Biology subjects

Xu, J.

Publications and source records attributed to Xu, J..

At least 271 records · Page 15Linked to original sources

bioRxiv2025

Decoding Gene Networks Controlling Hypothalamic and Prethalamic Neuron Development.

Neuronal subtypes derived from the embryonic hypothalamus and prethalamus regulate many essential physiological processes, yet the gene regulatory networks controlling their development remain poorly understood. Using single-cell RNA- and ATAC-sequencing, we analyzed mouse hypothalamic and prethalamic development from embryonic day 11 to postnatal day 8, profiling 660,000 cells in total. This identified key transcriptional and chromatin dynamics driving regionalization, neurogenesis, and differentiation. This identified multiple distinct neural progenitor populations, as well as gene regulatory networks that control their spatial and temporal identities, and their terminal differentiation into major neuronal subtypes. Integrating these results with large-scale genome-wide association study data, we identified a central role for transcription factors controlling supramammillary hypothalamic development in a broad range of metabolic and cognitive traits. Recurring cross-repressive regulatory relationships were observed between transcription factors that induced prethalamic and tuberal hypothalamic identity on the one hand and mammillary and supramammillary hypothalamic identity on the other. In postnatal animals, Dlx1/2 was found to severely disrupt GABAergic neuron specification in both the hypothalamus and prethalamus, resulting in a loss of inhibition of thalamic neurons, hypersensitivity to cold, and behavioral hyperactivity. By identifying core gene regulatory networks controlling the specification and differentiation of major hypothalamic and prethalamic neuronal cell types, this study provides a roadmap for future efforts aimed at preventing and treating a broad range of homeostatic and cognitive disorders.

neuroscience↗

bioRxiv2025

MicroRNA signatures of VO2peak in older adult participants of the Study of Muscle, Mobility and Aging

BackgroundPeak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the miRNA signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak. MethodsWe used small RNA sequencing to analyze serum samples from 72 participants (70-79 yrs old, 53% female) of the Study of Muscle, Mobility and Aging (SOMMA). We analyzed samples from individuals with low or high VO2peak (N=18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. We used receiver operating characteristic curve analysis to evaluate the Area Under the Curve (AUC) and sensitivity and specificity rates. ResultsWe identified 1,055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (p < 0.05). After p-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The five miRNAs had AUC ranging from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70 to 80% and 80 to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (p < 0.05) and miR-519a-3p remained significant based on adjusted of p-values. ConclusionsWe identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

molecular biology↗

bioRxiv2024

An Expanded Registry of Candidate cis-Regulatory Elements for Studying Transcriptional Regulation

Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression. Previously, The ENCODE consortium mapped biochemical signals across many cell types and tissues and integrated these data to develop a Registry of 0.9 million human and 300 thousand mouse candidate cis-Regulatory Elements (cCREs) annotated with potential functions1. We have expanded the Registry to include 2.35 million human and 927 thousand mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded Registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays like STARR-seq, MPRA, CRISPR perturbation, and transgenic mouse assays now cover over 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer/silencer roles in different cellular contexts. Integrating the Registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by discovering KLF1 as a novel causal gene for red blood cell traits. This expanded Registry is a valuable resource for studying the regulatory genome and its impact on health and disease.

genomics↗

bioRxiv2024

Antibiotics that Kill Gram-negative Bacteria by Restructuring the Outer Membrane Protein BamA

The essential outer membrane protein insertase BamA has recently emerged as a valid target for killing Gram-negative bacteria. Bamabactins, competitive inhibitors targeting the lateral gate of BamA, disrupt the substrate folding process, compromise the outer membrane integrity, and lead to bacterial cell death. Despite their promise, the full pharmacological potential of bamabactins remains underexploited. We applied phylogenetic genome mining and synthetic biology to identify xenorceptides which selectively kill Enterobacteriaceae. Mode of action studies show that xenorceptide A2 integrates itself into BamA as an additional {beta}-strand between {beta}1 and {beta}16 at the lateral gate, inducing a conformation of BamA that has not been observed before. Biological evaluation of xenorceptide A2 shows promising activity in vitro and in vivo, and limited resistance which differentiates it from other bamabactin antibiotics. Our data show that the chemical diversity of bamabactins is far greater than previously recognized and thus an attractive source for antibiotic discovery.

microbiology↗

bioRxiv2024

The CoREST complex inhibitor, corin, leads to decreased tumor growth, increased cellular differentiation and extended lifespan in atypical teratoid rhabdoid tumor xenograft models

BackgroundAtypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor in infants, and more than 60% of children with ATRT die from their tumor. ATRT is associated with mutational inactivation/deletion of SMARCB1, a member of the SWI/SNF chromatin remodeling complex, suggesting that epigenetic events play a critical role in tumor development and progression. Moreover, disruption of SWI/SNF allows unopposed activity of epigenetic repressors, which contribute to tumorigenicity. We therefore explored the role of the CoREST repressor complex in ATRT. MethodsWe evaluated the effects of the bifunctional LSD1/HDAC1/2 small molecule CoREST inhibitor, corin, on ATRT tumor cell growth, apoptosis, differentiation, gene expression and chromatin accessibility. ResultsWe found that corin inhibited the growth of ATRT cells regardless of their epigenetic subgroup, and was associated with increased tumor cell apoptosis and differentiation. ATAC-seq showed increases in chromatin accessibility in corin-treated ATRT cells, with changes seen at genes associated with neuronal differentiation and synaptic function. RNA-seq confirmed increased expression of neuronal differentiation genes and decreased DNA replication/cell cycle-associated genes in ATRT cells treated with corin. Corin suppressed orthotopic ATRT tumor growth, leading to significant extension of lifespan. In addition, increased histone acetylation (H3K9ac, H3K27ac) and methylation (H3K4Me1) was seen in corin-treated ATRT orthotopic xenografts, consistent with on-target pharmacodynamics. ConclusionThe CoREST inhibitor, corin, suppresses tumor growth, induces differentiation, and promotes apoptosis in ATRT, leading to significantly increased survival of mice bearing ATRT orthotopic xenografts. Our results suggest a potential application of CoREST complex inhibitors in patients with ATRT. Key PointsO_LICoREST complex inhibition by corin leads to decreased cell growth and increased apoptosis in ATRT C_LIO_LICorin promotes chromatin accessibility and neuronal differentiation in ATRT C_LIO_LICorin inhibits tumor growth and extends lifespan in ATRT animal models C_LI Importance of the StudyLoss of function of SMARCB1 is a hallmark of ATRT which leads to dysfunction of the mammalian SWI/SNF complex and an inability to counteract epigenetic repressor complexes. The CoREST complex functions as a chromatin remodeling complex that represses neuronal differentiation genes during development. Inhibition of the CoREST complex by corin in ATRT leads to decreased tumor cell growth, induction of apoptosis and increased survival of mice bearing ATRT orthotopic xenografts. These changes are associated with increased chromatin accessibility and expression of genes associated with neuronal differentiation. Corin therefore reverses the primary block of differentiation that maintains a stem cell state in ATRT, which contributes to tumorigenesis. These studies significantly improve our understanding of how to therapeutically address the underlying epigenetic drivers of ATRT and support further development of corin for ATRT.

cancer biology↗

bioRxiv2024

ΔNP63 defines an exocrine-committed multipotent progenitor subset in the murine pancreas

Cellular plasticity underpins heterogeneity in embryogenic progenitor cells and cancer cells. The transcription factor deltaNp63 ({Delta}Np63) has been implicated in regulating cellular plasticity in several epithelial tissues. Despite a recently established role in steering plasticity of pancreatic cancer, {Delta}Np63 remains unstudied in pancreatic development. Using murine single-cell sequencing data and RNA and protein in situ stainings, we assessed the spatio-temporal expression of Trp63 and {Delta}NP63 in the embryonic pancreas. {Delta}NP63 demonstrates a transient and spatially restricted expression in the multipotent pancreatic progenitor (MPP) compartment delineating pro-exocrine progenitor cells. Lineage tracing of TP63+ cells marks a subset of MPPs and descendant exocrine acinar and centro-acinar/terminal duct cells. Lack of {Delta}NP63 in knock-out mice leads to hypotrophic exocrine acini with reduced levels of differentiation markers. In summary, {Delta}Np63 confers heterogeneity within the MPP compartment, supporting exocrine cell development. These new insights in developmental plasticity have potential implications for pancreatic regeneration and cancer.

developmental biology↗

bioRxiv2024

Humans use overconfident estimates of auditory spatial and temporal uncertainty for perceptual inference

Making decisions based on noisy sensory information is a crucial function of the brain. Various decisions take each sensory signals uncertainty into account. Here, we investigated whether perceptual inferences rely on accurate estimates of sensory uncertainty. Participants completed a set of auditory, visual, and audiovisual spatial as well as temporal tasks. We fitted Bayesian observer models of each task to every participants complete dataset. Crucially, in some model variants the uncertainty estimates employed for perceptual inferences were independent of the actual uncertainty associated with the sensory signals. Model comparisons and analysis of the best-fitting parameters revealed that, in unimodal and bimodal contexts, participants perceptual decisions relied on overconfident estimates of auditory spatial and audiovisual temporal uncertainty. These findings challenge the ubiquitous assumption that human behavior optimally accounts for sensory uncertainty regardless of sensory domain.

