Biology subjects

Sun, Y.

Publications and source records attributed to Sun, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Maternal repression of imprinted genes in endosperm by gene body demethylation

Removal of TE-like DNA methylation from regulatory elements drives canonical genomic imprinting of both maternally and paternally expressed genes in endosperm (MEGs and PEGs). Here we report that removal of CG-only gene body methylation also drives imprinting in maize, resulting in maternally repressed PEGs. These CG body methylated PEGs express broadly across cell types and lack H3K27me3 except in endosperm, where maternal copies acquire it. We found that partial gene body demethylation is a widespread feature of endosperm genes, usually does not result in imprinted expression, and is mediated by DNA glycosylases/lyases (DNGs). These and other data indicate that gene body methylation can shield select genes from PRC2 repression, and its maternal removal by DNGs explains the majority of PEGs in maize and rice but has weak impact in Arabidopsis thaliana. We hypothesize that increased gene expression noise arising from gene body demethylation--both with and without imprinting--is beneficial in endosperm.

genetics↗

bioRxiv2026

RBM25 exhibits distinct RNA- and chromatin-associated target programs in human embryonic stem cells

RNA-binding proteins (RBPs) are increasingly recognized to perform chromatin-associated functions in addition to their canonical roles in RNA regulation, yet how these activities are coordinated in human embryonic stem cells (hESCs) remain poorly understood. Here, we characterize distinct RNA- and chromatin-associated activities for RBM25 in hESCs. Transcriptome-wide profiling showed that RBM25 preferentially associates with transcripts involved in RNA processing and splicing, consistent with its canonical role as an RBP involved in post-transcriptional regulation. Genome-wide chromatin profiling further uncovered a distinct chromatin-associated program, with RBM25 occupying accessible promoters of actively expressed cell-cycle genes and introns predominantly associated with transcriptionally inactive neuronal genes. Interestingly, RBM25 chromatin-binding sites showed substantial co-occupancy with regions bound by the transcription factor CEBPZ in hESCs. We further show that RBM25 and CEBPZ physically interact and exhibit shared chromatin-binding patterns at both promoter and intronic regions. Importantly, reciprocal depletion experiments revealed that RBM25 is required for CEBPZ occupancy at CCAAT-containing promoters of highly expressed cell-cycle genes, whereas CEBPZ is not similarly required for RBM25 chromatin occupancy. Together, our findings establish RBM25 as a multifunctional factor with distinct roles in RNA processing and chromatin-associated regulation and reveal a context-dependent RBP-TF interaction that contributes to transcriptional regulation in hESCs.

molecular biology↗

bioRxiv2026

Torque-optimized body morphing enables rapid surface to underwater diving in whirligig beetles

Known for their rapid water surface locomotion, whirligig beetles (Gyrinidae) are also fast divers. They can transition from the surface to underwater swimming in under 100 ms. Diving requires them to generate sufficient hydrodynamic torque to break the water surface and reorient the body. However, the mechanism by which whirligigs create the necessary pitch-down torque is unknown. Here, we show that their diving is achieved by bending the abdomen. The inertial hydrodynamic pressure on the flexed abdomen generates the torque necessary for surface breaking and body rotation. The torque is maximized at an abdominal angle of 45{degrees}, whereas for effective diving, whirligigs display a preferential abdominal angle of around 28{degrees}, closely aligning with the angle that maximizes the torque-to-drag ratio. This abdominal angle is optimized by balancing torque generation with the drag penalty. Our findings inspire a mechanism for surface-to-underwater transition, offering design principles for multimodal robots capable of locomotion across the air-water interface.

biophysics↗

bioRxiv2026

A 3D in vitro follicle-endometrial organoid co-culture model recapitulates ovarian control of human endometrial decidualization

