Biology subjects

Yang, H.

Publications and source records attributed to Yang, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Ileitis abolishes tolerogenic functions of the enterohepatic bile acid pool

Bile acids (BAs) regulate lipid uptake, epithelial integrity, and immune responses in the gut. Hepatocytes synthesize primary BAs, which microbiota metabolize into secondary metabolites. Together, these species form a composite pool that circulates enterohepatically between the liver and intestines. Here, we show that immunoregulatory outputs of the enterohepatic BA pools involve competition between multiple BA species for individual nuclear receptors and are dependent on intestinal health. In healthy mice, the primary BA, tauro {beta} muricholic acid (t{beta}MCA) antagonized ROR{gamma}t-mediated Th17 function in the presence of two secondary BAs (tDCA, tLCA) which activated ROR{gamma}t. Conversely, ileitis in Crohns disease patients and Tnf{delta}ARE mice depleted primary BAs by reducing the number and function of BA transporting enterocytes. In mice, ileitis driven t{beta}MCA depletion enhanced tDCA and tLCA mediated ROR{gamma}t activation and supported Th17 cell function. Replenishing t{beta}MCA in Tnf{delta}ARE mice reestablished BA dependent Th17 cell regulation. Thus, intra pool competition underpins BA immunoregulatory functions and reveals new opportunities for precision Crohns disease therapy.

immunology↗

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↗

bioRxiv2026

CynoBrain: A unified high-resolution framework for cross-modal data integration for macaque brain mapping

The cynomolgus macaque is a widely used primate model in neuroscience, yet existing brain atlas resources remain limited in resolution and lack a standardized framework for integrating structural, molecular, and connectivity data within a common reference space. Here we present CynoBrain, a high-resolution multi-modal brain atlas constructed from population-averaged MRI data at 9.4 Tesla, yielding a 75 micron isotropic template with significant improvement in resolution. A co-registered whole-brain autofluorescence template resolves cytoarchitectural boundaries not visible in MRI template. Three major parcellation schemes, D99 143-area, M132 105-area, and SARM are incorporated in CynoBrain space. Spatial transcriptomic based laminar definition, reconstructed from 2D sections into volumetric common space, provides a six-layer cortical segmentation spanning the whole cortex. As a demonstration of the integrative capability of this framework, 2D retrograde tracing data is reconstructed and mapped to the Cynobrain space, enabling volumetric compilation of 2D macaque brain mapping data across subjects. An online interactive platform was constructed to allow full access to Cynobrain, establishing it as a scalable, open platform for cross-modal data integration for primate neuroscience. Overall, CynoBrain is a unified framework for cross-modal data integration for macaque brain mapping with high-resolution, multiple atlases and transcriptomic based laminar definition.

neuroscience↗

bioRxiv2026

Manganese availability determines insulin sensitivity by enhancing Akt activity

Insulin signaling is a critical determinant of metabolic health, and impairments in insulin action contribute to the development of type 2 diabetes. The kinase Akt is a central mediator of insulin signaling and is required for insulin's suppression of hepatic glucose output. Although the regulation of Akt by the insulin receptor-PI3K pathway is well understood, there are instances in which signaling downstream of Akt is dissociated from proximal insulin signaling, for example in insulin resistance. Nonetheless, little is known about PI3K-independent mechanisms of Akt regulation. Here, we discovered that hepatocyte manganese concentrations are a key determinant of PI3K-independent Akt function in vivo. We further demonstrated that manganese increases Akt's catalytic efficiency, and quantitative phosphoproteomics revealed that manganese and insulin act additively to enhance Akt activity. Moreover, we uncovered that hepatic manganese concentrations fluctuate during fasting and feeding via carbohydrate-dependent transcriptional regulation of the manganese efflux transporter Slc30a10. This dynamic metal-signaling axis provides a mechanistic link between nutrient status and Akt activation, and suggests a molecular explanation for the glucose-lowering effects of manganese observed in humans. Our findings establish manganese as a physiologically regulated cofactor for Akt and position metal bioavailability as a previously unrecognized layer of insulin signaling control.

physiology↗

bioRxiv2026

Half-match recombination drives bridge RNA-guided excision and off-target insertion