neuroscience↗

bioRxiv2024

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

cancer biology↗

bioRxiv2024

Astrocyte-specific secretome profiling reveals its correlation with neurological disorders

Secreted proteins mediate intercellular communication throughout the lives of multicellular organisms. However, due to the lack of new technology for secreted protein capturing, the progress of "secretomics lags behind. Here, we report a two-step secretome enrichment method (tsSEM) combining unnatural amino acid labeling and click chemistry-based biorthogonal reaction, which enables in vitro secretome profiling in the presence of serum. Using this novel method, we systematically investigated the secretome of human iPSCs-derived astrocytes (iAst) in different disease models and identified a panel of astrocyte-secreted proteins that are responsible for its non-cell autonomous toxicity under disease conditions. Furthermore, we validated two astrocytes-derived novel neurotrophic proteins, FAM3C and KITLG, which we identified from disease models, and found that they could boost neurite outgrowth, protect neurons, and promote neural progenitor proliferation. Our study highlights the utility of secretome profiling of iAst and demonstrates its applications in disease study and target identification and validation in drug development.

neuroscience↗

bioRxiv2024

PanTax: Strain-level taxonomic classification of metagenomic data using pangenome graphs

Microbes are omnipresent, thriving in a range of habitats from oceans to soils and even within our gastrointestinal tracts. They play a vital role in maintaining ecological equilibrium and promoting the health of their hosts. Consequently, understanding the strain diversity within microbial communities is crucial, as variations between strains can lead to distinct phenotypic expressions or diverse biological functions. However, current methods for taxonomic classification from metagenomic sequencing data have several limitations, including their reliance solely on species resolution, support for either short or long reads, or their confinement to a given single species. Most notably, the majority of existing taxonomic classifiers rely solely on a single linear representative genome as a reference, which fails to capture the strain diversity, thereby introducing single-reference biases. Here, we present PanTax, a pangenome graph-based taxonomic classification method that overcomes the shortcomings of single-reference genome-based approaches, because pangenome graphs possess the capability to depict the genetic variability present across multiple evolutionarily or environmentally related genomes. PanTax provides a comprehensive solution to taxonomic classification for strain resolution, compatibility with both short and long reads, and compatibility with single or multiple species. Extensive benchmarking results demonstrate that PanTax drastically outperforms state-of-the-art approaches, primarily evidenced by its significantly higher precision or recall (at both species and strain levels), while maintaining comparable or better performance in other aspects across various datasets. PanTax is a user-friendly open-source tool that is publicly accessible at https://github.com/LuoGroup2023/PanTax.

bioinformatics↗

bioRxiv2024

Long-Read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons

Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing, and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of human fibroblasts, induced pluripotent stem cells, and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15,072 transcripts in stem cell-derived cortical neurons, 13,048 in fibroblasts, and 12,759 in induced pluripotent stem cells. Our analyses uncovered 35,519 differential transcript expression events and 5,135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types. Importantly, by integrating differential transcript expression and usage analyses, we gained deeper insights into transcript dynamics that are not captured by gene-level expression analysis alone. Notably, differential transcript usage analysis highlighted transcript-specific changes in disease-relevant genes such as APP, KIF2A, and BSCL2, associated with Alzheimers disease, neuronal migration disorders, and degenerative axonopathies, respectively. This added resolution emphasizes the significance of transcript- level variations that often remain hidden in traditional differential gene expression analyses. Overall, our work provides a framework for understanding transcript diversity in both pluripotent and specialized cell types, which can be used to investigate transcriptomic changes in disease states. Additionally, this study underscores the utility of differential transcript usage analysis in advancing our understanding of neurodevelopmental and neurodegenerative diseases, paving the way for identifying transcript-specific therapeutic targets.