Female infertility remains a major women's reproductive health challenge, with impaired endometrial receptivity contributing to recurrent implantation failure, early pregnancy loss, and pregnancy complications. Mechanistic studies of human early pregnancy are limited by the lack of physiologically relevant models, and existing in vitro endometrial models rely on exogenous hormone treatment and do not recapitulate the dynamic ovarian control of endometrial growth and differentiation. Here, as a proof of concept, we developed a 3D in vitro ovarian follicle-endometrial organoid co-culture model. Immature murine follicles were cultured in vitro to obtain preovulatory follicles, followed by human chorionic gonadotropin (hCG) stimulation to induce ovulation and luteinization. Luteinized follicles were co-cultured with human endometrial stroma organoids for 6 days. The results showed that luteinized follicles generated a dynamic endocrine environment characterized by progressively increasing progesterone levels and declining estradiol levels. Follicle co-culture induced morphological differentiation and expression of decidualization markers in human endo-organoids. Transcriptomic analysis revealed strong genome-wide concordance between follicle co-culture and conventional decidualization induction using estradiol/progesterone/cAMP (EPC), with significant enrichment of decidualization-associated genes and pathways under both conditions. Nevertheless, the two conditions also exhibited distinct transcriptional states, with EPC preferentially enriched for more mature decidualization-associated programs, whereas luteinized follicle co-culture retained features of the early stage of decidualization. Functional perturbation testing revealed that the progesterone receptor (PR) antagonist RU486 attenuated co-culture-induced endometrial decidualization. Together, these results establish a new in vitro new approach methodology (NAM) that recapitulates ovarian control of endometrial decidualization. This platform provides a human-relevant NAM model to investigate the physiology and pathophysiology of endometrial decidualization, and to evaluate how drugs and environmental chemicals perturb uterine receptivity and early pregnancy.

pharmacology and toxicology↗

bioRxiv2026

A population-scale landscape of the subgingival microbiome reveals divergent routes to periodontal dysbiosis

Periodontitis is an archetypical mucosal inflammatory disease in which microbiome dysbiosis at the tooth-epithelial interface interacts with host genetic and behavioral risk factors to drive immune-mediated tissue destruction. Although subgingival microbiome compositional shifts are thought to parallel disease severity, microbiome variation at the population-level and its relationship to periodontal clinical phenotypes and disease-modifying factors remain poorly defined. Here, we use unsupervised manifold learning to map the compositional landscape of the subgingival microbiome in 1,355 adults spanning periodontal health to severe periodontitis. We identified eight latent microbiome states organized along a branching continuum from eubiosis to dysbiosis. An intermediate microbial configuration marked ecological destabilization and bifurcation into two distinct periodontitis-associated dysbiotic trajectories, distinguished by links to gingival inflammation and smoking. Although the microbiome trajectories broadly tracked periodontal destruction, a minority of individuals showed discordant microbiome-clinical phenotypes, with some individuals with periodontitis retaining otherwise eubiotic microbiomes enriched for low-abundance pathobionts, while some cases of health or mild disease had highly dysbiotic communities, suggesting distinct host susceptibility. Together, these findings define a population-scale ecological landscape of the subgingival microbiome, reveal divergent trajectories to periodontal dysbiosis, and highlight heterogeneity in the relationship between microbial community structure and clinical disease expression.

microbiology↗

bioRxiv2026

Antibodies targeting a conserved cryptic epitope at the influenza hemagglutinin head-stem interface via distinct binding modes

Influenza A virus continues to pose pandemic threats, as demonstrated by the recent global spread of highly pathogenic H5N1 strains. Consequently, the development and characterization of vaccines targeting zoonotic influenza subtypes have become a major focus of the field. In this study, we characterize two broadly reactive antibodies previously isolated from H5N1 vaccines. Although they have distinct immunoglobulin germline gene usage and binding modes, cryo-EM analysis shows that both antibodies share a highly conserved cryptic epitope at the interface of the hemagglutinin (HA) head and stem domains. The antigenicity of this epitope is influenced by natural amino acid variation at residue 293 of HA subunit 1, and its access is facilitated by acid-induced conformational change of HA. Nevertheless, both antibodies are non-neutralizing and possess only marginal protective efficacy against seasonal and H5N1 viruses in vivo, thus representing suboptimal vaccine responses. Overall, our findings expand the interactions of cross-reactive antibodies with an under-characterized HA epitope and provide insights for next-generation influenza vaccine design.