IS110-family bridge recombinases are a recently identified class of compact, RNA-guided editors in which a bridge RNA (bRNA) directs the recombination of a donor DNA into a target site. In the current model, the bRNA engages fully complementary donor and target sequences within a single synaptic complex to drive double-stranded recombination, implying that the transposon is cut from its donor site rather than copied, yet neither the strandedness of the excised intermediate nor the requirement for full complementarity has been tested directly. Here we reconstituted IS621 recombination in a cell-free transcription-translation system, building representative arrangements of the excision and insertion reactions and characterizing the outcomes. We find that IS621 predominantly excises a single strand, releasing a single-stranded circle and leaving the donor site intact, consistent with copy-and-paste transposition. By introducing mismatches into the bRNA target sequences, we further find that excision proceeds independently of target-site complementarity, relying strictly on donor-arm recognition; we term this "half-match" recombination, because a substrate matching only half of the bRNA is sufficient. We also find half-match activity during insertion, both in vitro and in a published genome-editing experiment, where it accounts for approximately half of non-target insertion reads. Half-match recombination provides both a mechanistic explanation for off-target insertion and a framework for the rational design of high-fidelity bridge recombinases.

molecular biology↗

bioRxiv2026

TomatoPGFM: A graph-conditioned foundation model for tomato pangenomes

Most genomic foundation models are pretrained on independent linear assemblies and therefore do not explicitly represent population-level segment sharing or local graph connectivity. We developed TomatoPGFM, a graph-conditioned model pretrained on 54.65 Gb of sequence from 66 tomato (Solanum spp.) accessions. Sequence tokens were conditioned on pangenome node attributes and local adjacency, and the model was optimised using masked language modelling and graph-feature reconstruction. To evaluate model responses to graph-conditioned input, we compared aligned, shuffled and disabled graph inputs in 25,000 windows from the training panel. Sequence-aligned graph input produced lower masked language modelling loss than graph-off at all five curriculum stages in both training-panel strata, while the shuffled perturbation generally yielded intermediate losses. We then assessed sequence-only transfer in Solanum sitiens LA1974 and S. lycopersicum MicroTom, neither of which was used for graph construction or pretraining. Frozen-probe AUROC values for gene-versus-intergenic and coding-sequence-versus-intergenic classification ranged from 0.8489 to 0.9593. TomatoPGFM produced higher AUROC point estimates than DNABERT-2 in all four comparisons. Enabling the zero-feature GraphAdapter pathway with adjacency messaging disabled changed throughput by less than 1% at 512-2,048 positions under the tested configuration. Together, these results show that TomatoPGFM responds consistently to sequence-aligned pangenome context in training-panel sequences and provides informative sequence representations for genic-region classification in accessions excluded from graph construction and pretraining.

bioinformatics↗

bioRxiv2026

A multi-tissue epigenomic atlas links the sheep non-coding genome to domestication and complex traits

Non-coding regulatory variation drives complex traits, domestication, and evolutionary adaptation, yet the sheep genome lacks high-resolution functional annotation. Here we present SheepEpimap, a multi-tissue regulatory atlas harmonizing 516 CUT&Tag histone modifications, ATAC-seq, and RNA-seq datasets across 43 adult tissues in sheep. We annotated 2.93 million cis-regulatory elements, yielding 557,441 enhancer-gene pairs and 145,407 variants with allele-specific effects. By training a sequence-to-function deep-learning model, we decoded the base-pair syntax of chromatin accessibility, annotated transcription factor motif instances genome-wide, and constructed 12,210 tissue-specific gene regulatory networks (GRNs). Integrating this resource with multi-tissue expression quantitative trait loci, selection sweeps, and genome-wide association studies prioritized non-coding variants driving domestication and complex traits. Finally, cross-species analysis revealed that sequence-conserved, tissue-matched enhancers were significantly enriched in the heritability of complex traits and diseases in humans. In summary, SheepEpimap (https://genome.ucsc.edu/s/mengzhu/SheepEpimap) provides an open-access foundational ecosystem for sheep functional genomics, precision breeding, and comparative biology.

genetics↗

bioRxiv2026

Lipoproteins modulate the uptake and biological functionof cationic cell-penetrating peptides across the animal lineage.

