Biology subjects

Zhu, J.

Publications and source records attributed to Zhu, J..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

Role of genetic frustrations in cell reprogramming

The cell fate transition is a fundamental characteristic of living organisms. By introducing external perturbations, it is possible to artificially intervene in cell fate and trigger cell reprogramming. Revealing the general principle underlying the induced phenotypic reshaping of cell populations remains a central focus in the field of cell biology. In this study, we investigate the energetic and dynamic features of induced cell phenotypic transition from differentiated somatic state to pluripotent state by constructing a Boolean genetic network model. The simulation and experimental results highlight the critical role of genetic frustration in initiating cell fate transitions, although the two ending phenotypic states are typically featured by minimal frustration. In addition, the altered gene expression profiles exhibit a scale-free distribution, suggesting that there exist a small number of critical genes responsible for the cell fate transition. This study provides important insights into the dynamic principles governing effective cell reprogramming caused by artificial or exogenous interventions.

systems biology↗

bioRxiv2025

TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy

Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic {beta}-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin-and receptor-mediated mitophagy through the restriction of Parkin. Together, we illustrate that {beta}-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.

molecular biology↗

bioRxiv2025

Epidermal stem cell-derived extracellular vesicles induce fibroblasts mesenchymal-epidermal transition to alleviate hypertrophic scar via the miR-200s/ZEBs axis

Hypertrophic scar (HS) is a prevalent yet unresolved wound healing complication characterized by persistent hyperactive and proliferative fibroblasts, leading to excessive extracellular matrix (ECM) synthesis and collagen contraction. Our previous studies have identified epidermal stem cells (ESCs) as critical for wound healing and HS remodeling, with its extracellular vesicles (EVs) playing a vital role. However, the specific mechanisms remain unclear. In this study, we first discovered that ESC-EVs could effectively induce the mesenchymal-epidermal transition (MET) of HS fibroblasts (HSFs) and inhibit their biological activity. Furthermore, by next-generation sequencing and multiplexed CRISPR/Cas9 system, we elucidated that this therapeutic effect is mediated by the miR-200 family (miR-200s) encapsulated in ESC-EVs, which targeted and inhibited ZEB1 and ZEB2 in HSFs. This vital role and mechanism have been thoroughly validated in both in vitro cell experiments and in vivo rat tail HS (RHS) models. These findings not only shed light on a previously unidentified mechanism of ESC-EVs for HS, but also provide potential novel targets and strategies for its precise treatment.

cell biology↗

bioRxiv2025

Impact of infusion conditions and anesthesia on CSF tracer dynamics in mouse brain

Tracer imaging has been instrumental in mapping the brains solute transport pathways facilitated by cerebrospinal fluid (CSF) flow. However, the impact of tracer infusion parameters on CSF flow remains incompletely understood. This study evaluated the influence of infusion location, rate, and anesthetic regimens on tracer transport using dynamic contrast-enhanced MRI with Gd-DTPA as a CSF tracer. Infusion rate effects were assessed by administering Gd-DTPA into the cisterna magna (ICM) at two rates under isoflurane anesthesia. Anesthetic effects were evaluated by comparing transport patterns between isoflurane and ketamine/xylazine (K/X) anesthesia at the slower rate. Gd-DTPA transport was also examined after lateral ventricle (ICV) infusion, the primary site of CSF production. The results demonstrate that, besides anesthesia, both the location and rate of infusion substantially affected solute transport within the brain. ICV infusion led to rapid, extensive transport into deep brain regions, while slower ICM infusion resulted in more pronounced transport to dorsal brain regions. Cross-correlation and hierarchical clustering analyses of region-specific Gd-DTPA signal time courses revealed that ICM infusion facilitated transport along periarterial spaces, while ICV infusion favored transport across the ventricular-parenchymal interface. These findings underscore the importance of experimental conditions in influencing tracer kinetics and spatial distribution in the brain.

