Biology subjects

Kumar, R.

Publications and source records attributed to Kumar, R..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Extracellular vesicles facilitate the horizontal transfer of drug resistance and stem-like properties between ovarian tumor cells

Ovarian cancer stem cells (CSCs) can seed recurrent drug-resistant disease. Likewise, non-CSCs can acquire CSC phenotypic properties. How this process is orchestrated is of interest to inform how it might be prevented. We tested the hypothesis that ovarian CSC and/or drug-resistant tumor cells confer stem-like properties via extracellular vesicles (EVs). We focused our investigation on how EVs might mediate EZH2 signaling to promote a phenotypic change in drug-sensitive, non-CSCs. To accomplish this, we utilized paired PARP inhibitor-sensitive and - resistant ovarian cancer (OvCa) cell lines, EZH2 knockdown lines, and patient-derived organoids (PDOs) originating from recurrent high-grade serous OvCa. Small EVs isolated from drug-sensitive, CSC and/or drug-resistant enriched cultures, PARP inhibitor (olaparib) resistant lines, or drug-treated (olaparib or carboplatin) lines were cultured with treatment naive or sensitive lines for defined time points. The impact of small EV exposure was determined by assessing cell number, metabolic activity, viability, sphere and colony-forming capacity, ALDH activity, DNA damage, and changes in associated signaling pathways. We found that EVs from CSC or drug-resistant enriched cell fractions communicate CSC-like phenotypes to the more sensitive tumor cells via EZH2 canonical and non-canonical signaling pathways, promoting stemness. We conclude that EV-mediated activation of EZH2 signaling represents a targetable mechanism contributing to stemness-associated drug resistance in OvCa. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/699925v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@6b4ffborg.highwire.dtl.DTLVardef@1501931org.highwire.dtl.DTLVardef@1a5f31aorg.highwire.dtl.DTLVardef@1fb475f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Assembly and glycosylation of Helicobacter pylori sheathed flagella

The bacterial flagellum is a complex nanomachine essential for motility, colonization, and invasion in diverse species. Helicobacter pylori has evolved elaborate sheathed flagella that enable migration through the highly viscous gastric mucus layer to reach its colonization niche on the gastric epithelium, yet the molecular basis for these unique adaptations has remained elusive. Here, we use in-situ single particle cryo-electron microscopy to determine near-atomic structures of the flagellar filament within the membranous sheath of H. pylori. The major flagellin FlaA constitutes the bulk of the filament, whereas the minor flagellin FlaB contributes critically to the hook-proximal region. Both FlaA and FlaB form a conserved core surrounded by variable surface-exposed domains. Our structures further reveal that pseudaminic-acid glycans decorate these domains, where they mediate inter- and intra-subunit contacts that stabilize the filament and confer a negatively charged surface. Together, these findings support a model in which the filament rotates independently of the membranous sheath to drive H. pylori motility and provide a molecular framework for understanding how the sheathed flagellum enables colonization and persistence within the gastric niche. Significance StatementWe present the first in-situ near-atomic structure of the sheathed flagellar filament in Helicobacter pylori, revealing distinctive adaptations that underpin the pathogens unique motility and persistent infection. Our in-situ structures show that the two flagellins, FlaA and FlaB, assemble into an extended and exceptionally stable filament through an extensive hydrogen-bonding network. Pseudaminic acid glycans decorate the surface-exposed domains, where they stabilize inter-subunit packing and render the surface negatively charged and hydrophilic. These findings, which provide insight into the assembly of the flagellar filament and its relationship to the surrounding sheath, provide a structural framework for developing strategies to disrupt H. pylori motility and infection.

microbiology↗

bioRxiv2025

A multi-tiered microDicer with hierarchical blades achieves protein-preserving microdissection down to 10 microns

