Biology subjects

Yoon, S.

Publications and source records attributed to Yoon, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Epigenetic regulation of DPP4 receptor expression by NONO enables replication of MERS-CoV

Middle East respiratory syndrome coronavirus (MERS-CoV), first reported in 2012, belongs to the Betacoronavirus genus, including SARS-CoV and SARS-CoV-2. Human-to-human transmission of MERS-CoV appears inefficient, but repeated spillover events have been reported from at least 27 countries, raising concern for future emergent events. Coronaviruses (CoVs) rely extensively on host proteins to support their replication. Several studies have implicated the paraspeckle non-POU domain-containing octamer-binding protein (NONO) as an RNA-binding protein (RBP) that binds to CoV genomes, but the role of this protein in regulating replication is unknown. Here, we show that NONO is required for expression of dipeptidyl peptidase 4 (DPP4, also known as CD26), the major cellular receptor required for MERS-CoV attachment and entry. NONO did not impact DPP4 mRNA processing or stability but instead promoted DPP4 transcription through control of active H3K4me3 and repressive H3K27me3 histone modifications at the DPP4 locus. Together, these findings identify NONO as a key proviral host factor for MERS-CoV and reveal an epigenetic mechanism linking a host RBP to viral entry receptor expression that may represent a target for therapeutic strategies.

microbiology↗

bioRxiv2026

Extracellular Vesicles Derived from L-MYC Neural Stem Cells Mediate Neuroprotection in 3D Models of Chemotherapy- and Radiation-Induced Neurotoxicity

Background/Objectives: Cancer survivors frequently experience long-term neurocognitive impairments following chemotherapy and cranial irradiation, yet experimental models that enable mechanistic investigation of therapy-induced neurotoxicity at the transcriptional level remain limited. This study aimed to develop a human three-dimensional (3D) neural tissue model derived from L-Myc immortalized neural stem cells (LMNSCs) and use transcriptomic profiling to identify molecular pathways underlying chemotherapy- and radiation-induced neural injury and extracellular vesicle (EV)-mediated recovery. Methods: LMNSCs were differentiated in a 3D, methylcellulose-based culture to generate neural tissue containing neurons, astrocytes, and oligodendrocytes. Cultures were exposed to methotrexate (MTX) or ionizing radiation to induce neural injury and subsequently treated with LMNSC-derived EVs. Neural injury and repair mechanisms were evaluated by immunocytochemistry and bulk transcriptomics. Results: MTX and irradiation induced dose-dependent injury, exhibited by loss of neuronal complexity and reduced glial populations. LMNSC-EV treatment promoted recovery of neuronal and glial populations following MTX- and irradiation-induced injury. Transcriptomic analysis of irradiated cultures revealed activation of inflammation, DNA damage, and stress-response pathways, which were attenuated after treatment with LMNSC-EVs. Conclusions: LMNSC-based 3D neural tissue provides a human-relevant platform for modeling cancer therapy-induced neurotoxicity. Furthermore, LMNSC-EVs represent a promising cell-free regenerative therapeutic that restores injury-associated inflammatory, stress, and metabol-ic transcriptional programs after radiation-induced neural injury.

cancer biology↗

bioRxiv2026

The paraspeckle protein NONO potentiates the antiviral innate immune response through chromatin regulation

Type-I interferons (IFN-I) and IFN-stimulated genes (ISGs) are central to antiviral defense, while dysregulation can drive autoimmunity. IFNB1 expression is controlled by a highly ordered multiprotein complex composed of IRF3/7, NF{kappa}B, and ATF2/c-Jun (AP-1) that recruit coactivators and chromatin-remodeling proteins to expose the IFNB1 promoter for the RNA polymerase II (RNA Pol II) transcriptional machinery. Here, we identified the paraspeckle protein non-POU domain-containing octamer-binding protein (NONO) as a critical facilitator of innate immune activation. Loss of NONO enhanced replication of multiple orthoflaviviruses including West Nile virus due to impaired induction of IFN-I and ISGs. NONO did not affect upstream signaling but instead promoted chromatin accessibility and promoter access for RNA Pol II to drive expression of IFNB1, ISGs, and proinflammatory cytokines. These findings position NONO as a key regulator of antiviral gene expression and reveal chromatin-levels of control that determine effective antiviral immunity.

immunology↗

bioRxiv2026

An overlooked microbial pathway links organic nitrogen turnover in composts to nitrous oxide formation