Cationic cell-penetrating peptides (+CPPs) are pervasive killer peptides produced by all animals and found in innate immune systems, venoms and neurodegenerative diseases. Despite their ubiquity, the mechanisms underlying their uptake remain opaque and intensely debated. Here, we interrogate +CPPs spanning 600 million years of animal evolution and identify endocytosis as a conserved/convergent uptake mechanism across cell types and organisms, at physiological concentrations. By combining multiplex imaging, genetic screening, cryo-electron tomography, and biophysical methods, we uncover that +CPPs seemingly universally enter eukaryote cells via 'hitchhiking' on lipoproteins. We further show that the interaction of +CPPs with lipoproteins modulates their antimicrobial function. Combined, our findings establish a unified molecular framework describing a pan-eukaryote cell penetrance mechanism. As hyperlipidemia is a common comorbidity, our findings have direct implications for human health. Lastly, the insights gleaned from this work highlight design principles that may inform the future engineering of peptide-based therapeutics and delivery vehicles.

cell biology↗

bioRxiv2026

Canonically minimal RNA-guided insertion sequences expand into large elements that disseminate antimicrobial resistance

IS110 has emerged as a powerful genome-editing tool because it is the smallest RNA-guided system capable of diverse programmable insertions. Naturally existing elements are conventionally modeled as compact[~] 1.5-kb systems comprising a single transposase and a bridge RNA (bRNA). Using high-throughput junction mapping together with large-scale comparative genomics, we redefined the in vivo structural boundaries, growth, and mobilization of IS110 elements. We uncovered a previously unrecognized size continuum extending to[~] 100 kb, driven by progressive local expansion, with expanded loci being widespread across bacterial genomes. Experiments confirmed the activity of natural IS110s both well below and above the size range of previously characterized elements. These large systems preferentially accumulate adaptive cargo, including antimicrobial resistance determinants and heavy-metal detoxification systems, and are strongly enriched for plasmid-derived DNA. Boundary configurations at expanded loci and the range of partial excision intermediates they produce both indicate flexible sequence recognition by IS110, most commonly through half-matches between the bRNA and complementary DNA sequence. This sequence tolerance allows loci to expand with diverse cargo. Together, these findings redefine IS110 from a compact insertion sequence into a dynamic platform that disseminates adaptive cargo.

microbiology↗

bioRxiv2026

An intact primordial interferon antiviral signalling network in amphioxus illuminates the basal chordate origin of vertebrate IFN immunity

The evolutionary origin of the complete interferon (IFN) antiviral signalling cascade across chordates has long remained elusive, as fully functional IFN machinery had not been biochemically reconstituted in basal cephalochordates. Here we combine phylogenetics, AlphaFold3 structural prediction, multi-omic profiling and a full panel of in vitro and in vivo functional assays to characterize an intact primordial IFN network in amphioxus Branchiostoma japonicum, the extant sister group of all vertebrates. Amphioxus encodes a pair of undifferentiated BjTBK1/IKK{varepsilon} paralogs that form cytoplasmic heterodimers, whose conserved kinase-domain phosphorylation residues are mandatory for downstream IRF-driven IFN promoter activation. Despite minimal primary sequence homology with vertebrate IFNs, BjIFN1/2 possess compact -helical core folds that hint at potential structural analogy to vertebrate mucosal type III IFN-{lambda}. We identify two primitive class II cytokine receptors BjCRFB1 and BjCRFB2 that act as functional IFN sensors. Phylogenetic and tertiary structural validations confirm these undiversified ancestral receptor prototypes arose before vertebrate IFN receptor subfunctionalization, and their distinct temporal induction profiles upon viral challenge closely mirror the mucosal immune surveillance orchestrated by vertebrate IFN-{lambda}-IFNLR signalling. AlphaFold3 ligand-receptor docking identifies BjIFN2-BjCRFB2 as the optimal binding pair among all tested combinations, yet all modelled complexes yield low interface scores indicative of weak ancestral intermolecular interactions. Downstream signal transduction relies on two STAT paralogs, BjSTATa and BjSTATb, which jointly mediate transcriptional activation of core antiviral effector genes. The conserved GTPase BjMx serves as a central IFN-stimulated effector to suppress viral replication and maintain tissue immune homeostasis. Collectively, our structural and functional evidence demonstrates that the full hierarchical IFN signalling apparatus was fully assembled in basal cephalochordates prior to vertebrate radiation. The amphioxus IFN cascade preserves core ancestral molecular traits including structure-dependent ligand conservation and primitive low-affinity ligand-receptor interactions. This study resolves a long-standing evolutionary gap and provides definitive functional evidence demonstrating that IFN-mediated innate immunity constitutes an ancestral chordate trait, rather than a vertebrate-specific evolutionary innovation. It also puts forward the hypothesis that mucosal surveillance may represent the ancestral mode of chordate IFN defence.

