Biology subjects

Hong, D.

Publications and source records attributed to Hong, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy

Tertiary lymphoid structures (TLS) predict response to checkpoint inhibition, and conventional dendritic cells (cDC) are required to build and maintain them. What renders a niche permissive for their assembly is unknown: chemokines recruit the cellular constituents but do not specify how they organize. Here we show that the organizing signal is a matrix fragment. Proteolysis of the proteoglycan versican (VCAN) releases the matrikine versikine, constitutively in germinal center light zones and inducibly in tumor stroma. Versikine activates CD11b+ cDC and expands cDC1 to assemble TLS-archetypal triads, apposed DC: CD4+ T: CD8+ T units. Versikine-conditioned DC engage progenitor-exhausted CD8+ T cells (Tpex) and Th1-polarized follicular helper CD4+ T cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine supplied as mRNA or recombinant protein sensitizes refractory tumors to PD-L1 blockade. VCAN proteolysis prospectively predicted outcomes after PD-1 blockade in metastatic colorectal cancer. Matrikines organize chemokine-recruited cells into functional immune niches.

immunology↗

bioRxiv2026

Aberrant 3'UTR splicing drives FUS-dependent mRNA condensates and prevents β-catenin from adherens junctions to promote cancer aggressiveness

The protein-coding sequence has long been considered the primary determinant of protein function. Alternative splicing within 3'UTRs (AS-3'UTRs) generates multiple transcript isoforms from a single gene, yet their roles in protein function and disease relevance remain largely unexplored. Through systematic transcriptome-wide identification of cancer-associated AS-3'UTRs, we uncover that AS-3'UTRs of {beta}-catenin mRNA direct distinct subcellular localization of {beta}-catenin mRNA isoforms. Specifically, an aberrantly spliced 3'UTR isoform promotes cytoplasmic mRNA condensate formation through FUS binding to a cancer-associated alternative exon (Exon 16A). Because {beta}-catenin function is exquisitely dependent on its subcellular distribution between adherens junctions and the nucleus, this aberrant 3'UTR isoform reprograms {beta}-catenin localization. By sequestering {beta}-catenin in the cytoplasm, the aberrant 3'UTR isoform prevents its incorporation into E-cadherin-based adherens junctions, thereby inducing epithelial-mesenchymal transition (EMT)-associated transcriptional programs. Notably, the expression signature of the aberrant 3'UTR isoform robustly correlates with poor clinical outcomes in colorectal cancer patients. Together, our findings reveal that AS-3'UTRs operate as a previously unrecognized post-transcriptional regulatory mechanism through which the untranslated region of mRNA, without altering a single amino acid, reprograms protein subcellular fate to drive oncogenic phenotypes.

cell biology↗

bioRxiv2026

Human hindbrain organoids with segment-specific 5-HT neurons for motor modulation

The serotonergic system regulates human mood, reward, and motor control, and its impairment contributes to debilitating psychiatric disorders. Serotonergic neurons (SNs) arise predominantly in the hindbrain and acquire segment-specific identities and functions; however, the lack of human models remains a challenge to understanding the human serotonergic system. Here, we generate human serotonergic-enriched rostral and caudal hindbrain organoids (hsrHOs and hscHOs) that produce segment-specific SNs with regional identities corresponding to rhombomeres r2-r3 and r5-r8, respectively. hsrHOs and hscHOs produce SNs that recapitulate their in vivo counterparts in transcriptomic profiles, function, and ascending or descending projection preferences. Assembly with human neuromusculoskeletal organoids enables modeling of serotonergic modulation of motor control. This system further reveals that deficiency of the schizophrenia risk gene DISC1 disrupts human serotonergic development and impairs motor modulation. Together, our study establishes a human organoid platform for modeling development, circuit function and disease-associated dysfunction of the serotonergic modulatory system.