To study tissue heterogeneity at the sub-millimeter scale, laser capture microdissection (LCM) has been the leading technology for isolating regions of interest (ROI) for downstream molecular profiling. As the ROI approaches cellular dimensions ([~]10 m), laser-induced photothermal damage and challenges in capturing microtissues in conventional LCM can compromise protein preservation and quantitative fidelity. This work introduces multi-tiered Dicers, fabricated by two-photon polymerization, to mechanically dissect tissue slices into uniform microtissues down to 10 m. The hierarchical blade architecture limits instantaneous blade-tissue engagement and lowers the cutting force relative to single-tier designs. For benchmarking, proteomic analysis is performed on ethanol-fixed human squamous cell carcinoma microtissues generated by Dicers and by LCM. Under identical Nanodroplet Processing in One pot for Trace Samples (nanoPOTS) and liquid chromatography-mass spectrometry (LC-MS) conditions, Dicers yield more peptides and proteins than LCM, with the largest gains at 10-20 m spatial resolution. Confocal imaging shows catapult-associated cavities in LCM-generated microtissues. This material loss, along with membrane-limited protein extraction, likely reduces protein coverage. In contrast, multi-tiered Dicers enables reproducible microdissection down to 10 m while maintaining high protein coverage. With spatial registration of microtissues under development, Dicers have potential to complement LCM for next-generation spatial proteomic workflows.

bioengineering↗

bioRxiv2025

Near-atomic in-situ architecture and membrane-coupled dynamics of the Vibrio cholerae sheathed flagellum

The sheathed flagellum of Vibrio cholerae is a self-assembling membranous organelle that must coordinate axial assembly, sheath biogenesis, and rapid motor rotation. Here, we determine in-situ near-atomic structures of the sheathed flagellar motor inside intact cells. The motor anchors to the outer membrane through lipidated HL-rings without forming a membrane pore, thereby allowing axial assembly to drive sheath formation. Conserved LP-rings act as slide-rotary bushings that permit high-speed rotation within a dynamic envelope yet can constrict to seal the pore upon stress-induced ejection. We further show that stator activation requires a specific PomB-MotX interaction rather than peptidoglycan engagement. Together, these findings reveal how the distinctive architecture and dynamics of the sheathed flagellum promote V. cholerae motility, environmental survival, and persistent colonization of the human gut.

microbiology↗

bioRxiv2025

Iron addicted colorectal cancers exploit Heme-Complex II axis to resist oxidative cell death

Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and rapid proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most other cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. One pathway thought to mediate iron toxicity is ferroptosis, an iron-dependent form of cell death. However, most ferroptosis regulators were identified through synthetic chemical screens or small molecule activators, and it remains unclear whether these canonical pathways explain how iron itself triggers cell death, particularly in vivo. Here, using multi-omics profiling, CRISPR screening, and in vivo models, we uncover a heme-succinate dehydrogenase (SDH)-Coenzyme Q (CoQ) axis that enables CRC cells to buffer iron-induced oxidative stress. Heme-dependent SDH reduces CoQ, which redistributes to mitochondrial and plasma membranes to detoxify lipid ROS as a radical trapping antioxidant. This pathway functions alongside, and in some contexts independently of, canonical ferroptosis regulators. These findings reveal that CRCs co-opt metabolic cofactors not only for growth but also for survival under physiologically toxic iron levels, uncovering new vulnerabilities for therapy.

cancer biology↗

bioRxiv2025

Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss

Abstract1-2% of all human pregnancies suffer from idiopathic recurrent pregnancy loss (RPL) and underlying molecular causes are poorly understood. Here we show that defective Protein Arginine Methyltransferase 1 (PRMT1) function in trophoblast progenitors is a molecular cause for early pregnancy failure. PRMT1 is conserved in trophoblast progenitors and conditional deletion of PRMT1 in mouse trophoblast progenitors arrests placenta and embryonic development leading to lethality [~]E7.5. Remarkably, a subset of idiopathic RPL is associated with loss of PRMT1 in cytotrophoblast progenitors (CTBs). Experiments with human trophoblast stem cells (hTSCs), derived from these RPL-patients as well as PRMT1-depleted hTSCs revealed that PRMT1 is crucial for trophoblast progenitors self-renewal. Employing RNA-seq and CUT&RUN-sequencing in hTSCs, CTBs and primary mouse trophoblast progenitors we discover that PRMT1 promotes transcription of trophoblast stem-state regulators, like TEAD4 and MYBL2, by directly enriching histone H4 arginine 3 asymmetric di-methylation (H4R3Me2a) at their chromatin loci. PRMT1 is also essential for extravillous trophoblast (EVT) development during human placentation, while loss of PRMT1 in hTSCs spontaneously promotes syncytiotrophoblast (STB) differentiation. Our findings indicate that PRMT1 is an epigenetic governor that orchestrates mammalian trophoblast development and implicate the therapeutic potential of targeting the PRMT1-H4R3Me2a axis to mitigate early pregnancy loss.