physiology↗

bioRxiv2025

Target-based de novo design of cyclic peptide binders

Cyclic peptides have become a new focus in drug discovery due to their ability to bind challenging targets, including "undruggable" protein-protein interactions, with low toxicity. Despite their potential, general methods for de novo design of cyclic peptide ligands based on target protein structures remain limited. Here, we developed CYC_BUILDER, a reinforcement learning based fragment growing method for efficient assembly of peptide fragments and cyclization to generate diverse cyclic peptide binders for target proteins. CYC_BUILDER employs a Monte Carlo Tree Search (MCTS) framework to integrate seed fragment exploration, fragment fusion based peptide growth, structure optimization, evaluation and peptide cyclization. It supports peptide cyclization through both head-to-tail amide bond and disulfide bond formation. We first validated CYC_BUILDER on known protein-cyclic peptide complexes, demonstrating its ability to accurately re-generate cyclic peptide binders in terms of both sequences and binding poses. We then applied it to design cyclic peptide inhibitors for TNF, a key mediator in inflammation-related diseases. Among the nine experimentally tested designed peptides, four showed potent binding to TNF and inhibited its cellular activity. CYC_BUILDER provides an efficient tool for cyclic peptide drug design, offering significant potential for addressing challenging therapeutical targets.

biochemistry↗

bioRxiv2025

Invasive lobular carcinoma integrated multi-omics analysis reveals silencing of Arginosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistance

Invasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and strong hormone receptor positivity. ILC faces significant challenges in clinical management due to advanced stage at diagnosis, late recurrence, and development of resistance to endocrine therapy - a cornerstone of ILC treatment. To elucidate the mechanisms underlying endocrine resistance in ILC, ILC cell lines (MDA-MB-134-VI, SUM44PE) were generated to be resistant to tamoxifen, a selective estrogen receptor modulator. The tamoxifen-resistant (TAMR) cells exhibit a 2-fold increase tamoxifen IC50 relative to parental cells. Metabolomics and RNA-sequencing revealed deregulation of alanine, aspartate, and glutamate metabolism, purine metabolism, and arginine and proline metabolism in TAMR cells. Among the fifteen commonly dysregulated genes in these pathways, low ASS1 expression was identified in the TAMR cells and was significantly correlated with poor outcome in ILC patients, specifically in the context of endocrine therapy. Our study reveals methylation mediated silencing of ASS1 in TAMR cells as a likely mechanism of downregulation. Demethylation restored ASS1 expression and correspondingly reduced tamoxifen IC50 toward parental levels. Nucleic acid biosynthesis is augmented in TAMR cells, evidenced by increase in nucleotide intermediates. Both TAMR cell lines demonstrated increased expression of several nucleic acid biosynthesis enzymes, including PAICS, PRPS1, ADSS2, CAD, and DHODH. Furthermore, CAD, the key multifunctional protein of de novo pyrimidine biosynthesis pathway is differentially activated in TAMR cells. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveils ASS1 downregulation as a novel mechanism underlying acquired tamoxifen resistance in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. Restoring ASS1 expression or inhibiting pyrimidine biosynthesis restored tamoxifen sensitivity. ASS1 could be a potential biomarker and therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.

cancer biology↗

bioRxiv2025

Multiple Types of Context-Specific Brain Causal Regulatory Networks and their Applications to Autism Spectrum Disorder

One of the primary goals of systems biology is to understand how different cell types are regulated at various developmental stages and how dysregulation in these cells contributes to disease. With advances in high-throughput omics profiling technologies, vast amounts of both bulk tissue and single-cell data have been generated to study cellular regulation. To investigate the types of gene-gene regulatory interactions that can be uncovered from bulk versus single-cell profiling data, we constructed multiple context-specific brain gene regulatory networks using brain bulk and single-cell RNA-seq datasets and applied two distinct computational methods: an integrative Bayesian Network (BN) and a deep learning model, Geneformer. A total of 39 networks were generated, comprising 13 brain region-specific Bayesian networks from bulk RNA-seq data (bulk_BNs), 13 cell-type and developmental stage-specific Bayesian networks, and 13 corresponding Geneformer-based networks from scRNA-seq data (sc_BNs and sc_GFs, respectively). We compared these networks in terms of their topological features, biological pathway regulation, and known regulatory relationships among disease-related genes. Our analysis revealed distinct network properties driven by data source type (bulk vs. single-cell RNA-seq) and network inference method (integrative Bayesian Network vs. deep learning Geneformer). Neurodegenerative disease-related pathways were co-regulated in bulk_BNs, while sc_BNs and sc_GFs captured pathways associated with neuroactive ligand-receptor interactions. To demonstrate the utility of these networks, we leveraged them to investigate potential disease mechanisms of Autism Spectrum Disorder (ASD). We found that ASD risk genes were enriched among hub genes common across networks but were more frequently hubs in context-specific networks, underscoring the significance of inhibitory interneurons during early developmental stages in ASD. Additionally, we showed that these networks could effectively recapitulate context-specific ASD gene signatures. In summary, this study highlights the complementary value of integrating multiple data types through different computational approaches to advance our understanding of disease-related molecular mechanisms, such as those involved in ASD. Our findings provide a framework for using context-specific gene regulatory networks to identify disease-causal genes and key regulators of signaling pathways, potentially guiding future therapeutic strategies.

