC enables continuous and high-capacity lineage tracing of liver tumor initiation Fatty liver-associated hepatocytes acquire regenerative and premalignant cell states before malignant transformation Lineage reconstruction identifies Hep_Bi-zonal cells as the cellular origin of liver tumor initiation Transcriptional and regulatory programs distinguish tumor-fated hepatocytes from failed-to-transform lineages Peroxisomal metabolism is required for progenitor-state formation and liver tumor initiation Spatial remodeling identifies a macrophage niche associated with tumor-fated hepatocytes Dual ontogenies and functional specialization of lipid-associated macrophages shape the tumor-fated hepatocyte niche Fatty liver disease predisposes to primary liver cancer, yet the lineage routes and niche mechanisms that select rare tumor-fated hepatocytes remain unclear. Here we developed CERAMIC, a high-capacity CRISPR-Cas9 lineage recorder that co-recovers editing scars and transcriptomes from single cells, and applied it to an AKT/NRAS-driven model of MASLD-associated liver tumor initiation. Longitudinal lineage, single-cell and spatial analyses revealed a hierarchical trajectory in which bipotential bi-zonal hepatocytes (Hep_Bi-zonal), rather than pericentral-like hepatocytes (Hep_CVlike), generated regenerative and neoplastic hepatocyte progenitor states that progressed toward both hepatocellular carcinoma and intrahepatic cholangiocarcinoma lineages. Tumor-fated cells preferentially expanded along a remodeled midlobular-periportal axis and depended on ACOX1-mediated peroxisomal beta-oxidation to withstand lipotoxic and oxidative stress. Spatial and lineage analyses further identified a sequential lipid-associated macrophage niche, in which monocyte-derived LAMs engaged tumor-fated hepatocytes through an LGALS9-P4HB axis, and P4HB inhibition suppressed tumor expansion. These findings define liver tumor initiation as a lineage-restricted process licensed by peroxisomal metabolic adaptation and macrophage-derived niche signals.

cancer biology↗

bioRxiv2026

Placental invasion mismatch underlines pregnancy disorders and cancers

Mammalian placentas vary dramatically in invasiveness, parallel aggressive cancers, and are dysregulated in pregnancy disorders, yet whether they share regulatory architecture remains unclear. We investigated single-cell transcriptomes of the maternal-fetal interface across nine mammals spanning all major placental morphotypes and integrated it with thirteen cancers and five pregnancy complications. A conserved cellular framework is deployed through three discrete regulatory programs: a cancer-like program in hemochorials, endothelial-cooperation program in endotheliochorials, and collagen-rich invasion-suppressing program in epitheliochorials. Aggressive cancers selectively converge on hemochorial program, and we functionally validated share invasion regulators including the VGLL3-TEAD1 interaction and APOE. Pregnancy disorders are partially, mismatched deployments of these programs; placental APOE knockdown in mice phenocopies preeclampsia with concurrent collapse of both M1/M2 macrophage programs. These findings unify placental diversity, cancer convergence, and obstetric disorders under a regulatory-mismatch principle, whereby evolved placental invasion programs becomes pathological when deployed outside their evolutionary context.

evolutionary biology↗

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

First community challenge for automated virus taxonomy

The rapid rate of virus discovery renders manual curation by taxonomy experts increasingly impractical, creating a need for reliable software that can reproducibly assign viral contigs to taxa at all fifteen ranks of the virus taxonomy. We led an open community challenge for the computational taxonomic classification of viruses and assembled a dataset of virus sequences combining expert-curated and metagenomic sequences. Seventeen teams contributed a total of thirty-four automated, fully reproducible classification pipelines. Most tools correctly assigned viruses belonging to established species, genera, or families, but viruses that are unclassified at those lower ranks remain challenging. This study provides datasets, open-source software, novel approaches, and recommendations to benchmark computational taxonomic classification of viruses, and support organizing the many viruses discovered in big omics data.

microbiology↗

bioRxiv2026

An integrative single-cell and spatial transcriptomics atlas highlights candidate regulatory factors in the development of gerbera capitulum

In Asteraceae species, the capitulum is a compact inflorescence, featuring a characteristic reproductive structure. Despite the identification of a few key regulatory factors, the transcriptome-level information on the developing capitulum remains limited. Here, we applied single-cell and spatial transcriptome sequencing to investigate the developing Gerbera hybridas capitulum during floret differentiation. We obtained a transcriptomics atlas encompassing different stages of the Gerbera capitulum and analyzed the cellular and spatial dynamics of gene expression. Using marker gene expression and GO enrichment of cluster-specific DEGs, we annotated putative cell types and described changes in gene expression across sampled stages, potentially associated with ongoing developmental processes. We detected activity of previously undescribed MADS-box genes and defined their spatial expression patterns. Notably, the MADS-box gene GAGL12 was found to be enriched in the putative capitulum phloem cells. The GAGL12 protein was shown in yeast two-hybrid assays to interact with several other MADS-domain proteins with hypothesized functions in vasculature development, and further detailed in silico analyses supported a candidate role in the development of capitulum vasculature. Altogether, we provide integrative and dynamic transcriptomic insight into capitulum and floret development and lay a basis for future functional studies of the control and development of this intriguing reproductive structure.