biochemistry↗

bioRxiv2026

Resilience of multispecies biofilm communities: Comparative analysis of a Veillonella dispar-dominant oral biofilm under diverse oxygen conditions in vitro

Oral multispecies biofilms developing on dental implants drive peri-implant mucositis and peri-implantitis. They are shaped by the physicochemical conditions of their surrounding environment, among which oxygen availability is an important influential factor. However, while oxygen tension fluctuates significantly within the peri-implant pocket, whether these environmental shifts are sufficient to influence the structure and composition of an established microbial community remains unclear. For this purpose, we evaluated the structure and composition of a four-species oral biofilm model comprising the species Streptococcus oralis, Actinomyces naeslundii, Veillonella dispar and Porphyromonas gingivalis, which was cultivated under normoxic (21% O2), hypoxic (1% O2) and anoxic (0% O2;) conditions for a period of 21 days. Biofilm 3D architecture, volume and membrane integrity was analyzed by LIVE/DEAD staining combined with confocal laser scanning microscopy. Community composition was assessed by quantitative real-time PCR and complemented by Fluorescence In Situ Hybridization (FISH) to provide structural context. While normoxia transiently promoted higher early biofilm volume and membrane integrity, the community exhibited remarkable long-term resilience, consistently maintaining a V. dispar-dominated structure across all oxygen gradients. Crucially, the obligate anaerobic pathogen P. gingivalis persisted as a viable minority (~1%) even under 21-day normoxic cultivation, sheltered within the deeper layers of the biofilm. These results suggest that clinical oxygen levels alone are not able to drastically modulate established oral biofilm communities and that oxygen-sensitive pathogens persist in a subclinical sanctuary protected by the surrounding non-pathogenic species.

microbiology↗

bioRxiv2026

Generative Access to Make-on-Demand Chemical Space Enables Ultra-Large Virtual Screening

Ultra-large-scale virtual screening (ULVS) increasingly relies on make-on-demand chemical spaces, but efficient access to these spaces remains challenging because their scale far exceeds what can be exhaustively enumerated and docked. Here, we present REAL-SWIT, a generative ULVS framework that learns Enamine REAL Space as a synthesizable molecular distribution and couples this generator with a target-specific scoring model to enable docking-guided exploration of REAL Space at the level of complete molecule. The generative model learned transferable features of the REAL Space distribution: approximately 96% of generated molecules were found in REAL Space, and a subset of generated molecules absent from the training release appeared in later expanded releases. In computational benchmarks, REAL-SWIT identified more molecules with favorable docking scores than representative fragment-based search strategies, including cooperative building-block combinations that fragment-level prioritization tended to miss. Experimental validation for ROCK1 yielded six biochemical inhibitors among 23 synthesized compounds, including RX-3 with an IC50 of 0.17 M. These results establish generative access to make-on-demand chemical space as a practical strategy for ULVS.

bioinformatics↗

bioRxiv2026

Phosphoregulation of hierarchical protein condensate formation during clathrin-mediated endocytosis

The sequential assembly of over 50 proteins during clathrin-mediated endocytosis (CME) is well documented in yeast. However, the mechanisms governing this ordered recruitment remain poorly understood. Biomolecular condensation is proposed to orchestrate CME, but defining biophysical parameters in vivo remains challenging. Here, we developed a quantitative in vivo titration strategy to systematically determine CME protein assembly profiles. Beyond the previously reported Ede1 (yeast Eps15), seven additional proteins formed enlarged, concentration-dependent assemblies with distinct biophysical properties. Single-cell profiling revealed two biophysical classes among these eight proteins: homeostatic buffers with defined saturation boundaries and continuous assemblers that scale linearly. Acting as scaffolds and clients, these conserved proteins form an interconnected network of kinases, phosphatase recruiters, and substrates. Within this network, reversible phosphorylation modulates assembly stability to drive recruitment transitions. Collectively, this work establishes a two-stage model of protein condensation that drives CME progression from initiation to maturation and offers a general framework for how protein phosphorylation dynamically modulates biomolecular condensation in vivo.