neuroscience↗

bioRxiv2026

KRAS inhibition is an effective therapy for appendiceal adenocarcinoma

BackgroundAppendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear. MethodsWe evaluated KRASG12D-specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRASmut organoid and orthotopic PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. Clinical outcomes were also assessed in six heavily pre-treated AA patients treated with KRAS inhibitors. ResultsMRTX1133 was highly effective for KRASG12D organoids (IC50=4.1 nM); both KRASG12D and KRASG12V organoids were sensitive to RMC-6236 (IC50=4.4 nM vs 0.5 nM, respectively). In orthotopic PDX models of peritoneal carcinomatosis from AA, MRTX1133 significantly reduced tumor growth in the KRASG12D model TM00351, and RMC-6236 reduced tumor growth in KRASG12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Sets Enrichment Analysis (GSEA) revealed significant downregulations of E2F targets (NES=-1.9, p-adj=0.06) and the newly developed RAS/ERK (NES=-2.3, p-adj=0.06) gene set, consistent with the observed decrease in cell proliferation. There was marked upregulation of EMT (NES=2.7, FDR<0.001) and TGF-{beta} signaling (NES=2.3, FDR=0.004) in remaining tumor cells, suggesting these pathways could confer resistance. scRNA-seq analysis of TME showed dramatic shifts in cancer-associated fibroblasts (CAFs), with KRAS inhibition driving a shift from normal fibroblasts to inflammatory CAFs, and upregulation of interferon alpha and gamma pathways, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. In a cohort of 6 heavily pre-treated patients with AA treated with KRAS inhibitors (1 G12D, 3 G12C, 2 pan-KRAS), all had biochemical response based on CEA/Ca19-9 or ctDNA and clinical benefit by RECIST criteria (1 CR, 1 PR, 4 SD). ConclusionsWhile effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of EMT and TGF-{beta} pathways may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

cancer biology↗

bioRxiv2026

Acute degron-mediated RUNX1 loss reprograms enhancer activity to epigenetically drive epithelial destabilization and initiate cancer hallmarks

The RUNX1 transcription factor mediates cell-type specific gene expression. RUNX1 suppression and perturbations are recurrently associated with breast tumor initiation and progression. However, the mechanisms governing the dual roles of RUNX1 in sustaining the mammary epithelial phenotype while epigenetically suppressing initiation of cancer-compromised gene expression are poorly understood. To address this, we used the power of degron-mediated acute, selective, and complete RUNX1 ablation in human mammary epithelial cells. RUNX1 mediates promoter and distal enhancer-driven expression of a gene cohort. Dynamic epigenomic responsiveness upon RUNX1 ablation reveals a rapid and selective decrease in chromatin accessibility and H3K27ac at RUNX1-bound enhancers, but not promoters. While differentially initiated and expressed genes contacted by RUNX1-bound enhancers are enriched in pathways involved in epithelial maintenance and stemness, genes with RUNX1-promoter occupancy support DNA damage responsiveness. Modified cell morphology, metabolic control, increased breast cancer stemness, plasticity, anchorage-independent survival, chemoresistance, and perturbed DNA damage reactivity are observed upon RUNX1 ablation. Together, these findings define RUNX1 as an epigenetic tumor suppressor that maintains epithelial cell state by preserving enhancer activity and preventing gene expression associated with hallmarks of cancer.

cancer biology↗

bioRxiv2026

Cannabis Use by People with HIV is Associated with an Anti-Inflammatory Immunometabolic Phenotype in Monocyte-Derived Macrophages

Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naive/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/709579v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@15fb1adorg.highwire.dtl.DTLVardef@189d79corg.highwire.dtl.DTLVardef@aa6a89org.highwire.dtl.DTLVardef@3852f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

A novel uN2CpolyG Transgenic Mouse Model Recapitulates Multisystemic polyG Proteinopathy Pathology of Neuronal Intranuclear Inclusion Disease

Neuronal intranuclear inclusion disease (NIID) is a polyglycine disease that primarily affects the neuronal and neuromuscular systems. Here, we developed a novel transgenic mouse model that faithfully recapitulates the multisystemic impairments associated with polyG intranuclear inclusions. Our findings demonstrate that polyG expression induces neurodegeneration, behavioral deficits, and age-dependent accumulation of uN2CpolyG aggregates across multiple tissues.

animal behavior and cognition↗

bioRxiv2025

Deciphering Features of Metalloprotease Cleavage Targets Using Protein Structure Prediction