Biological N2O production from organic nitrogen is generally assumed to require canonical nitrification, which generates oxidized nitrogen that subsequently fuel denitrification. Whether this paradigm universally applies to nitrogen-rich microbial communities remains unclear. Here, we investigated N2O production across an industrial poultry manure composting process and found that substantial N2O formation occurred despite the apparent absence of canonical ammonia oxidation. Neither allylthiourea inhibition nor metagenomic analyses provided evidence for ammonia-oxidizing microorganisms or their activity. Instead, metagenomic analyses identified abundant bacterial nitric oxide synthase (bNos) genes, many of which were phylogenetically affiliated with Bacilli, the dominant bacterial group throughout composting. Physiological experiments with Bacillus isolates demonstrated a nitrification-independent route in which L-arginine was oxidized to NO2-/NO3-, consistent with bNOS-mediated NO formation followed by abiotic oxidation. Recovery of 15N-labelled N2O following 15NO2- addition established NO2- as an immediate precursor of aerobically produced N2O, confirming that the oxidized nitrogen generated through this alternative route subsequently fueled denitrification. Metagenomic analyses further revealed extensive denitrification potential but comparatively low nosZ abundance. Together, these findings identify a previously overlooked route linking organic nitrogen turnover to denitrification independently of canonical nitrification, thereby expanding current models of microbial N2O production in composts and potentially other protein-rich thermophilic environments.

microbiology↗

bioRxiv2026

Neural decoding of speech using deep neural ensembles

Speech brain-computer interfaces (BCIs) can restore rapid communication to people with paralysis, but decoding errors still limit performance. In recent brain-to-text decoding competitions, deep ensemble methods, which combine predictions from multiple independently trained decoders, have delivered striking accuracy improvements and account for the largest gains over baseline approaches. However, these methods have not previously been tested in real-time, require substantial computational resources, and their performance under various clinically relevant constraints remains poorly understood. Here, we present the first closed-loop test of deep ensembles in a participant with bilateral intracortical microelectrode arrays, demonstrating a reduction in word error rate from 33.7% to 26.0% on a large-vocabulary task. Using additional data from three participants, we then assess how these gains depend on baseline error rate, training dataset size, and ensemble size, including the resource-accuracy tradeoffs most relevant for real-world deployment. Finally, we introduce a computationally efficient pseudoensembling approach based on test-time augmentation that improves decoding accuracy while requiring only a single base decoder, greatly reducing the computational burden of ensembling. Together, these results show that the benefits of deep ensembling can be realized in real time and under practical resource constraints, bringing speech BCIs closer to broader clinical adoption.

neuroscience↗

bioRxiv2026

Ligand stabilization enables physiological GITR signaling and antitumor immunity

Agonistic antibodies targeting the costimulatory receptor GITR have failed in clinical trials despite a strong preclinical rationale, revealing fundamental limitations of receptor-targeted approaches to TNF superfamily agonism. Here, we demonstrate that pharmacological stabilization of the trimeric structure of human GITRL represents a mechanistically distinct strategy to overcome these limitations. Small-molecule stabilization of GITRL preserves its membrane residency. It enables bidirectional signaling between antigen-presenting cells and T cells, a physiological context that receptor-targeted antibodies bypass through non-physiological clustering of GITR. In humanized GITR/GITRL double-knock-in mice bearing syngeneic tumors, GITRL stabilization expands cytotoxic CD8 T cells, selectively depletes intratumoral regulatory T cells, activates APCs, and restructures the immune spatial architecture. In patient-derived tumor explants, GITRL stabilization reactivates suppressed CD8 T cells in an APC-dependent manner. Our findings establish ligand stabilization as a mechanistically distinct therapeutic strategy and provide a framework for engaging TNF receptor superfamily costimulatory pathways by modulating their native ligands.

cancer biology↗

bioRxiv2026

Mitochondrial metabolic remodeling drives innate immune activation in Drosophila hemocytes