evolutionary biology↗

bioRxiv2026

An AI System for Autonomous Algorithm Evolution in Drug Development

Artificial intelligence (AI) is increasingly permeating the drug development pipeline. Numerous algorithms for accelerating this multi-stage and multi-task process have been constructed, which depends heavily on expert design and labor-intensive task-specific optimization. Given that AI-driven acceleration of drug development is recognized as a cumulative, often synergistic, effect across multiple stages, the autonomous evolution of existing algorithms across the entire pipeline is demanded to achieve a holistic advancement. Here, we present DrugEvolve, a multi-role large language model system for systematic and autonomous algorithm evolution in drug development. DrugEvolve realizes a closed-loop evolution process by incorporating Researcher, Engineer, and Analyst domains, and enables an iterative design, implementation, evaluation, and refinement of algorithm by leveraging scientific knowledge and accumulated evolutionary experience. Across eleven representative tasks spanning target identification, drug discovery, preclinical study, and clinical trial, DrugEvolve autonomously evolved the corresponding task-specific algorithms and achieved substantial performance enhancement on 120 benchmark test sets. Moreover, it showed robust generalizabilities across heterogeneous data modalities (ranging from biological sequence and graph to molecular topology and textual language), and realized gains in both predictive and generative tasks. Collectively, this AI system can serve not only as an algorithmic infrastructure for drug development, but also as a transferable paradigm for broader scientific domains.

pharmacology and toxicology↗

bioRxiv2026

The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells

Circulating tumor cells (CTCs) encounter multiple challenges within the blood microenvironment, including oxidative stress, flow shear forces, and immune surveillance, often leading to anoikis. Recently, a transitional state of CTC senescence has been identified, contributing to metastatic inefficiency. However, the molecular mechanisms linking senescent CTCs to disease relapse remain to be defined. By integrating a genetic model of cortactin knockdown-induced CTC senescence with single-cell multi-omic analyses, we revealed two distinct senescent CTC subpopulations marked by HES1 expression levels. These HES1low and HES1high subpopulations exhibited differential evolutionary trajectory dynamics and unique molecular and metabolic signatures, which were significantly correlated with adverse clinical outcome across several patient cohorts. HES1low senescent CTCs displayed enhanced mitochondrial fitness, oxidative phosphorylation, and ROS-detoxifying capabilities, resulting in more efficient tumor regrowth with a pro-inflammatory and thrombotic phenotype when compared to the HES1high group. Mechanistically, HES1 directly bound to the Sod1 promoter and repressed its expression, leading to redox imbalance and mitochondrial dysfunction that were linked to weakened tumor regrowth capacity. Both senescent CTC subpopulations were broadly resistant to cytotoxic and targeted therapies, yet they showed elevated dependency on anti-apoptosis programs that make them susceptible to dual blockade by SOD1 inhibitor and the anti-senolytic drug ABT737 in vivo. Finally, in a prospective cohort of on-treatment melanoma patients, HES1 senescent CTCs were highly enriched in patients with progressive disease. Thus, the HES1-SOD1 antagonism shapes CTC senescence heterogeneity and contributes to differential tumor relapse, which can be therapeutically explored for eliminating residual metastatic disease.

cancer biology↗

bioRxiv2026

APOBEC3G Splicing Defects in Nonhuman Primate Models Result in Disparate Viral Mutational Profiles Relative to Humans