developmental biology↗

bioRxiv2025

Mutations in antimicrobial peptides differently affect sleep and plasticity

Molecules implicated in host defense can, independent of their roles as immune mediators, regulate sleep. In mammals, cytokines such as Tumor Necrosis Factor (TNF ) and Interleukin 1{beta} (IL1{beta}) promote sleep. In Drosophila, infection stimulates the systemic release of a battery of anti-microbial peptides (AMPs). These fly immune effectors have been understudied as sleep modulators. We obtained mutants in different AMPs and characterized their functions in sleep and sleep dependent outputs. AMP mutants sleep less with a longer sleep latency, and lowered arousal thresholds. Group C mutant flies, doubly mutant for the anti-fungal peptides Metchinikowin (Mtk) and Drosomycin (Drs), showed the greatest impairments. These Group C mutants also showed an exaggerated sleep rebound. Sleep rebound was unaltered in other mutants. Different sets of AMP mutants exhibited specific disruptions in socialization and rocking induced sleep. These data are a detailed characterization of sleep regulation in AMP mutants. We also evaluated sleep functions. Group C mutants uniquely exhibited normal learning and memory, and lower synapse abundance, despite sleeping the least. Group C mutants are thus able to carry out some sleep functions without sleeping very much. Glial knockdown of Metchnikowin and Drosomycin mimicked the sleep phenotypes of the null mutants, these genes thus act from glia. Sleep and memory defects in AMP mutants was reversible - enhancing sleep of Bomanin mutants pharmacologically or behaviorally improved learning and memory. Together, these data suggest that AMPs are potent sleep modulators and that different classes of AMPs differently affect sleep and sleep dependent outcomes.

neuroscience↗

bioRxiv2025

Essential role for Nup43 in Drosophila fertility and spermiogenesis through Myosin VI-dependent actin cone assembly dynamics

Nuclear pore complexes, composed of nucleoporins (Nups), are critical for bidirectional nucleocytoplasmic transport. Studies on Nups have linked them with various cellular processes, including cell division, contributing significantly to organismal development. Intriguingly, Nup43, an integral member of Nup107 complex, is linked with premature ovarian insufficiency in humans. Here, we report that Nup43 is integral to the maintenance of Drosophila fertility. Both the females and males of Nup43 null mutant are sterile. In Nup43 mutants, embryonic development is halted at the first division stage, and males are sterile due to an arrest at the canoe stage of spermiogenesis. The nuclear elongation, shaping, and actin cone assembly steps of individualization complex formation are adversely affected, suspending sperm maturation. Expression through Nup43 transgene in Nup43 null mutants completely rescues spermiogenesis defects. Actin-based motor, Myosin VI (jar), interacts with Nup43 and rescues the actin cone assembly but not the sterility defects. We have uncovered a novel non-canonical function for Nup43 in Drosophila spermiogenesis, and propose that Nup43, along with jar, facilitates sperm individualization by promoting actin cone assembly.

developmental biology↗

bioRxiv2025

Gasdermin C links nutrient and immune signaling to protist-induced type 2 immunity and intestinal repair

The Gasdermin family of proteins has recently been implicated in tissue repair and homeostasis through their effector function in type 2 immunity and pyroptosis. Yet the role of Gasdermin C proteins has not been fully characterized in the mammalian intestine, where environmental factors can influence epithelial regeneration and repair. Here we report that Gsdmc2-4 genes are regulated in a nutrient-dependent manner and are suppressed with aging. We uncover that commensal protists in the gut regulate Gsdmc2-4 expression through activation of type 2 immune responses. In intestinal organoid experiments, we find that STAT6 is necessary for Gsdmc2-4 induction in response to type 2 cytokines; however, basal expression of Gsdmc2-4 in vivo is only partially diminished in Stat6 knockout animals. Finally, in protist-colonized animals, loss of Gsdmc1-4 exacerbated mucosal erosion and inflammation in response to Dextran sodium sulfate (DSS) exposure, implicating these proteins in coordinating epithelial responses to injury.

physiology↗

bioRxiv2025

Oxidative stress-induced proteolytic activation of polyphenol oxidase triggers an oxidized flavonoids-mediated stress signaling in Camellia sinensis