bioinformatics↗

bioRxiv2025

Interaction of Gut-Microbial Amyloids with Endogenous Amyloids can Drives Microglial Hyperactivity and Neuroinflammation in Alzheimers Disease

Gut bacteria have emerged as silent drivers in the pathology of Alzheimers disease (AD). They also make amyloids with structure analogue to pathological amyloids and have potential to cross-seed and propagate in a prion-like manner. AD is characterised by the accumulation of mature extracellular Amyloid-{beta} (A{beta}) plaques which are surrounded by inflammatory microglia. We report that exposure to interspecies microbial amyloids of FapC (fimbriae) and CsgA (curli) from opportunistic gut pathogens Pseudomonas aeruginosa and Escherichia coli hyperactivates microglia against A{beta} fibrils. Microbial amyloids and A{beta} fibrils converge in phagocytic compartments through subsequent internalization, not observed with A{beta} fibrils alone. This convergence promotes pro-inflammatory microglia with a defective proteome similar to those observed in AD brains. The resulting clusters develop a pro-inflammatory, indigestible interactome that is eventually regurgitated, inducing progressive degeneration in bystander neurons and ultimately leading to cognitive decline. Collectively, these findings provide compelling evidence that microbial amyloids can trigger progressive AD pathology through microglia-driven neuroinflammation.

cell biology↗

bioRxiv2025

Precision mRNA Nanomedicine for Targeted Vascular Therapies in ARDS and Atherosclerosis

Vascular diseases, including acute respiratory distress syndrome (ARDS) and atherosclerosis, are leading causes of global morbidity and mortality, underscoring the critical need for innovative therapies. While human genetics has uncovered specific molecular mechanisms in endothelial cells that drive acute and chronic vascular inflammation central to these conditions, effective in vivo strategies to spatiotemporally target these disease-causing pathways using therapeutic mRNAs remain limited. Here, we present a modular and tunable nanoparticle platform (PROGRAMMED nanoparticles) engineered to selectively deliver therapeutic mRNAs to target cells with distinct molecular signatures, such as inflamed endothelial cells expressing vascular cell adhesion molecule 1 (VCAM1). This approach restores key genetics-informed endothelial pathways implicated in disease, including the loss of Kruppel-like factor 2 (KLF2) in acute inflammation underlying ARDS and the suppression of phospholipid phosphatase 3 (PLPP3) in chronic inflammation driving atherosclerosis. In multiple preclinical models, these precision mRNA nanomedicine strategies demonstrated compelling therapeutic efficacy. VCAM1-targeting PROGRAMMED nanoparticles delivering KLF2 mRNA to inflamed lung microvascular endothelial cells significantly improved microvascular health and alleviated virus-induced ARDS. Similarly, PLPP3 mRNA delivery by VCAM1-targeting PROGRAMMED nanoparticles attenuated arterial inflammation, slowed atherosclerosis progression, and promoted regression of advanced plaques. This innovative platform offers a transformative approach for spatiotemporal mRNA therapies targeting inflamed endothelial cells, providing a minimally invasive and highly specific strategy to address acute and chronic vascular diseases. Moreover, the modularity of PROGRAMMED nanoparticles, particularly their ability to display diverse targeting motifs, holds substantial potential for addressing a broad spectrum of vascular complications and other diseases that require precise spatiotemporal correction of dysregulated genes.

bioengineering↗

bioRxiv2025

Inhibition of EMT driver PTK6 enhances anti-tumor immune responses against triple-negative breast cancer