Nonhuman primates (NHPs), particularly macaques, are indispensable models for studying human infectious diseases due to their close immunological and physiological similarities. Understanding species-specific molecular differences is essential for maximizing the translational value of these models. Here we report that APOBEC3G (A3G), a potent antiviral restriction factor and the major source of genetic variations in HIV, exhibits a widespread mRNA splicing defect in the Cercopithecinae subfamily, which includes the commonly used NHP models. Driven by intronic polymorphisms, this splicing defect substantially reduces A3G protein levels and consequently results in a markedly reduced A3G-mediated mutation signatures, fewer defective viral genomes, and greater viral diversification in SIV compared to HIV. This species-specific effect is not restricted to lentiviruses: reduced A3G signatures have also been reported in simian foamy virus and simian T-cell leukemia virus, suggesting broader effects across primate retroviruses. These findings reveal a lineage-specific alteration in a major antiviral restriction factor, with important implications for viral restriction, evolution, drug resistance, and immune evasion. They also highlight the importance of incorporating naturally occurring genetic variation into NHP model selection to improve the reproducibility, translational fidelity, and biological relevance of preclinical research.

genomics↗

bioRxiv2026

SAMHD1 enhances HIV-1-induced glycolysis in monocytic cells through hexokinase 2 upregulation

SAMHD1 is a mitochondria-associated cellular protein that restricts HIV-1 replication by depleting intracellular dNTP pools in non-dividing immune cells, such as macrophages, dendritic cells, and resting CD4+ T cells; however, its role in host metabolism remains unclear. Building on our previous finding that SAMHD1 promotes mitochondrial membrane damage in HIV-1-infected monocytic cells, here we identify a new function for SAMHD1 in enhancing HIV-1-induced glycolysis through upregulation of hexokinase 2 (HK2). In monocytic THP-1 cells, but not differentiated macrophage-like cells, SAMHD1 amplifies HIV-1-triggered glucose uptake and basal glycolysis. Mechanistically, SAMHD1 increases HK2 expression and promotes its cytosolic accumulation, leading to elevated reactive oxygen species (ROS) production. This SAMHD1-dependent metabolic rewiring links antiviral restriction to glycolytic control and cellular stress responses. Our findings reveal a cell state-specific role for SAMHD1 in regulating glycolysis during HIV-1 infection, identify HK2 as a key effector, and uncover an unanticipated layer of host-virus interaction in monocytic cells. IMPORTANCESAMHD1 is best known as a restriction factor that inhibits HIV-1 replication mainly through its dNTPase activity. However, emerging evidence suggests that SAMHD1 also regulates mitochondrial homeostasis and cellular metabolism. We previously demonstrated that SAMHD1 promotes HIV-1-induced apoptosis in monocytic cells through a mitochondrial pathway, implicating SAMHD1 in the control of mitochondrial function during infection. Because mitochondria are central regulators of cellular energy metabolism, we investigated whether SAMHD1 influences glycolytic reprogramming in HIV-1-infected monocytic cells. Our results show that SAMHD1 enhances glucose uptake, glycolysis, HK2 expression, and ROS production during HIV-1 infection. These findings reveal a previously unrecognized role for SAMHD1 in coordinating metabolic and oxidative stress responses to HIV-1 infection and provide new mechanistic insight into the interplay between antiviral factors, cellular metabolism, and HIV-1 pathogenesis. Understanding how SAMHD1 regulates glucose metabolism may uncover novel links between innate immune defenses and metabolic disease.

microbiology↗

bioRxiv2026

Repurposing the Antiviral Agent Pibrentasvir: In Vitro Synergistic Effects in Combination with Different Azole Antifungal Agents