cell biology↗

bioRxiv2026

High-order enhancer hubs buffer allelic regulatory variation through kinetic compensation

Diploid genomes carry millions of heterozygous variants in cis-regulatory DNA, yet most genes produce similar RNA output from two parental alleles. How this balance is maintained is unclear. We developed Nanopore-HiChIP, a long-read method that maps high-order enhancer hubs on each haplotype. Over half of these enhancer hubs differ in chromatin architecture and transcription-factor occupancy between homologous chromosomes, but their target genes show substantially lower rates of allele-specific expression than genes lacking hub regulation. Single-cell kinetic modeling shows that burst frequency and burst size change in opposite directions, thereby preserving balanced transcriptional output. This hub-mediated kinetic buffering is enriched at haploinsufficient genes and coincides with smaller effects of expression quantitative trait loci. Enhancer hubs therefore absorb allelic regulatory variation through kinetic compensation, protecting dosage-sensitive transcription.

genomics↗

bioRxiv2026

GPR182 promotes atherosclerosis via facilitating arterial lipid deposition

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for atherosclerosis; however, the molecular mechanisms underlying lipid plaque formation within the artery wall remain poorly understood. Here, we identify GPR182, a recently characterized lipoprotein receptor of the atypical chemokine receptor family, as a key mediator of lipid deposition in the aortic endothelium during atherosclerosis. Genetic depletion of GPR182 protects against atherosclerosis across multiple mouse models without altering circulating cholesterol levels or immune cell recruitment to plaques. GPR182 is expressed by aortic endothelial cells (ECs) and is further upregulated during disease progression. GPR182 mediates LDL uptake by aortic ECs both in vitro and in vivo. Blockade of GPR182 with a monoclonal antibody reduces lipid uptake in the aorta and attenuates disease progression under hypercholesterolemic conditions. Collectively, these findings identify endothelial GPR182 as a critical regulator of aortic lipid deposition and atherosclerotic plaque formation and support GPR182 inhibition as a promising therapy for atherosclerotic cardiovascular disease.

molecular biology↗

bioRxiv2026

A lifespan-scale single-cell atlas defines an early-childhood immunometabolic transition linked to age-referenced immune states

Childhood represents a critical period with rapid metabolic and immune remodeling, during which perturbations may have lasting consequences for health. We integrated single-cell RNA sequencing (scRNA-seq) profiles of peripheral blood mononuclear cells (PBMCs) from 2,008 healthy individuals aged 0-100 years. Age-resolved modeling highlighted an early-childhood transition centered at age 6, characterized by coordinated remodeling of metabolism-related transcriptional programs, particularly in monocyte and B-lineage cells. Matched serum metabolomics and lipidomics in a pediatric subcohort detected a temporally concordant wave of metabolite and lipid changes around ages 6-8 and extensive metabolite/lipid-transcript associations, prominently involving steroid and phospholipid species. Building on these findings, we developed an immunometabolic transition score and age-specific reference chart, which were evaluated in an independent healthy cohort and applied to quantify deviations in pediatric immune disorders. These findings highlight a coordinated immunometabolic transition in early childhood and provide an age-referenced framework for distinguishing atypical immune-state variation from healthy age-associated variation.

immunology↗

bioRxiv2026

A self-limiting dimeric TIR effector specialised for type III CRISPR-mediated immunity