Innate immune cells rapidly reprogram their metabolism upon activation, yet the metabolic basis of this flexibility in invertebrate systems remains largely unexplored. Here, we investigate the metabolic landscape of Drosophila larval hemocytes, functional analogs of vertebrate myeloid cells, across developmental stages, genotypes, and immune activation states, by combining metabolic flux measurements with single-cell transcriptomics. Under homeostatic conditions, hemocytes rely predominantly on mitochondrial oxidative phosphorylation for ATP production, with minimal glycolytic contribution. Immune activation, particularly lamellocyte differentiation, drives enhanced mitochondrial respiration and metabolic flexibility, accompanied by structural remodeling of the mitochondrial network. Mechanistically, functional lamellocytes require Drp1-mediated mitochondrial fission and utilize glucose and trehalose as primary carbon sources to sustain mitochondrial respiration, which is essential for effective immune responses. Overall, these findings establish that mitochondrial metabolic reprogramming is a conserved feature of innate immune activation in myeloid-like immune cells and reveal an evolutionarily ancient link between mitochondrial dynamics and immune cell activation, with implications for understanding metabolic regulation of innate immunity in invertebrate models and beyond.

developmental biology↗

bioRxiv2026

Tonsillar expression quantitative trait loci verify and expand genetic contributors to childhood atopic diseases

The spectrum of causal variants, mechanisms, and immunologic gene networks that influence pediatric atopic traits are not completely understood. Human genetic variation associated with transcript abundance (eQTLs) can help to advance our understanding, yet prior work has focused on profiling immune cell populations collected from peripheral blood primarily in adult populations, leaving uncharacterized tissue-resident lymphocytes collected from children. Here, we paired genotyping with gene expression profiling across four populations of tonsil-derived immune cell types - including previously uncharacterized germinal center B cells - collected from 103 children across development (ages 1-18). Using these data, we report cell-type specific gene networks and identify 13,393 eGenes (1,793 eGenes not previously reported in similar datasets) influenced by 27,603 eQTLs (5,199 not previously reported). We link discovered eQTLs to associations identified in pediatric and adult asthma and atopy traits, nominating 78 eGenes like TRAF3, ZBTB10 and JAZF1 in disease relevant cell types. Our resource is freely available and exemplifies the importance of discovery in native tissues and across human development.

immunology↗

bioRxiv2026

Circulating miR-10b-5p drives Kawasaki vasculitis through endothelial reprogramming and nominates CXCL8 as an early diagnostic biomarker

BackgroundKawasaki disease (KD) is an acute systemic vasculitis of unknown etiology and the leading cause of acquired heart disease in children. Coronary artery aneurysm formation represents its most serious complication, yet no specific biomarker exists for early diagnosis at emergency department (ED) presentation. We sought to define the molecular mechanisms driving KD vasculitis and to identify a clinically actionable early diagnostic marker. MethodsWhole microRNA sequencing was performed on buffy coat specimens from KD patients and febrile controls presenting to the ED. Disease-associated miRNA candidates were validated in two independent murine KD-like vasculitis models: Lactobacillus casei cell wall extract (LCWE; n=12-20) and Candida albicans water-soluble fraction (CAWS; n=12). The functional role of miR-10b-5p was assessed by antagomir-mediated inhibition in the LCWE model. Transcriptomic and chromatin-level reprogramming were characterized by single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and assay for transposase-accessible chromatin with sequencing (ATAC-seq) in human coronary artery endothelial cells (HCAECs). Transcription factor binding was validated by in vitro binding assays and chromatin immunoprecipitation. Serum chemokine (C-X-C motif) ligand 8 (CXCL8) was quantified by enzyme-linked immunosorbent assay. ResultsForty miRNAs were upregulated in KD patients and fourteen miRNAs were prioritized for further analysis. miR-10b-5p was consistently elevated across both vasculitis models, and its antagomir-mediated inhibition attenuated aortic root inflammation in vivo. In HCAECs, miR-10b-5p suppressed its direct targets marker of proliferation Ki-67 (MKI67)/Chromobox5 (CBX5), driving a cell-state transition from proliferative/metabolic programs toward a pro-inflammatory phenotype. Consistently, analyses of bulk RNA-seq supported cell-cycle arrest and altered chromatin remodeling. ATAC-seq revealed increased chromatin accessibility at the CXCL8 and Matrix metalloproteinases 10 (MMP10) promoters, and motif analysis identified CCAAT/enhancer-binding protein alpha (CEBPA) as the key transcriptional activator; CEBPA knockdown abrogated miR-10b-5p-induced CXCL8 and MMP10 upregulation. Serum CXCL8 was markedly elevated in KD patients relative to febrile controls at first ED presentation, prior to definitive diagnosis, and declined significantly at 8-week follow-up. ConclusionsWe define a miR-10b-5p-MKI67/CBX5-CEBPA-CXCL8 axis as a mechanistic driver of endothelial reprogramming and neutrophil-recruiting inflammation in KD. Serum CXCL8 emerges as a candidate early diagnostic biomarker that may facilitate timely KD recognition at ED presentation.