plant biology↗

bioRxiv2026

METTL1 regulates glioma proliferation through internal m7G methylation of EPHA2

BackgroundMethyltransferase-like 1 (METTL1) is highly expressed in organs like the pancreas but less so in the brain. The METTL1-WDR4 complex catalyzes N7-methylguanosine (m7G) methylation in tRNA, miRNA, mRNA, and rRNA, which impacts RNA stability and function. These modifications affect mRNA translation and tRNA functionality, influencing protein production and cellular activities. Such modifications can regulate tumor growth, invasion, and metabolism by selectively controlling protein expression. MethodGene expression data from public databases were analyzed to compare METTL1 expression in normal and tumor tissues. Western blot (WB) and immunohistochemistry (IHC) were used to quantify METTL1 levels in glioma samples and assess their prognostic significance. Cell viability, migration, invasion, and proliferation were evaluated using Cell Counting Kit-8 (CCK-8), wound healing, Transwell, cell cycle analysis, and colony formation assays. RNA immunoprecipitation PCR (RIP-PCR) identified m7G methylation sites on EPHA2 mRNA, and RNA stability was assessed with actinomycin D. ResultsBioinformatics analysis revealed that METTL1 is overexpressed in gliomas, correlating with poor prognosis. Knockdown of METTL1 significantly affected cell proliferation, migration, and invasion. RNA sequencing (RNA-seq) and m7G analysis identified EPHA2 as a downstream target, influencing the cell cycle via the AKT pathway. RIP and methylated RNA immunoprecipitation (MeRIP) confirmed two m7G sites on EPHA2 mRNA regulated by METTL1. Small interfering RNA (siRNA)-mediated METTL1 knockdown in EPHA2 mutants affected mRNA stability. Rescue experiments restored cell proliferation and AKT pathway gene expression. ConclusionMETTL1 methylates EPHA2 mRNA, enhancing its stability and expression, which activates the AKT signaling pathway and influences glioma cell proliferation. METTL1 could be a potential therapeutic target in glioma treatment.

cell biology↗

bioRxiv2026

VirProtRAG: Literature-grounded viral protein function annotation with retrieval-augmented generation

Viruses play indispensable roles in ecosystems and human health, yet deciphering their molecular functions remains challenging. Many viral protein annotations are incomplete or poorly characterized. Existing tools typically predict functional categories without linking to verifiable evidence, hindering the credibility of functional interpretation. Here, we present VirProtRAG, a viral protein function annotation framework that integrates information retrieval with evidence-grounded knowledge generation. It introduces three task-adapted components: a hybrid retrieval module combining keyword-based and semantic dense retrieval to maximize literature coverage, synonym-expanded and rank-aware retrieval with reciprocal rank fusion for improved search effectiveness, and literature quality and evidence-oriented re-ranking to enhance reliability and interpretability. Results show that hybrid retrieval strategy performed best, with quality and evidence features further enhancing re-ranking. Compared with direct LLM prompting without retrieved literature, it consistently improves generation performance, underscoring the critical role of external knowledge. Finally, we built a searchable database comprising all 17,484 reviewed Swiss-Prot viral proteins, supporting both sequence- and text-based queries. VirProtRAG introduced 32.53% non-overlapping function annotations beyond existing expert curation, and independently supported 56.34% of sequence-inferred function points with retrieved literature. Case studies further demonstrate its capability to augment and refine the characterization of previously unannotated or poorly understood viral proteins. Key MessagesO_LIVirProtRAG bridges large-scale biomedical literature and viral protein annotation, enabling traceable and biologically interpretable annotations grounded in verifiable publications. C_LIO_LIBy integrating hybrid sparse-dense retrieval, synonym expansion, and adaptive re-ranking using literature quality and evidence-type features, VirProtRAG substantially improves recall and ranking of biologically relevant publications, helping ground LLM outputs in traceable literature evidence. C_LIO_LILeveraging this framework, VirProtRAG automatically annotated all 17,484 reviewed Swiss-Prot viral proteins under the Virus taxonomic group and established an interactive, continuously expandable database. The resource may assist curators in rapid validation while supporting large-scale studies of viral evolution and host interactions. C_LI

bioinformatics↗

bioRxiv2026

POGZ safeguards neuronal gene chromatin architecture and transcription

Disruption of chromatin organization is a common pathogenic mechanism in neurodevelopmental disorders, yet how changes in 3D genome architecture relate to transcriptional dysfunction in the developing brain remains unclear. POGZ, a transposase-derived chromatin regulator mutated in White-Sutton syndrome and autism spectrum disorder (ASD) has been linked to both heterochromatin and accessible regulatory DNA, but its in vivo function in the brain is unresolved. Using immunoprecipitation-mass spectrometry in embryonic day 13.5 (E13.5) mouse cortex, we identify the H3K9 methyltransferases G9a/GLP as principal POGZ interactors, placing POGZ within the core H3K9 methylation machinery in vivo. We find that POGZ loss in embryonic mouse cortex drives bidirectional, megabase-scale redistribution of H3K9me3, with ectopic losses and gains over discrete neuronal gene loci. In developing Pogz-/-cortex, regions with H3K9me3 gains are repositioned to the nuclear lamina and exhibit strengthened B-compartment scores by Micro-C, locus-restricted erosion of TAD architecture, weakened boundary insulation, and reduced CTCF occupancy. Within these domains, nascent RNA synthesis at neuronal genes is markedly diminished. These results identify POGZ as a G9a/GLP-associated chromatin regulator that protects neurodevelopmental gene domains from heterochromatinization and perinuclear sequestering, preserving 3D architecture and transcription during cortical development. Major PointsO_LIPOGZ interacts with the G9a/GLP H3K9 methyltransferase complex in the developing mouse cortex, identified by IP-mass spectrometry. C_LIO_LILoss of POGZ drives megabase-scale redistribution of H3K9me3 and increases compartmentalization and nuclear-lamina association of neurodevelopmental gene loci, shown by ChIP-seq, Micro-C, and DNA FISH. C_LIO_LIMicro-C reveals disrupted TAD architecture at specific neuronal gene loci in Pogz-/-.PRO-seq shows POGZ is required to maintain nascent RNA synthesis of neurodevelopmental genes within disrupted chromatin domains. C_LI

neuroscience↗