Antiviral defence systems frequently utilise cyclic nucleotide second messengers. A prominent example is the type III CRISPR-Cas system, which generates cyclic oligoadenylates (cOA) on detecting viral RNA. cOA molecules can bind and activate a wide range of effectors to provide antiviral defence. In both prokaryotes and higher plants, activation of a catalytic Toll/Interleukin Receptor (TIR) domain by multimerization results in degradation of NAD+, limiting cell metabolism and thus viral replication. Here, we describe a CRISPR-associated TIR-containing effector that includes a SAVED (SMODS-associated and fused to various effector domains) domain for nucleotide sensing and a cOA-degrading ring nuclease Crn4 domain. We demonstrate that the TIR-SAVED-Ring nuclease (TSR1) effector binds cA3, resulting in activation of the TIR NADase activity. The Crn4 domain, which imposes an unusual dimeric quaternary structure on the effector, degrades cA3, providing a mechanism to auto-deactivate the effector. TSR1 is thus a highly unusual example of a dimeric and self-limiting TIR effector in antiviral immunity.

microbiology↗

bioRxiv2026

An Artificial Intelligence Model for Longitudinal Assessment of TCR Repertoires in SARS-CoV-2 Vaccine Recipients

T cells play a crucial role in reducing disease severity during SARS-CoV-2 infection and in shaping long-term immune memory. However, the precise molecular immune responses, particularly involving T-cell receptor (TCR) repertoire changes after full vaccination, and the use of TCR analysis to evaluate vaccine efficacy, remain incompletely understood. In this study, we developed the DeepAir-Cov19 model (AUC=0.94), a large language model tailored to identify SARS-CoV-2-specific TCRs, and observed significant differences in the TCR profiles between antibody-negative and antibody-positive populations before and after vaccination, indicating that the immune status of pre-vaccine recipients can directly assess the efficacy of vaccination. Notably, SARS-CoV-2-specific TCRs expanded to peak levels after the second dose and remained detectable in most subjects up to 10 months post-vaccination. Meanwhile, we also identified three specific V genes, 20 V-J combinations, and 3 epitopes associated with these responses. Finally, by leveraging vaccine-specific TCRs as novel biomarkers, we developed a vaccine efficacy model that predicts antibody levels with a mean AUC of 0.96. These findings underscore the accuracy of the large model in predicting SARS-CoV-2-specific TCRs and reveal a strong correlation between SARS-CoV-2-specific TCR responses and antibody levels. This highlights the complementary and synergistic roles of T cells and antibodies in providing vaccine-mediated protection. Our results offer valuable insights into the longitudinal dynamics of SARS-CoV-2-specific TCRs and illustrate the potential for developing potency evaluation models based on these TCR insights.

bioinformatics↗

bioRxiv2026

Shigella flexneri undergoes niche-specific adaptation during infection

Shigella flexneri is a leading cause of diarrheal disease worldwide, yet bacterial factors required within distinct host niches remain poorly understood. Here, we used genome-wide transposon sequencing in an infant rabbit model of shigellosis to identify genes promoting bacterial fitness in vivo. The screen identified virulence factors on the large virulence plasmid and novel chromosomal fitness factors. Characterization of zitB, encoding a cation diffusion facilitator family Zn transporter, revealed a niche-specific fitness contribution. The {Delta}zitB mutant showed no growth defect in vitro in rich media or in vivo during the early infection phase (8 hpi) in epithelial cells. However, bacterial burden was reduced during the late infection phase (24 hpi) in vivo, when bacteria interact with immune cells, in both competitive and mono-infection assays. Reduced bacterial burden was associated with increased MARCO-specific macrophages, suggesting impaired colonization and killing by the {Delta}zitB mutant. Consistently, {Delta}zitB fitness was impaired in THP-1-derived macrophages. Metal chelation increased bacterial burden, indicating a role for macrophage-mediated metal toxicity. The {Delta}zitB mutant also showed increased sensitivity to zinc and copper. Finally, macrophage depletion in vivo restored bacterial burden to wild-type levels. Together, these findings identify ZitB as a niche-specific bacterial factor promoting S. flexneri fitness during macrophage-associated metal stress.

microbiology↗

bioRxiv2026

A bispecific antibody targeting a membrane-proximal ASGPR1 region promotes TNF-α recruitment and uptake