IntroductionADAM10 (A Disintegrin and Metalloproteinase 10) cleaves specific substrates, influencing diverse physiological and pathological processes. However, its substrate specificity and cleavage sites remain insufficiently characterized. This study aimed to identify and classify substrate features and elucidate cleavage sites using computational approaches. MethodsProtein structure prediction was performed on 13 substrates with experimentally defined cleavage sites to analyze ADAM10-substrate interactions and assess their structural and spatial characteristics. ResultsBased on protein structure prediction of experimentally validated substrates, we identified four recurrent structural features associated with ADAM10-mediated cleavage. First, most substrates were predicted to interact with the proteolytically active form of ADAM10 (92.3%). Second, interaction sites were typically located in the extracellular region rather than intracellular or transmembrane domains (76.9%). Third, cleavage sites predominantly resided in unstructured or extended loop regions, corresponding to linear secondary structures ([~]70%). Lastly, cleavage sites were spatially enriched in octants (1, 4, 5, and 8) relative to the catalytic Zn{superscript 2}{square} ion in the active site (84.0%). These percentages were calculated per determinant. On the basis of these determinants, we developed a classification algorithm and organized 51 substrates accordingly. As a result, 82.4% of the substrates were assigned to either Group 1 (51.0%) or Group 2 (31.4%). DiscussionThis study presents a structure-informed classification approach for predicting ADAM10 cleavage substrates, enabling candidate identification without direct experimental validation. ConclusionsWe present a novel structure-based framework for classifying the substrates of ADAM10 and demonstrate its applicability to other Metalloproteases.

bioinformatics↗

bioRxiv2024

Annotation Vocabulary (Might Be) All You Need

Protein Language Models (pLMs) have revolutionized the computational modeling of protein systems, building numerical embeddings that are centered around structural features. To enhance the breadth of biochemically relevant properties available in protein embeddings, we engineered the Annotation Vocabulary, a transformer readable language of protein properties defined by structured ontologies. We trained Annotation Transformers (AT) from the ground up to recover masked protein property inputs without reference to amino acid sequences, building a new numerical feature space on protein descriptions alone. We leverage AT representations in various model architectures, for both protein representation and generation. To showcase the merit of Annotation Vocabulary integration, we performed 515 diverse downstream experiments. Using a novel loss function and only $3 in commercial compute, our premier representation model CAMP produces state-of-the-art embeddings for five out of 15 common datasets with competitive performance on the rest; highlighting the computational efficiency of latent space curation with Annotation Vocabulary. To standardize the comparison of de novo generated protein sequences, we suggest a new sequence alignment-based score that is more flexible and biologically relevant than traditional language modeling metrics. Our generative model, GSM, produces high alignment scores from annotation-only prompts with a BERT-like generation scheme. Of particular note, many GSM hallucinations return statistically significant BLAST hits, where enrichment analysis shows properties matching the annotation prompt even when the ground truth has low sequence identity to the entire training set. Overall, the Annotation Vocabulary toolbox presents a promising pathway to replace traditional tokens with members of ontologies and knowledge graphs, enhancing transformer models in specific domains. The concise, accurate, and efficient descriptions of proteins by the Annotation Vocabulary offers a novel way to build numerical representations of proteins for protein annotation and design.

bioinformatics↗

bioRxiv2024

AIVE: accurate predictions of SARS-CoV-2 infectivity from comprehensive analysis

An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the Receptor Binding Motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in Variants of Concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 was detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.

genomics↗

bioRxiv2024

Zinc finger transcription factors BnaSTOP2s regulate sulfur metabolism and confer resistance to Sclerotinia sclerotiorum in Brassica napus

Rapeseed (Brassica napus L.) has a high sulfur requirement for optimal growth, development, and pathogen resistance. In this study, we identified zinc finger transcription factors, BnaSTOP2s, that play key roles in sulfur metabolism and Sclerotinia sclerotiorum resistance. First, our results suggested that BnaSTOP2s are involved in sulfur as evidenced from extensive protein interaction screening. Knockout of BnaSTOP2s reduced the response sensitivity in both sulfur-deficient and sulfur-excessive conditions by promoting the elongation of primary roots of seedlings. Furthermore, the content of essential sulfur-containing metabolites, including glucosinolate and glutathione, were substantially down-regulated in roots and leaves of Bnastop2 mutants, which is consistent with the significantly lowered transcriptional levels of key players of GSL synthesis and transportation, BnaMYB28s and BnaGTR2s, respectively. Through comprehensive RNA-seq analysis, we revealed the substantial effect of BnaSTOP2s on sulfur metabolism from source to sink. Additionally, we observed a significant decrease while increase in leaf lesion sizes of the BnaSTOP2-OE and Bnastop2 mutants, respectively, when compared to the wild type during Sclerotinia sclerotiorum infection, suggesting the vital role of BnaSTOP2 in plant defense response. Overall, our findings highlight that BnaSTOP2s seems to be global regulators of sulfur metabolism and confer resistance to Sclerotinia sclerotiorum infection in B. napus.

plant biology↗

bioRxiv2024

Single cell RNA sequencing of nc886, a non-coding RNA transcribed by RNA polymerase III, with a primer spike-in strategy