The non-receptor tyrosine kinase PTK6 is expressed in 70% of triple negative breast cancers (TNBC) and is an oncogenic driver of epithelial-mesenchymal transition (EMT). EMT promotes metastasis and immune evasion of TNBC. Therefore, targeting EMT drivers could reverse these properties and lead to more favorable outcomes. Treatment of TNBC tumors with a small molecule inhibitor of PTK6 kinase (P21d) suppressed their growth in vivo. Tumor inhibition by P21d is dependent on an induced immune response because: 1) inhibition is observed in immunocompetent, but not immunodeficient, mice; 2) P21d increases tumor-infiltrating CD8+ T and NK cells and decreases immunosuppressive myeloid-derived suppressor cells; and 3) tumor inhibition by P21d is abrogated by co-treatment with NK or CD8+ T cell-depleting antibodies. These effects on tumor growth and cytotoxic TILs are phenocopied by the knockdown of tumoral PTK6 or SNAIL, which supports EMT inhibition as a mechanism for enhanced anti-tumor immune response. RNA sequencing (RNA-seq) profiling of P21d-treated tumors also revealed changes consistent with activation of the immune response and identified CXCL10 as a critical chemokine induced intratumorally by P21d that promotes recruitment of NK/CD8+ T cells to the tumor site, leading to tumor growth inhibition. Our study highlights the novel tumor immune microenvironmental functions of PTK6 with important consequences for tumor growth that could lead to new immunotherapeutic approaches for TNBC.

cancer biology↗

bioRxiv2025

Anticancer synthetic arylsulfonamides with Wnt1-modulating activity

Dysregulation of the Wnt1/{beta}-catenin signaling pathway has been demonstrated to be a driving factor in the propagation of several human cancers. Previous studies have discovered methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate (MSAB) as a selective inhibitor of the Wnt1/{beta}-catenin signaling pathway, which putatively functions through direct engagement of {beta}-catenin. To understand how changes to the identity and position of the methyl ester affect the in vitro potency of this compound in Wnt1-driven mammalian cell lines, we prepared and evaluated three analogs of MSAB with 3- and 4-substituted methyl and ethyl esters. In MTT assays, analogs with methyl esters showed significantly more activity than their ethyl ester counterparts and both 4-substituted esters exhibited significantly attenuated antiproliferative activity, with MSAB exhibiting dose-dependent activity across cancerous cell lines. Further analysis by flow cytometry reveals low-Annexin V signal, suggesting that these compounds do not function via a pro-apoptotic pathway. Additionally, through a TCF/LEF-activated luciferase reporter cell assay, we observe that the 4-substituted methyl ester analogous to MSAB exhibits slightly diminished Wnt1-inhibitory activity, while 3- and 4-substituted ethyl esters exhibit minimal Wnt1-inhibitory activity. This difference in potency with a simple ester substitution might be attributed to several factors that ultimately drive antiproliferative activity, prompting the investigation of other potential substituents to further investigate the structure-activity relationship of these compounds as Wnt1-based antiproliferative agents.

cancer biology↗

bioRxiv2024

Bovine Formative Embryonic Stem Cell Plasticity in Embryonic and Extraembryonic Differentiation

Bovine embryonic stem cells (bESCs) can greatly enhance understanding of bovine embryonic development and applications for disease-resistance, biomedical and zoonotic pre-clinical models. However, formative bESCs with distinct morphology and complete differentiation capacity are still unreported. We document here the generation of bESCs which are pluripotent both in vitro and in vivo, and efficiently converted into neural progenitor cells (NPCs) and primordial germ cell-like cells (PGCLCs) by direct differentiation. These cells exhibited distinct metabolic features from human and mouse ESCs and early embryos. Formative bESCs contributed to a wide range of cell types within embryonic and extraembryonic tissues after aggregating with mouse and bovine embryos. The establishment of bovine formative ESCs with dual developmental plasticity represents a milestone for agricultural biotechnology and decoding the underlying mechanism of bona fide bovine pluripotency. Summary statementGenerating bovine ESCs would greatly enhance understanding of bovine embryonic development and bioengineering of cattle for disease-resistance, biomedical and zoonotic pre-clinical models.

developmental biology↗

bioRxiv2024

Identification of potent HSV antivirals using 3D bioprinted human skin equivalents