Environmental perturbations often increase reactive oxygen species (ROS) production, inducing oxidative damage to various biomolecules. The cellular system utilizes ROS or ROS-generated metabolites to instigate signaling pathways, resulting in acclimation, growth inhibition, or programmed cell death (PCD) for sustaining stress. Various stress-generated or stress-activated signaling components and downstream pathways are identified in model plants; however, they are largely unexplored in non-model plants. Here, we report a stress-induced proteolytic activation of an evolutionarily conserved chloroplast-localized enzyme, polyphenol oxidase (PPO), that oxidizes catechins into theaflavins (TFs) and initiates a stress signaling under drought in Camellia sinensis (Tea). Germplasm-based analysis revealed a heightened proteolytic activation of PPO and consequent TFs accumulation in drought-susceptible genotypes. Transcriptome analysis revealed that PPO activation and TFs accumulation were linked to the activation of UPR(unfolded protein response)-like response, which was reinforced by virus-induced silencing and overexpression of PPO, and direct feeding of TFs in tea plants. Pharmacological treatments revealed that TFs interact with HSP90, activating a canonical IRE-bZIP60-dependent ER stress pathway resulting in PCD. Similar proteolytic activation of PPO and subsequent instigation of stress signaling in other plant species (tomato and wheat) demonstrated that PPO acts as an evolutionarily conserved stress sensor, instigating an inter-organelle communication in plants. Significance statementPPO, an evolutionarily conserved and chloroplast/plastid localized enzyme, senses stress and undergoes proteolytic activation to generate oxidized flavonoids/quinones that function as signaling molecules in Tea and likely in other plants. The oxidized flavonoids modulate protein folding machinery and augment folding stress, especially in the ER, inducing canonical IRE1-bZI60-dependent PCD. The finding shows that specific secondary metabolites likely have roles in instigating intra- and intercellular communication to sustain the adversities of stress in different plant species.

plant biology↗

bioRxiv2025

Exploring the effect of dynamic deformation on the tight junctions of endothelial cells

Atherosclerosis (Ath) is a leading cause of cardiovascular deaths, accounting for approximately 17.1 million fatalities annually. This condition arises from plaque-induced arterial narrowing, which obstructs blood flow. Traditional animal models face ethical, economic, and translational limitations, while current in vitro models often oversimplify plaque formation by using fixed channels and neglecting the dynamic effects of narrowing on endothelial junctions. The study addresses the limitations by developing a microfluidic device that mimics human-relevant stenosis with dynamic channel narrowing under continuous perfusion. Endothelial cells, which are crucial for maintaining barrier integrity through tight junctions, are subjected to physiological shear stress and hyperlipidaemic conditions by administering free fatty acids. The model evaluates cell alignment, junctional stability, and disease progression under mechanically deformed static conditions. To validate the translational potential of this system, ROS scavenging drug, quercetin is tested for its ability to reverse oxidative stress and barrier dysfunction. This innovative microphysiological system offers a robust platform for investigating endothelial dysfunction in Ath and provides a valuable alternative to animal models for cardiovascular drug testing. By integrating both biochemical and mechanical cues in a controllable environment, this model aims to enhance our understanding of Ath and facilitate the development of more effective therapeutic strategies.

bioengineering↗

bioRxiv2025

Genome-wide association study, network analysis, and reverse genetics pinpoint novel genes associated with seedling root growth variation of Arabidopsis thaliana under drought

Development of drought-resilient crops requires a precise understanding of molecular signaling in the root, the primary organ encountering drought. This study unraveled novel genetic loci contributing to drought tolerance by exploiting the natural variation in seedling root growth of Arabidopsis thaliana under PEG-induced drought stress. Through a genome-wide association study (GWAS) of 207 worldwide Arabidopsis thaliana ecotypes from regions with varied rainfall, 68 protein-coding genes were identified, associated with the top 50 single-nucleotide polymorphisms (P < 10- 3), explaining 63% of the observed variation in root length. Subsequent network and functional enrichment analyses of the GWAS-delineated genes demarcated key biological processes crucial for maintaining root growth under drought, including DNA repair, tRNA editing, protein folding and quality control, cell cycle regulation, stress granule assembly, and the pyridoxal 5'-phosphate (PLP) salvage pathway regulating oxidative stress in roots. Expression level polymorphisms, promoter cis-element variations, and amino acid substitutions affecting predicted protein dynamics, with phenotype and climate associations, were identified. Finally, reverse genetic evaluation using T-DNA insertion knockout/knockdown mutants confirmed a direct association of the identified candidate genes, AT1G06690 (PLP pathway), AT4G26990 and RBP45C (stress granule assembly), ACD55.5 (protein folding), PCMP-A4 (RNA modification), SKS6 and ANAC094 (cell wall remodeling), and INCENP (cell cycle regulation), with seedling drought tolerance. Furthermore, the knockdown of AT1G06690 led to higher accumulation of hydrogen peroxide in root tissues, inhibiting growth. Future translation of the current findings into crops will provide new tools for the improvement of drought tolerance by modulating root traits through biotechnology and breeding.