neuroscience↗

bioRxiv2024

DNA-SaM, a robust system for large-scale data storage

DNA data storage offers a viable strategy to address the impending data explosion. Early attempts to harness DNA as a storage medium have encountered scalability limitations, largely due to the complexity of codec algorithms, the generation of biochemically harmful sequences and lack of a robust architecture. We present "DNA-SaM", a novel system designed for DNA data storage, which achieves linear computational complexity and strict bio-constraint adherence, ensuring high coding efficiency and fidelity. It encoded data at speeds surpassing classic systems by over 2 orders of magnitude, with this superiority changes across various encoding algorithms. Importantly, DNA-SaM effectively eliminates any sequence that could be deleterious to in vitro and in vivo biochemical processes, including homopolymer runs, tandem repeat motifs, and potential promoter sequences, etc. It also involves an advanced DNA data storage architecture that incorporates a two-tiered indexing system and a novel "storage unit" distribution paradigm for large-scale data storage. It is further validated by practical data storage both in vitro and in vivo with a 100% success rate. Our system is capable of storing data over 1039 PB, which marks a critical advancement in the scalability of DNA-based data storage.

synthetic biology↗

bioRxiv2024

A Structural Mechanism for Noncanonical GPCRSignal Transduction in the Hedgehog Pathway

SUMMARY PARAGRAPHThe Hedgehog (Hh) signaling pathway is fundamental to embryogenesis, tissue homeostasis, and cancer. Hh signals are transduced via an unusual mechanism: upon agonist-induced phosphorylation, the noncanonical G protein-coupled receptor SMOOTHENED (SMO) binds the catalytic subunit of protein kinase A (PKA-C) and physically blocks its enzymatic activity. By combining computational structural approaches with biochemical and functional studies, we show that SMO mimics strategies prevalent in canonical GPCR and PKA signaling complexes, despite little sequence or secondary structural homology. An intrinsically disordered region of SMO binds the PKA-C active site, resembling the PKA regulatory subunit (PKA-R) / PKA-C holoenzyme, while the SMO transmembrane domain binds a conserved PKA-C interaction hub, similar to other GPCR-effector complexes. In contrast with prevailing GPCR signal transduction models, phosphorylation of SMO promotes intramolecular electrostatic interactions that stabilize key structural elements within the SMO cytoplasmic domain, thereby remodeling it into a PKA-inhibiting conformation. Our work provides a structural mechanism for a central step in the Hh cascade and defines a paradigm for disordered GPCR domains to transmit signals intracellularly.

biochemistry↗

bioRxiv2024

Habenula-ventral tegmental area functional coupling and risk-aversion in humans

Maladaptive responses to uncertainty, including excessive risk avoidance, are linked to a range of mental disorders. One expression of these is a pro-variance bias (PVB), wherein risk-seeking manifests in a preference for choosing options with higher variances/uncertainty. Here, using a magnitude learning task, we provide a behavioural and neural account of PVB in humans. We show that individual differences in PVB are captured by a computational model that includes asymmetric learning rates, allowing differential learning from positive prediction errors (PPEs) and negative prediction errors (NPEs). Using high-resolution 7T functional magnetic resonance imaging (fMRI), we identify distinct neural responses to PPEs and NPEs in value-sensitive regions including habenula (Hb), ventral tegmental area (VTA), nucleus accumbens (NAcc), and ventral medial prefrontal cortex (vmPFC). Prediction error signals in NAcc and vmPFC were boosted for high variance options. NPEs responses in NAcc were associated with a negative bias in learning rates linked to a stronger negative Hb-VTA functional coupling during NPE encoding. A mediation analysis revealed this coupling influenced NAcc responses to NPEs via an impact on learning rates. These findings implicate Hb-VTA coupling in the emergence of risk preferences during learning, with implications for psychopathology.

neuroscience↗

bioRxiv2024

Phage CRISPR-like regulatory RNAs silence bacterial adaptive and innate immunity

CRISPR RNAs (crRNAs) encoded by CRISPR arrays direct Cas nucleases against viruses. Some CRISPR-Cas loci also contain mini-arrays encoding crRNA-like RNAs (crlRNAs), which modulate transcription of cas or associated toxin genes that safeguard CRISPR-Cas activity. Here, we report that phages hijack these host crlRNA regulatory circuits to suppress bacterial immunity. Viral crlRNAs compete with host crRNAs for Cas protein binding and reprogram Cas proteins to silence their own expression or suppress transcription of CRISPR-safeguarding toxins. These anti-defense crlRNAs are found across diverse phages and plasmids, frequently organized into multiplexed transcriptional units resembling CRISPR arrays, and often synergize with co-encoded anti-CRISPR proteins to disable hierarchical host immune responses. Furthermore, we demonstrate that these compact viral crlRNA architectures can be harnessed for efficient mammalian genome editing. Our findings uncover widespread viral hijacking of host Cas proteins via crlRNAs, highlighting the recurrent exaptation of CRISPR-Cas regulatory functions to counter multilayered bacterial immune defenses.

microbiology↗

bioRxiv2024

Spatial Expression of Long Non-Coding RNAs in Human Brains of Alzheimer's Disease