molecular biology↗

bioRxiv2026

NetCrafter: Ontology-derived gene network modeling and interpretation

Understanding the complex nature of multi-functional interactions among genes is crucial for interpreting omics data. We developed NetCrafter, an ontology-driven platform for constructing de novo gene networks that are specific to each input gene list and quantitatively defined by ontology-weighted similarity. By incorporating the probabilistic association of ontology or curated gene sets into a weighted Tanimoto similarity metric, NetCrafter transforms enrichment results into quantitative semantic similarity scores between genes, enabling the creation of context-specific statistical networks. These networks can be further decomposed into optimal sub-networks, facilitating multi-functional interpretation and the identification of gene interaction hotspots. NetCrafter also supports the integration of heterogeneous omics-derived gene lists through consensus ontology scoring. Importantly, this list-specific, quantitative framework reveals functional hotspots and target-biomarker relationships - even in cases where ontology terms alone are not predictive of node-level attributes such as CRISPR efficacy. NetCrafter provides an interactive platform for constructing and interpreting dynamic, context-specific gene networks, leveraging ontology-based functional associations to uncover underlying mechanisms and identify key nodes. It is freely available at https://netcrafter.sookmyung.ac.kr and integrated into Q-omics platform (https://qomics.ai) to enhance the utility of cancer omics data.

bioinformatics↗

bioRxiv2025

Drug-Eluting, Radiopaque, Tumor-Casting Hydrogels for Endovascular Locoregional Therapy of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. For patients with unresectable disease, locoregional therapies, such as transarterial chemoembolization (TACE), are the standard of care. However, even with this treatment, the average survival rate is only 27% at 5 years. Recent studies have demonstrated the potential of novel approaches to improve responses through more complete embolization and targeting ischemia-induced molecular dependencies. To build on these findings, we developed an injectable chitosan-based hydrogel system (AuNP-Lys05-gel) that we hypothesized might be a more effective embolic material by (i) enabling a more complete filling of tumor feeding blood vessels in a cast-like manner, (ii) encapsulating Lys05, a potent autophagy inhibitor, and (iii) providing X-ray contrast for direct visualization of the embolization. Chitosan hydrogels of varying composition were formed and characterized. We found that Lys05 could be loaded in this type of hydrogel and that it was released gradually over 7 days. We found that AuNP was better retained by the hydrogel than iopamidol, an FDA-approved contrast agent, indicating that AuNP would provide longer-lasting CT monitoring. In a rat model of HCC, AuNP-Lys05-gel reduced tumor growth and resulted in a 67% objective response rate vs 26% for a clinically used particle embolic. Histology indicated effective vascular occlusion by the gel. These findings indicate that AuNP-Lys05-gel merits further investigation as a treatment for HCC.

cancer biology↗

bioRxiv2025

Flavobacteria buffer nitrous oxide emissions from partial denitrifiers in coastal sediments

Nearly one-fifth of global emissions of the potent greenhouse gas nitrous oxide (N2O) originate from the ocean, particularly from nutrient-polluted coastal regions. Permeable (sandy) sediments, which cover half of the continental shelf worldwide, are potential sources of N2O due to increasing nutrient inputs from urbanization and agriculture. Yet, the microbial processes determining N2O emissions in these dynamic and unique ecosystems remain understudied. Here, we combined environmental measurements, bacterial cultivation, and genomic analyses to understand the microbes and processes controlling N2O cycling in permeable sediments from Port Phillip Bay (Australia). We established a genomic resource comprising 249 metagenome-assembled genomes and 95 new isolate genomes. Genome-based metabolic reconstructions and culture-based gas measurements revealed diverse bacteria in these sediments produce N2O through incomplete denitrification pathways. However, these bacteria co-occurred with highly abundant clade II N2O-reducing bacteria from the Flavobacteriaceae family. Kinetic profiling revealed both clade II nosZ flavobacterial isolates and whole sand communities exhibit a low affinity for N2O, contrary to previous reports that clade II N2O reducers generally have a high substrate affinity. This indicates adaptation to the high residence times of N2O within production and consumption zones in the sands. Collectively, these N2O reducers remove most N2O produced in permeable sediments, supporting lower-than-expected coastal emissions predicted by biogeochemical models. We conclude that permeable sediments host specialised microbial communities that mitigate N2O emissions and buffer marine nitrogen cycling amid rising nutrient pollution.