genetics↗

bioRxiv2025

The Annotated Blueprint: Integrated Functional Genomic Resources for a Model Tetraploid Wheat Triticum turgidum cv. Kronos

Triticum turgidum cv. Kronos is a tetraploid wheat cultivar that underpins one of the richest community platforms for functional genomics. Over the past decade, about 3,000 exome- and promoter-capture datasets, linked to mutagenized seed stocks, and transcriptomic and phenotypic resources have accumulated, yet the absence of a reference genome has constrained their impact. Here, we present a chromosome-scale reference genome of Kronos with high-confidence annotations, including manual curation of over 1,000 disease resistance (NLR) genes. This reference revealed previously hidden NLR diversity and clarified their genomic organization at chromosomal ends. Re-analysis of exome- and promoter-capture datasets enabled high-resolution mutation discovery in genes and regulatory regions that were previously inaccessible, uncovering the full standing variation present in Kronos mutant lines. We further re-curated transcriptomic and small RNA datasets, generating improved, genome-wide maps of microRNAs and phasiRNAs important for wheat development. Collectively, these resources elevate Kronos to reference quality and establish it as a versatile platform for functional and translational wheat research.

plant biology↗

bioRxiv2025

Chronic Cadmium Exposures and Hyperglycemia Additively Drive Mitochondrial Dysfunction in Hepatic Cells: Key Implications for MASLD Etiopathogenesis

Effects of chronic heavy metal stress on hepatocellular pathophysiology remains ill-understood. Human livers are a long-term accumulative site for many toxic heavy metals (e.g., cadmium and arsenic) whose effects are unknown. In the current study, we studied effects of chronic, low-dose exposures of cadmium (CLEC) modulated by normoglycemic (5.6 mM) and hyperglycemic (15 mM) exposures, focusing on hepatocellular mitochondrial function. HepG2 and HUH7 cell lines were exposed to CLEC and glucose for 24 weeks, mimicking a chronic heavy metal exposure paradigm seen in normal and type II diabetic individuals. We observe that CLEC exposures significantly affect the long-term health of mitochondria, including decreased mitochondrial mass, increased superoxide production, and loss of mitochondrial membrane potential (MMP) in a CLEC and glucose-dependent manner. Furthermore, the Seahorse MitoStress assay revealed CLEC induced significant chronic oxidative stress. In particular, CLEC cells showed altered levels of basal and non-mitochondrial respiration, causing dysregulation in mitochondrial oxygen consumption rates (OCRs). Lastly, we identified significant impacts of CLEC and glucose exposures on the mitochondrial dynamics (fission/fusion) of the CLEC cells, which showed enhanced mitochondrial fragmentation and turnover rates. We also identified novel cell compensatory mechanisms that may mask the true extent of chronic Cd exposure induced damage in liver cells. CLEC and glucose work additively to damage hepatocellular mitochondrial function. New approach methodologies (NAMs), such as the current vitro toxicology study, establish the insidious effects of chronic heavy metal pollutant exposures on human hepatocellular function.

pharmacology and toxicology↗

bioRxiv2025

Fundamental Limits of Inferring Dynamical Gene Regulatory Models from Single-Cell Data