Single cell RNA sequencing (scRNA-seq) has emerged as a versatile tool in biology, enabling comprehensive genomic-level characterization of individual cells. Currently, most scRNA-seq methods generate barcoded cDNAs by capturing polyA tails of mRNAs, which excludes many non-coding RNAs (ncRNAs), especially those transcribed by RNA polymerase III (Pol III). Although previously thought to be expressed constitutively, Pol III-transcribed ncRNAs are expressed variably in healthy and disease states and play important roles therein, necessitating their profiling at the single cell level. In this study, we have developed a measurement protocol for nc886 as a model case, as an initial step for scRNA-seq for Pol III-transcribed ncRNAs. Specifically, we spiked in an oligo-tagged nc886-specific primer during the polyA tail capture process for the 5-reading in scRNA-seq. We then produced sequencing libraries for standard 5 gene expression and oligo-tagged nc886 separately, to accommodate different cDNA sizes and ensure undisturbed transcriptome analysis. We applied this protocol in three cell lines which express high, low, and zero levels of nc886, respectively. Our results show that the identification of oligo tags exhibited limited target specificity, and sequencing reads of nc886 enabled the correction of non-specific priming. These findings suggest that gene-specific primers (GSPs) can be employed to capture RNAs lacking a polyA tail, with subsequent sequence verification ensuring accurate gene expression counting. Moreover, we embarked on an analysis of differentially expressed genes in cell line sub-clusters with differential nc886 expression, demonstrating variations in gene expression phenotypes. Collectively, the primer spike-in strategy allows us for a combined analysis of ncRNAs and gene expression phenotype.

genomics↗

bioRxiv2023

Dense Sampling of Taxa and Genomes Untangles the Phylogenetic Backbone of a Non-model Plant Lineage Rife with Deep Hybridization and Allopolyploidy

Phylogenetic networks, rather than purely bifurcating trees, more accurately depict the intricate evolutionary dynamics of most lineages, especially those characterized by extensive hybridization and allopolyploidization events. However, the challenges of achieving complete taxon sampling, and limited financial resources for studying non-model plant lineages, have hindered comprehensive and robust estimation of phylogenetic backbones with guidance from networks. The bellflower tribe, Campanuleae, characterized by a reticulate evolutionary history, serves as an ideal model to investigate how to diagnose nested ancient reticulation events. Here, by integrating multiple genomic data sources and a range of phylogenetic inference methods, we produced a robust phylogenetic backbone for the tribe Campanuleae. Our investigation of reticulate evolution indicates that hybridization and allopolyploidization were instrumental in shaping the diversity of the bellflower tribe, particularly during the initial diversification of the subtribe Phytematinae. Additionally, we ascertained that conflicting topologies resulting from distinct genomic datasets and inference methodologies significantly impact downstream estimates of divergence dating, ancestral area construction, and diversification rates. This study offers a universally relevant framework for deciphering how to use network-based phylogenetic structures using various genomic sources and inference methods. [Campanulaceae, Campanuleae, Cytonuclear discordance, paralog, phylogenomics, reticulate evolution]

plant biology↗

bioRxiv2023

Dynamics of motor direction representation in the primate premotor and primary motor cortices during sensorimotor learning

Sensorimotor learning requires reorganization of neuronal activity in the premotor cortex (PM) and primary motor cortex (M1). However, how PM- and M1-specific reorganization occurs in primates remains unclear. We conducted calcium imaging of these areas in common marmosets while they learned a two-target reaching (pull/push) task. Throughout learning, the dorsorostral PM (PMdr) showed peak activity earlier than the dorsocaudal PM (PMdc) and M1. PMdr showed decreased representation of newly introduced (push) movement, whereas PMdc and M1 maintained high representation. Many task-related neurons in PMdc and M1 exhibited a strong preference to either movement direction. PMdc neurons dynamically switched their preferred direction, whereas M1 neurons stably retained their preferred direction. Differences in preferred direction between adjacent neurons in PMdc increased during learning. These results suggest that in primate sensorimotor learning, dynamic motor representation in PMdc converts the cognitive sensorimotor signals of PMdr to stable and specific motor representation of M1.

neuroscience↗

bioRxiv2023

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

genomics↗

bioRxiv2022

Deciphering the Evolutionary History of Complex Rearrangements in Head and Neck Cancer Patients Using Multi-Omic Approach