microbiology↗

bioRxiv2025

Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation

Multiple enhancers, often located across vast genomic distances, regulate key genes. However, how chromatin topology organization at individual alleles enables cell-type-restricted multi-enhancer gene regulation remains unclear. Using acute protein degradation and time-course population-average chromatin conformation capture in lymphoma, we found that the B-cell- lineage-determining transcription factor EBF1 preferentially positions multiple enhancers at loci containing sparsely distributed genes essential for B-cell identity and oncogenesis. Our time-resolved sub-diffraction optical chromatin architecture tracing of >100,000 alleles in individual lymphoma cells further revealed diverse topological conformations facilitating multi-enhancer interactions. Mechanistically, we found that positioning of enhancers at allelic topological centers is required for their interactions with target promoters, with EBF1 serving as a barrier to the loop-extruding cohesin on enhancers. These findings, which we demonstrate their generalizability to the T-cell-lineage-determining transcription factor TCF1 in T-cell leukemia, suggest that lineage-determining transcription factors radially position enhancers and promoters to enable multi-enhancer regulation of key oncogenes.

cancer biology↗

bioRxiv2025

Development of human iPSC-derived cardiomyocytes-based heart-on-a-chip with customized multi-electrode array for drug-induced cardiotoxicity evaluations

The heart is an essential organ at the beginning and end of life. Cardiotoxicity directly related to life is emphasized as an absolute safety factor in drug development, so it is indispensable to evaluate it accurately. That is why establishing a novel platform that can precisely recapitulate human cardiophysiological properties is necessary. Here, we report a human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes-based heart-on-a-chip integrated with a customized multi-electrode array (cMEA), capable of actualizing a cardiac muscle fascicle and surrounding capillaries tridimensionally. The differences in experimental reproducibility, scale of field potential wave, and gene expression patterns according to the two-dimensional cell-level and three-dimensional tissue-level culture are confirmed. Excellent accuracy of drug efficacy/toxicity of the chip is also verified relative to other conventional cell culture platforms by looking at heart rate changes depending on drug type and concentration/time. Additionally, we checked that kinetic/electrophysiological/molecular biological analysis can be performed with our chip by applying motion tracking, cMEA, and RNA sequencing. Thus, our platform is expected to be used as a tool for more exact cardiotoxicity tests with high reproducibility and multi-angle analysis in line with new pharmacological safety assessments such as comprehensive cardiac arrhythmias assessment (CiPA).

bioengineering↗

bioRxiv2025

Rapid CAR Screening and circRNA-driven CAR-NK Cells for Persistent Shed-resistant Immunotherapy

Chimeric antigen receptor (CAR)-based immunotherapies against solid tumors face two major hurdles, the "decoy effect" of shedding antigens that sequester CARs, and the limited persistence of immune effectors within the immunosuppressive tumor microenvironment. Here, we present a mechanistic approach to overcome these barriers by integrating a physiologically relevant screening platform with circular RNA (circRNA) engineering. Unlike conventional screens using immortalized cell lines, we performed rapid functional screening directly in human primary natural killer (NK) cells to identify a novel scFv, CLMS10. Structural modeling revealed that CLMS10 targets a membrane-proximal epitope that overlaps the proteolytic cleavage site, thereby evading inhibition by soluble mesothelin (solMSLN). Furthermore, we demonstrated that circRNA-mediated CAR expression, when codelivered with interleukin-21 (IL-21), confers sufficient stability to withstand the continuous antigen shedding induced by cancer-associated fibroblasts (CAFs), resulting in reduced CAR downregulation. In an in vivo metastatic pancreatic cancer model, IL-21-augmented circCAR-MS10-NK cells exhibited potency comparable to that of lentivirally engineered CAR-NK cells while offering superior manufacturability. Overall, this study establishes a paradigm for generating shed-resistant CAR therapeutics through the strategic integration of epitope-specific functional selection and enhanced RNA stability.

bioengineering↗

bioRxiv2025

Development of ultrasound molecular contrast agents by site-specific conjugation of gas vesicles to antibodies