A long-standing goal in systems biology is to construct computational models that capture gene regulatory dynamics. On the one hand, graph-based regulatory network models rely on prior knowledge but are constrained by unknown kinetic parameters. On the other hand, recent advancements in single-cell sequencing technologies, particularly RNA velocity and pseudotime analysis, offer data-driven approaches to infer kinetic parameters. However, accurate modeling of biological dynamics requires the estimation of the Jacobian matrix, which captures signal propagation within a regulatory system. Several computational methods have recently emerged to infer Jacobians from single-cell data, including SpliceJAC, scMomentum, and Dynamo. Here, we evaluate these methods by analyzing Jacobian eigenvalues, assessing their ability to capture stability and oscillatory properties. Using simulated ground truth data, we find that methods such as Dynamo and scMomentum generate models that capture the behavioral properties of the cells, however, they do not reliably capture the structural properties. Our results highlight the limitations of dynamic GRN inference, namely, the inability of kinetics to alleviate the need for further structural constrains for the models to adequately reflect the structural properties of the GRN. Developing more robust approaches for Jacobian estimation from single-cell data will be essential for building accurate, large-scale dynamical models of gene regulation. Graphical AbstractOverview of Benchmarking Jacobian-based inference in single-cell RNA Data. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/674509v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@13496e2org.highwire.dtl.DTLVardef@19e0250org.highwire.dtl.DTLVardef@a9db39org.highwire.dtl.DTLVardef@17789e2_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Positive Selection Screen for Natural Product β-Catenin Inactivators

Many genetically validated targets in cancer, including the transcription factor {beta}-catenin ({beta}-cat), have historically been viewed as undruggable. Cell-based phenotypic screening of chemical compounds can reveal new biological and pharmacological principles. Natural products are powerful probes because of their superior structural diversity, drug-like properties, and biological activities as compared to unoptimized synthetic compounds. We screened 326,304 natural product mixtures (40,744 extracts and 285,560 fractions derived from them) using mammalian cells expressing an oncogenic version of {beta}-cat fused to a suicide protein. Multiple fractions degraded the {beta}-cat fusion protein or drove it into a compartment where both fusion partners were apparently inactive. The active natural product from one of the latter specifically activates novel, but not classical, protein kinase Cs (PKCs) and thereby relocates {beta}-cat to juxtamembrane vacuolar structures. These findings suggest a path for inactivating oncogenic {beta}-cat and underscore the power of screening natural product collections with robust phenotypic assays.

cancer biology↗

bioRxiv2025

Comprehensive Transcriptomic and Epigenomic Insights into Environmental Toxicant Exposures: The TaRGET II Resource

Environmental exposures to toxic chemicals can profoundly alter the transcriptome and epigenome in both humans and animals, contributing to disease development across the lifespan. To elucidate how early-life exposure to toxicants exerts such persistent effects, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 2,564 epigenomes and 1,043 transcriptomes from longitudinal studies in mice. All data are publicly available through the TaRGET II data portal and the WashU Epigenome Browser. This resource from target (liver, brain, lung, heart) and surrogate (blood) tissues at weaning (3 weeks) and two adult time-points (5 and 10 months) characterized the molecular response to arsenic (As), lead (Pb), bisphenol-A (BPA), di-2-ethylhexyl phthalate(DEHP), tributyltin (TBT), tetrachlorodibenzo-p-dioxin (TCDD), and particulate matter with a diameter of <2.5m (PM2.5). The findings revealed persistent, toxicant-specific, sex-dependent epigenomic and transcriptomic perturbations, resulting in disrupted expression of 14,908 genes, altered chromatin accessibility at 87,409 regulatory elements, DNA methylation changes at 113,186 genomic regions, and chromatin state switching of histone modifications. The resulting high-resolution map of how environmental exposures reprogram the epigenome and transcriptome is broadly accessible via ToxiTaRGET database, offering unparalleled opportunities for the scientific community to investigate the molecular underpinnings of environmental toxicant exposures and their contributions to disease pathogenesis.

pharmacology and toxicology↗

bioRxiv2025

ToxiTaRGET: a multi-omics resource for toxicant-responsive molecular targets

Environmental toxicant exposures can induce widespread alterations in both the transcriptome and epigenome of mammals, and directly contribute to the increased risk of various diseases, including cardiovascular disorders, cancer, and neurological disorders. To evaluate how early-life toxicants produce long-term impacts on the transcriptome and epigenome in mice, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 3,607 multi-omics from longitudinal studies in mice. The molecular changes in responding to distinct environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.5), were systematically identified and visualized on an integrative platform, ToxiTaRGET, to allow quickly search and browse by researchers. ToxiTaRGET houses a rich repository of molecular signatures, including gene expression, chromatin accessibility, and DNA methylation profiles, in response to early-life toxicant exposures. These molecular signatures span multiple biologically important tissues in both male and female mice at three distinct life stages, offering a valuable resource for the environmental health and toxicogenomic research communities.

bioinformatics↗