ObjectiveTo investigate the combined effects of multiple drugs and provide more therapeutic options for invasive fungal infections, this study evaluated the in vitro susceptibility of Aspergillus spp., Candida auris, Cryptococcus neoformans, and Exophiala dermatitidis to pibrentasvir (PIB) in combination with itraconazole (ITR), voriconazole (VOR), posaconazole (POS), or fluconazole (FLU). MethodsAccording to the M27-A3 and M38-A2 guidelines established by the Clinical and Laboratory Standards Institute (CLSI), the in vitro antifungal activities of PIB combined with ITR, VOR, POS, or FLU against 78 clinical isolates, including Aspergillus spp., E. dermatitidis, C. auris, and C. neoformans, were determined. The minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indices (FICIs) were calculated to evaluate the synergistic effects. ResultsPIB alone exhibited no antifungal activity. Significant synergistic effects were observed when PIB was combined with azole antifungal agents. The PIB-POS combination showed synergistic effects against Aspergillus spp. (27/41, 65.90%), C. auris (9/10, 90.00%), C. neoformans (2/9, 22.20%), and E. dermatitidis (11/18, 61.11%). The PIB-ITR combination also showed synergistic effects against Aspergillus spp. (18/41, 43.9%), C. auris (9/10, 90.0%), C. neoformans (2/9, 22.2%), and E. dermatitidis (10/18, 55.5%). Synergistic effects were less frequently observed with the PIB-VOR or PIB-FLU combinations, and no antagonistic effects were observed. ConclusionThis study demonstrates that PIB acts as an azole sensitizer, with the strongest synergistic effects observed when combined with POS or ITR, providing a new research direction for combination therapy against invasive fungal infections.

microbiology↗

bioRxiv2026

Modular counterplays shape condensation and signaling of chimeric antigen receptor

Chimeric antigen receptor-engineered T (CAR T) cell therapy has achieved remarkable clinical efficacy against hematological malignancies but exhibits limited therapeutic outcomes in solid tumors, where immune checkpoint signaling is highly active. Here, we demonstrate that the second-generation CD28-CD3{zeta} (28Z) CAR undergoes liquid-liquid phase separation with the Src-family kinase LCK to assemble a signaling condensate crucial for CAR activation. PD-1, but not LAG3 or CTLA4, disrupts these CAR-LCK condensates through competitive binding to CAR rather than through its canonical phosphotase-dependent inhibitory pathway. Incorporation of a CD3{varepsilon} cytoplasmic module into the CAR introduces additional LCK interactions that reinforce CAR-LCK condensation, thus limited PD-1 incorporation and stabilize signalosome assembly. Consequently, the CD3{varepsilon}-engineered CAR (E-CAR) resists PD-1-mediated condensates disassembly, preserves immunological synapse organization, and sustains proximal signaling following PD-L1 engagement. E-CAR T cells are therefore resistant to PD-1-mediated functional suppression and maintain potent antitumor activity against PD-L1-positive solid tumors. Together, these findings identify disruption of CAR signaling condensates as a previously unrecognized mechanism of PD-1-mediated inhibition and establish CD3{varepsilon} modular signalosome engineering as a rational engineering strategy to overcome immune checkpoint suppression.

immunology↗

bioRxiv2026

Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.

cancer biology↗

bioRxiv2026

Chromatin state shapes site-specific A-to-I RNA editing

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism that diversifies the transcriptome. While ADAR enzymes catalyze this reaction, the upstream mechanisms that determine why individual adenosines are edited at markedly different efficiencies remain poorly understood. Here, we integrated multi-omics datasets from human cell lines and mouse embryonic tissues and developed machine learning models that distinguish high-and low-frequency editing sites based on local epigenetic features. Across species, tissues, and developmental stages, H3K36me3 consistently emerges as the strongest negative predictor of editing frequency, whereas the histone variant H2A.Z.1 shows a positive association. Functional validations in H2AFZ-knockdown cells reveal that H2A.Z.1 preferentially facilitates editing at high-frequency sites (76.3% of sites decreased, mean {Delta} =-0.07), whereas SETD2-knockout-mediated loss of H3K36me3 selectively derepresses editing at low-frequency sites (86.9% upregulated, [~]2.7-fold increase). These findings establish chromatin state as an upstream regulatory layer that modulates RNA editing independently of editing enzyme abundance and reveal opposing roles for H3K36me3 and H2A.Z.1 in shaping RNA editing landscapes. Together, our study provides a conceptual framework linking epigenetic regulation to post-transcriptional RNA modification, suggesting that chromatin-mediated regulation contributes to the establishment of site-specific RNA editing programs across mammalian genomes.

genetics↗