Abstract Recruiting an endocytic receptor through an antibody offers a route to redirect extracellular cytokines into cells. Here, we developed BiAb J31, an IgG like bispecific antibody linking TNF recognition to a membrane-proximal region of asialoglycoprotein receptor 1 (ASGPR1). J31 was isolated by immunization with an engineered ASGPR1 extracellular domain followed by screening against wild-type ASGPR1 and HepG2 cells. Its variable domains were combined with unmodified adalimumab variable regions using knobs into holes and CrossMab engineering, with L234A/L235A/P329G Fc substitutions. BiAb J31 retained HepG2 binding and engaged both antigens in bridging assays. Sequential binding experiments demonstrated recruitment of TNF to BiAb J31 treated cells. Live cell imaging showed uptake of fluorescent antibody-containing complexes and overlap with LysoTracker-positive compartments. In HepG2 cultures containing BiAb J31, TNF and a PE conjugated detection antibody, supernatant PE fluorescence fell by approximately 60% over 90 minutes. Truncation and synthetic-peptide assays localized J31 recognition to ASGPR1 residues 62~100, outside the carbohydrate-recognition domain, and AlphaFold 3 modeling proposed an Fv peptide interface. These findings identify a membrane-proximal ASGPR1 binding antibody that is compatible with bispecific engineering and supports cellular recruitment and uptake of TNF containing complexes. BiAb J31 provides a molecular starting point for antibody based cytokine redirecting approaches.

immunology↗

bioRxiv2026

Division-Specific Organization of a Shared Functional Scaffold in the Early-Life Human Brain

Early cognition and behavior emerge from coordinated maturation of functional systems spanning the brain, making cross-division integration essential for defining whole-brain architecture and understanding its role in neurodevelopment. Yet early human functional development is still largely investigated through cortical networks or through isolated, coarsely resolved noncortical structures, leaving unclear how this integrated architecture is organized across the cerebral cortex, subcortex and cerebellum. Moving beyond structure-isolated and adult-derived maps, we create a reproducible, fine-grained Early-Life Whole-Brain Functional Parcellation (UNC-ELF) spanning birth to six years. Using this framework, we identify a shared functional scaffold expressed through distinct division-specific modes: differentiated and dual-polarity cortical organization, spatially graded cerebellar organization with blended functional transition zones, and nucleus-constrained subcortical mosaics of multi-system affiliation. Across early childhood, the scaffold is selectively refined through heterogeneous, nonlinear connectivity trajectories, with major inflections concentrated in infancy. Age-, sex- and prospective cognition-related variation is differentially encoded across distinct connectomic components. Together, these findings reframe early functional brain development as coordinated refinement of a shared but nonuniform whole-brain scaffold and establish UNC-ELF as a unified reference for resolving typical and atypical functional organization across the developing brain.

neuroscience↗

bioRxiv2026

LucaCell: a sequence-centric foundation model for cross-species single-cell analysis

Single-cell foundation models have transformed transcriptomic analysis, yet most rely on fixed gene identifiers that limit transfer across species and data types. Here we present LucaCell, a sequence-centric foundation model that represents genes through pre-trained mRNA sequence embeddings rather than static gene annotations. Gene expression is discretized into bins and modeled with a Transformer encoder, enabling sequence-informed cell representation without a fixed gene-ID vocabulary. Pre-training on 85 million human and mouse single cells, LucaCell is evaluated on human, mouse and lemur gene expression profiles, human chromatin accessibility data, unaligned reads from more than 50 prokaryotic taxa, and five influenza A virus genomes. LucaCell enables manual-mapping-free cross-species cell type annotation and an alignment-free microbial embedding framework that simultaneously distinguishes bacterial species identity and intra-species physiological states. It also improves gene expression reconstruction by incorporating donor-specific exonic SNP information into mRNA sequence embeddings, and predicts cellular viral load across influenza A virus strains while highlighting infection-like transcriptional states in mock-infected cells. These results show that sequence-informed gene representation can improve the generalization of single-cell foundation models across species, data types, and predictive tasks.

bioinformatics↗