Herpes simplex virus (HSV) infection has worldwide public health concerns and lifelong medical impacts. The standard therapy, acyclovir, has limited efficacy in preventing HSV subclinical virus shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. HSV manifests in the skin and mucosal epithelium. Here, we found acyclovir significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. To recapitulate in vivo tissue architecture, we 3D bioprinted human skin equivalents (HSE) in a 96-well plate format amenable for antiviral screening and preclinical testing. We screened a library of 738 compounds with broad targets and mechanisms of action and identified potent antivirals, including 23 known or experimental HSV treatments, validating the translational relevance of our assay. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways displayed similar potency across cell types and donor sources in 2D and 3D models. Our 3D bioprinted platform allowed for integrating patient-derived cells and incorporating genetic variability early in drug development. The reduced potency in keratinocytes helps explain the limited benefit acyclovir and its congeners play in reducing sexual transmission. These data indicate that the 3D bioprinted HSE assay platform provides a more physiologically relevant approach to identifying potential antivirals for HSV. One Sentence SummaryHigh-throughput screen using 3D bioprinted human skin equivalents to identify antivirals against HSV and evaluate cell-type specific effects.

bioengineering↗

bioRxiv2024

Enantioselective photoenzymatic C(sp3)-H functionalization via single-electron oxidation of carbanions

Established strategies for enantioselective hydroalkylation for C(sp3)-C(sp3) bond formation usually require pre-functionalized substrates as radical precursors in both transition-metal and photoenzymatic catalysis. Based on a sequential proton transfer/electron transfer (PT/ET) strategy, here we show a cooperative photoenzymatic system consisting of a flavin-dependent ene-reductase (ER) and an organophotoredox catalyst fluorescein (FI) to achieve atom-economic enantiodivergent hydroalkylation of electron-deficient C(sp3)-H with olefins. Mechanistic studies revealed a pathway for radical intermediate formation via excited-state FI*-induced single-electron oxidation of carbanions under alkaline conditions. The overall catalytic efficiency is enhanced by the electron transfer (ET) between FMNox and FI-*, while the stereoselectivity is controlled by ERs through enantioselective hydrogen atom transfer (HAT). We anticipate that this mode of photoenzymatic catalysis will inspire new pathways for generating free radical intermediates and foster innovative strategies for achieving photoenzymatic new-to-nature reactions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/627421v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@11b6c1eorg.highwire.dtl.DTLVardef@1575346org.highwire.dtl.DTLVardef@1c24a2org.highwire.dtl.DTLVardef@1a93c0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Optimization of metagenomic detection method for human breast milk microbiome

This study aims to optimize the metagenomic detection methodology of the human breast milk microbiome and analyze its composition. Twenty-two milk samples were collected from the left and right sides of lactating women during re-examinations at the Haidian Maternal and Child Health Hospital, Beijing. Microbial cell wall disruption parameters were optimized, and a nucleic acid extraction method was developed to construct a microbial DNA/RNA library. Metagenomic next-generation sequencing (mNGS) sequencing was performed, and microbial composition was analyzed using the k- mer Lowest Common Ancestor (LCA) method with a self-generated database constructed via Kraken2 software. Data showed Q20 > 95% and Q30 > 90%, with an average total data volume of 5,567 {+/-} 376.6 Mb and non-human sequence data of 445.1 {+/-} 63.75 Mb, significantly enhancing sequencing efficiency. The microbiome included 21 phyla, 234 genera, and 487 species, with Firmicutes and Proteobacteria as dominant phyla. Predominant genera included Staphylococcus and Streptococcus, and major species were Staphylococcus aureus, Streptococcus bradystis, and Staphylococcus epidermidis. Species levels exhibited significant variations among different individuals. Microbial profiles of left- and right-sided milk samples were consistent at the phylum, genus, and species levels. In addition to common bacteria, diverse viral, eukaryotic, and archaeal sequences were detected. This study refined metagenomic detection methods for human breast milk microbiota. Specific flora colonization occurred in healthy breast milk, with the left and right sides exhibiting both correlations and distinct flora environments. ImportanceBreast milk is a vital source of nutrition and immunity for infants, with its microbial composition playing a critical role in shaping the neonatal gut microbiome and supporting early development. However, technical challenges in detecting microorganisms in milks complex, lipid-rich environment have limited understanding of the diversity and function of these microbial communities. This study developed an optimized metagenomic sequencing method to analyze the microbial communities in breast milk from healthy mothers, identifying a wide array of bacteria, viruses, eukaryotes, and archaea. Key bacterial genera such as Staphylococcus and Streptococcus were predominant, with specific flora exhibiting inter-individual variability. Additionally, the study revealed distinct yet correlated microbial environments in the milk from the left and right breasts. These findings advance the understanding of breast milk microbiota and provide a foundation for exploring its implications for maternal and infant health.

microbiology↗

bioRxiv2024

HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma.