Despite the large efforts in international cancer genome consortium studies, there are still a large proportion of tumors with complex genomic rearrangement often remained without a clinically relevant molecular characterization. Integration of multi-omic data helps elucidating evolutionary history of such cases and identifying predictive molecular markers. Here we present the findings of our proof-of-principle study that investigated the evolutionary history of complex rearrangements in primary head and neck tumor genomes integrating long-read whole-genome, Hi-C, and RNA sequencing. We report a HPV-positive case with development of complex genomic rearrangements tracing back to HPV-mediated genomic instability and a HPV-negative case with an enhancer hi-jacking in a region of chromothripsis predicted to co-occur with a neoloop and a super-enhancer. These structural alterations resulted in overexpression of the oncogenes CCND1 and ALK, respectively, validated with immunohistochemistry assay. Furthermore, we introduce a novel analytic approach utilizing long-read whole-genome data distinguishing somatic mutations before and after structural variants. Our findings highlight the need for multi-modal sequencing strategies to increase our understanding of cancer evolution and rare biomarkers in poorly understood cancers.

genomics↗

bioRxiv2022

Complexity of enhancer networks predicts cell identity and disease genes revealed by single-cell multi-omics analysis

Many enhancers exist as clusters in the genome and control cell identity and disease genes; however, the underlying mechanism remains largely unknown. Here, we introduce an algorithm, eNet, to build enhancer networks by integrating single-cell chromatin accessibility and gene expression profiles. Enhancer network is a gene regulation model we proposed that not only delineates the mapping between enhancers and target genes, but also quantifies the underlying regulatory relationships among enhancers. The complexity of enhancer networks is assessed by two metrics: the number of enhancers and the frequency of predicted enhancer interactions (PEIs) based on chromatin co-accessibility. We apply eNet algorithm to a human blood dataset and find cell identity and disease genes tend to be regulated by complex enhancer networks. The network hub enhancers (enhancers with frequent PEIs) are the most functionally important in enhancer networks. Compared with super-enhancers, enhancer networks show better performance in predicting cell identity and disease genes. The establishment of enhancer networks drives gene expression during lineage commitment. Applying eNet in various datasets in human or mouse tissues across different single-cell platforms, we demonstrate eNet is robust and widely applicable. Thus, we propose a model of enhancer networks containing three modes: Simple, Multiple and Complex, which are distinguished by their complexity in regulating gene expression. Taken together, our work provides an unsupervised approach to simultaneously identify key cell identity and disease genes and explore the underlying regulatory relationships among enhancers in single cells, without requiring the cell type identity in advance. HighlightsO_LIeNet, a computational method to build enhancer network based on scATAC-seq and scRNA-seq data C_LIO_LICell identity and disease genes tend to be regulated by complex enhancer networks, where network hub enhancers are functionally important C_LIO_LIEnhancer network outperforms the existing models in predicting cell identity and disease genes, such as super-enhancer and enhancer cluster C_LIO_LIWe propose a model of enhancer networks in gene regulation containing three modes: Simple, Multiple and Complex C_LI

bioinformatics↗

bioRxiv2021

A human antibody that broadly neutralizes betacoronaviruses protects against SARS-CoV-2 by blocking the fusion machinery

The repeated spillovers of {beta}-coronaviruses in humans along with the rapid emergence of SARS-CoV-2 escape variants highlight the need to develop broad coronavirus therapeutics and vaccines. Five monoclonal antibodies (mAbs) were isolated from COVID-19 convalescent individuals and found to cross-react with multiple {beta}-coronavirus spike (S) glycoproteins by targeting the stem helix. One of these mAbs, S2P6, cross-reacts with more than twenty human and animal {beta}-coronavirus S glycoproteins and broadly neutralizes SARS-CoV-2 and pseudotyped viruses from the sarbecovirus, merbecovirus and embecovirus subgenera. Structural and functional studies delineate the molecular basis of S2P6 cross-reactivity and broad neutralization and indicate that this mAb blocks viral entry by inhibiting membrane fusion. S2P6 protects hamsters challenged with SARS-CoV-2 (including the B.1.351 variant of concern) through direct viral neutralization and Fc-mediated effector functions. Serological and B cell repertoire analyses indicate that antibodies targeting the stem helix are found in some convalescent donors and vaccinees but are predominantly of narrow specificity. Germline reversion of the identified cross-reactive mAbs revealed that their unmutated ancestors are specific for the endemic OC43 or HKU1 viruses and acquired enhanced affinity and breadth through somatic mutations. These data demonstrate that conserved epitopes in the coronavirus fusion machinery can be targeted by protective antibodies and provide a framework for structure-guided design of pan-{beta}-coronavirus vaccines eliciting broad protection.

immunology↗