BackgroundLong non-coding RNAs (lncRNAs) are critical regulators of physiological and pathological processes, with their dysregulation increasingly implicated in aging and Alzheimers disease (AD). To investigate the spatial and cellular distribution of lncRNAs in the aging brain, we leveraged published spatial transcriptomics (ST), single-nucleus RNA sequencing (snRNA-seq), and bulk RNA-seq datasets from the dorsolateral prefrontal cortex (DLPFC) of ROSMAP participants with and without pathological AD. ResultsLncRNAs exhibited greater subregion-specific expression than mRNAs, with enrichment in antisense and lincRNA biotypes. Subregion-enriched lncRNAs were generally not cell-type specific, and vice versa. Differential expression analysis of ST data identified AD-associated lncRNAs with distinct spatial patterns and moderate overlap with differentially expressed (DE) lncRNAs from bulk RNA-seq. Gene set enrichment revealed their involvement in chromatin remodeling, epigenetic regulation, and RNA metabolism. We also identified AD DE lncRNAs across major brain cell types using snRNA-seq but overlap with ST DE lncRNAs was limited. Among previously reported lncRNAs, OIP5-AS1 was consistently upregulated in AD in all cortical subregions. Antisense oligonucleotide (ASO) knockdown of OIP5-AS1 in iPSC-derived microglia led to upregulation of pro-inflammatory genes and downregulation of DNA replication and repair pathways. Immunoassays confirmed increased secretion of pro-inflammatory cytokines. The knockdown expression pattern was enriched for microglia-specific AD DE genes and microglia states. ConclusionsThis study provides a spatial and cellular map of lncRNAs in the aging human cortex and identifies subregion-and cell-type-enriched DE lncRNAs in AD. Our findings implicate OIP5-AS1 in microglial activation, suggesting its potential contribution to AD pathogenesis.

neuroscience↗

bioRxiv2024

The YTHDF Proteins Shape the Brain Gene Signatures of Alzheimer's Disease

The gene signatures of Alzheimers Disease (AD) brains reflect an output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulation., yet the dominant factor shaping these signatures remains unclear. To identify the most significant factor that shapes the AD brain signatures, we integrated cellular and molecular features with differential gene expression in in an explainable machine learning framework. Our result indicates that YTHDF proteins, the canonical readers of N6-methyladenosine RNA modification (m6A), are the most influential predictors of the AD brain signatures. We then show that protein modules containing YTHDFs are downregulated in human AD brains, and knocking down and pharmacologically inhibiting YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulate the AD-associated transcriptional signatures. Furthermore, eCLIP-seq analysis revealed that YTHDF proteins influence AD signatures through both m6A-dependent and independent pathways. These results highlight the central role of YTHDF proteins in shaping the gene signatures of AD brains.

neuroscience↗

bioRxiv2024

Zika and Dengue Viruses Differentially Modulate Host mRNA Processing Factors Defining Its Virulence

Rising global temperatures coupled with increasing international travel, and trade are contributing to spread of vectors such as ticks and mosquitoes, resulting in a surge of vector-borne flavivirus infection in human population. Furthermore, this increase in flavivirus infection pose threat to the safety of biologics such as cell and gene therapy products as human-derived materials are commonly used during manufacturing of these drug products. In this study, we conducted time-course transcriptomic and protein analyses to uncover the host molecular factors driving the virulence of Zika virus (ZIKV) and Dengue virus (DENV) in the context of host defense mechanisms, as these two viruses have caused the most recent and significant flavivirus outbreaks. Compared to DENV, ZIKV exhibited stronger virulence and cytopathic effects. RNA sequencing analysis revealed differential expression of various cellular factors, including RNA processing factors. Further investigation identified cell-type and time-dependent upregulation nonsense-mediated RNA decay (NMD), RNA degradation factors and nuclear pore complex (NPC) transcripts. Protein analysis showed that ZIKV, unlike DENV, degrades NMD factors in host cells, which along with mis-regulation of RNA degradation factors resulted in accumulation in host intronic transcripts as revealed by RNA-seq data. We also found that active nuclear transport is required for ZIKV replication, suggesting that therapeutic targeting of the NPC could potentially be effective in controlling ZIKV infection. Furthermore, from our findings we hypothesize that, ZIKV, but not DENV, drives early host cell cytopathy through targeted protein degradation. Current studies are underway to develop novel strategies to detect ZIKV, DENV and other flaviviruses in biologics based on transcriptomics and proteomics. TeaserExploring the molecular basis of flavivirus virulence in host cells.

genomics↗