The role of HIF2, encoded by EPAS1, in neuroblastoma remains controversial. Here we demonstrate that induction of high levels of HIF2 in MYCN-amplified neuroblastoma cells results in a rapid and profound reduction of the oncoprotein MYCN. This is followed by an upregulation of genes characteristic of noradrenergic cells in the adrenal medulla. Additionally, upon induction of HIF2, the proliferation rate drops substantially, and cells develop elongated neurite-like protrusions, indicative of differentiation. In vivo HIF2 induction in established xenografts significantly attenuates tumour growth. Notably, analysis of sequenced neuroblastoma patient samples, revealed a negative correlation between EPAS1 and MYCN expression and a strong positive correlation between EPAS1 expression, high expression levels of noradrenergic markers, and improved patient outcome. This was paralleled by analysis of human adrenal medulla datasets wherein EPAS1 expression was prominent in populations with high expression levels of genes characteristic of noradrenergic chromaffin cells. Our findings show that high levels of HIF2 in neuroblastoma, leads to drastically reduced MYCN protein levels, cell cycle exit, and noradrenergic cell differentiation. Taken together, our results challenge the dogma that HIF2 acts as an oncogene in neuroblastoma and rather suggest that HIF2 has potential tumour suppressor capacity in this particular disease. Significance statementHIF2 has been proposed as a neuroblastoma oncogene and a tractable target for clinical intervention, this has been questioned by several studies. Thus, it is necessary to move beyond correlative studies and better determine the function of HIF2 in neuroblastoma. Our study shows that induced expression of HIF2 in MYCN-amplified neuroblastoma substantially reduces MYCN protein levels and attenuates proliferation while it induces several features of noradrenergic differentiation and impedes xenograft tumour growth. Together with bioinformatic analysis of sequenced neuroblastoma patient samples and the developing human adrenal medulla, this couples HIF2 to low-risk neuroblastoma with a substantially better patient outcome. Thus, in neuroblastoma HIF2 exhibit tumour suppressor capacity rather than oncogenic capacity.

cancer biology↗

bioRxiv2024

Mapping Pesticide-Induced Metabolic Alterations in Human Gut Bacteria

Pesticides can modulate gut microbiota (GM) composition, but their specific effects on GM remain largely elusive. Our study demonstrated that pesticides inhibit or promote growth in various GM species, even at low concentrations, and can accumulate in GM to prolong their presence in the host. Meanwhile, the pesticide induced changes in GM composition are associated with significant alterations in gut bacterial metabolism that reflected by the changes of hundreds of metabolites. We generated a pesticide-GM-metabolites (PMM) network that not only reveals pesticide-sensitive gut bacteria species but also report specific metabolic changes in 306 pesticide-GM pairs (PGPs). Using an in vivo mice model, we further demonstrated a PGPs interactions and verified the inflammation-inducing effects of pesticides on the host through dysregulated lipid metabolism of microbes. Taken together, our findings generate a PMM interactions atlas, and shed light on the molecular level of how pesticides impact host health by modulating GM metabolism. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/623895v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@17ed5f5org.highwire.dtl.DTLVardef@10d3e0org.highwire.dtl.DTLVardef@c61b43org.highwire.dtl.DTLVardef@27d035_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Molecular Basis of Sperm Methylome Response to Aging and Stress

Changes in the sperm epigenome induced by age and/or stressors often follow common unexplained patterns affecting genes responsible for embryonic development and neurodevelopment. The stochastic epigenetic variation (SEV) hypothesis proposes that in response to stressors naturally variable methylation regions (VMRs) associated with morphogenic genes increase in methylation variation to diversify phenotypes and improve chances of survival of the genetic lineage. Here, we test predictions from the SEV hypothesis using mouse and rat sperm DNA methylation and other -omics data. We demonstrate that the context of DNA regions determines the response of sperm methylome to various factors rather than the stressors and/or timing of these factors. We propose a model explaining age/stress-dependent shifts in methylation in VMRs by an asymmetric increase in methylation variation of these regions. Because methylation variation in VMRs increases with age, sperm methylome response to stressors may be characterized as an acceleration of epigenetic aging.

systems biology↗