Ultrasound technology is a powerful tool for medical imaging and diagnosis especially when used in conjunction with a contrast agent to target proteins of interest. However, current ultrasound contrast agents are lacking the combination of specificity, stability, and size optimization. In this study we introduce and confirm the feasibility of using nanometer sized gas vesicles (GV) chemically click conjugated to antibodies (mAb) to make the first site-specific mAb-GV conjugates as a durable cancer cell targeting ultrasound molecular contrast agents. Protein expression of human epidermal growth factor receptor 2 (HER2) and programmed death-ligand 1 (PD-L1) were tested along with the antibody targeting efficiency using cancer cell lines and primary cells isolated from tumor bearing mice. The mAb conjugation was optimized to a site-specific method using the mAb glycans and tested with the addition of a clinically used mAb to target trophoblast cell surface antigen 2 (Trop-2). The developed contrast agents utilize the stability of GVs and the specificity of antibodies to label cancer biomarkers in various types of tumors for ultrasound imaging.

bioengineering↗

bioRxiv2025

Signal Detection of Point Targets Using Eigen-Images for Super-Resolution Ultrasound Imaging and Gas Vesicle Localization

Accurate signal detection of ultrasound contrast agents, such as microbubble (MB) and gas vesicle (GV), in the presence of clutter and noise is essential to increase image quality in super-resolution ultrasound imaging (SRUS) and achieve precise GV localization. We developed and evaluated an eigen-image based signal detection method using singular value decomposition (SVD) and changepoint detection to automatically segment the data that are closely related to physical events such as MB flow and GV collapse. Eigen-image based method was compared with the elbow point and hard thresholding method when selecting MB signals after SVD of raw data, acquired from phantom and in vivo experiments. Image reconstructed by eigen-image based method was also compared with unregistered difference image for GV localization when moving GVs in a phantom were collapsed by ultrafast plane waves. The eigen-image based MB signal detection method resulted in higher vessel density (VD) visualization in both the phantom and in vivo mouse tumor. It also achieved increased signal-to-noise ratio (SNR) in both cases. Moreover, this method localized moving GVs more efficiently than the difference imaging method, without requiring pixel registration based on landmarks. The eigenimage based method offers a reliable and automated approach to MB and GV signal detection for both SRUS and point target localization. This approach is a valuable tool for medical imaging providing high-quality vessel images along with accurate locations of moving ultrasound contrast agents, which can be potentially translatable to clinical diagnosis and pre-clinical research. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/662077v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@d03b0corg.highwire.dtl.DTLVardef@d4b318org.highwire.dtl.DTLVardef@3a2894org.highwire.dtl.DTLVardef@3e2962_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAn approach to efficiently detect point targets including microbubbles and gas vesicles is developed using eigenimages that describe the changes of point targets over time for super-resolution ultrasound imaging and gas vesicle localization. C_LIO_LISignals from point targets were automatically identified from clutter and noise by the changepoint detection method without prior Information. C_LIO_LIThis approach enhances microvasculature visualization of tumors in mice and improves the localization of gas vesicles in a phantom. C_LI

bioengineering↗

bioRxiv2025

Inference of multi-enhancer interactions in T lymphocytes using Hi-Cociety

AbstractsThree-dimensional (3D) enhancer communities are key regulators of gene expression, shaping cell fate decisions and contributing to disease pathogenesis. Assays such as H3K27ac HiChIP have been used to map enhancer-enhancer interactions and define enhancer communities; however, their reliance on antibody-based enrichment restricts scalability and cross-cell-type applicability. In contrast, Hi-C provides an unbiased, genome-wide view of chromatin architecture but lacks direct annotation of regulatory elements, limiting its utility for enhancer-focused analyses. To bridge this gap, we introduce Hi-Cociety--a graph-based computational framework and accompanying R package that infers 3D enhancer communities directly from Hi-C data, without relying on histone modification or chromatin accessibility measurements. Hi-Cociety constructs a network of significant interactions and applies clustering algorithms to define chromatin interaction modules. Applying Hi-Cociety to Hi-C measurements in T lymphocytes, we identified highly connected modules enriched for active transcription, chromatin accessibility, and histone acetylation. Notably, modules identified in T cells pinpoint critical genes central to T cell biology. Hi-Cociety also detects cell-type-specific differences in chromatin organization, highlighting dynamic regulatory rewiring across T cell states. Our findings underscore the importance of network properties-- connectivity, transitivity, and centrality--in shaping gene regulation through 3D genome organization. Hi-Cociety provides a scalable and versatile tool for mapping enhancer communities at scale, advancing our understanding of immune cell identity and the regulatory logic encoded in 3D chromatin structure.

bioinformatics↗