Biology subjects

WANG, Z.

Publications and source records attributed to WANG, Z..

8 recordsLinked to original sources

bioRxiv2026

Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer

Obesity has an adverse effect on survival of women with ovarian cancer (OC), supporting a link between obesity, metastatic progression, and therapeutic response, but comprehensive mechanistic insight is lacking. In pre-clinical models of diet-induced obesity and OC, mice fed a high fat diet (HFD) exhibit substantially increased tumor burden relative to low fat diet (LFD) mice and respond poorly to standard-of-care (SOC) chemotherapy. Both HFD murine tumors and tumors from women with BMI>30 show increased expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of lipogenesis and lipid transport. The objective of this study was to assess whether inhibition of SREBP1 processing could improve SOC chemotherapy response in obesity-associated OC. We evaluated the FDA-approved drug Nelfinavir (NFV), a pharmacologic inhibitor of site-2 protease that blocks SREBP1 processing, in combination with SOC (paclitaxel+carboplatin) chemotherapy in preclinical models of diet-induced obesity and OC. Our results demonstrate significantly improved therapeutic response, corresponding changes in intra-tumoral adipocytes, and reprogramming of the obesity-driven ascites immune microenvironment. These findings support a model in which NFV-mediated inhibition of SREBP1 processing disrupts obesity-associated metabolic pathways linked to immune suppression and therapeutic resistance, thereby enhancing response to SOC chemotherapy in obesity-associated OC. Collectively, these results highlight metabolic targeting as a strategy to improve therapeutic outcomes in obesity-associated ovarian cancer.

cancer biology↗

bioRxiv2026

Bacteriophage host prediction using a genome language model

Computational bacteriophage host prediction from genomic sequences remains challenging because host range depends on diverse, rapidly evolving genomic determinants--from receptor-binding proteins to anti-defense systems and downstream infection compatibility--and because the signals available to predictors, including sequence homology, CRISPR spacer matches, nucleotide composition, and mobile genetic elements, are sparse, unevenly distributed across taxa, and constrained by incomplete host annotations. Here, we frame host prediction as an unsupervised retrieval problem. We asked whether embeddings from the pretrained genome language model Evo2 captured a reliable host-range signal without training on phage-host labels. We generated whole-genome embeddings for phages and candidate bacterial hosts with the Evo2-7B model, applied normalization, and ranked hosts by cosine similarity. Using the Virus-Host Database, we selected embedding and fusion choices on a Gram-positive validation cohort and then evaluated the approach on a held-out Gram-negative test cohort to minimize data leakage. We found that Evo2 was strongest at retrieving multiple plausible hosts, with the recorded host in the top 10 for 55.4% of phages. However, it did not maximize species-level top-1 accuracy (19.4% vs. 23.2% for the best baseline). At higher taxonomic ranks, Evo2 captured a coarser host-range signal: top-1 accuracy reached 43.4% at the genus level and 51.6% at the family level. Reciprocal rank fusion of Evo2 with BLASTN, VirHostMatcher, and PHIST improved all retrieval metrics. Top-10 retrieval rose to 58.5% and top-1 accuracy to 26.9%. Stratified analyses by phage genome length, host clade, and host mobile genetic element coverage revealed scenario-dependent performance. Evo2 embeddings excelled for intermediate-length phages and when host mobile element content was low, whereas alignment and k-mer methods dominated when local homology was abundant. These results suggest that pretrained genome embeddings complement established alignment- and k-mer/composition-based methods and that context-aware hybrid pipelines may help improve phage host prediction. Author summaryBacteriophages are viruses that prey on bacteria and play central roles in microbial ecosystems, nutrient cycling, and the spread of antibiotic resistance genes. Knowing which bacterium a phage can infect is important for applications such as phage therapy, where viruses are used to treat bacterial infections, but making this prediction from DNA sequence data alone remains difficult. Existing computational tools each exploit different types of genomic evidence, and none works reliably across all settings. We asked whether an artificial intelligence model trained to read raw DNA--without ever being shown which phages infect which hosts--could contribute a new, complementary signal. We found that this approach was particularly effective at narrowing the field to a short list of candidate hosts and at capturing broad evolutionary relationships between phages and bacteria. When we combined it with established sequence-comparison tools, overall prediction improved beyond what any single method achieved alone. By examining when each method succeeded or failed, we identified biological factors that govern prediction difficulty, offering practical guidance for building more robust prediction systems.

bioinformatics↗

bioRxiv2025

Unveiling differential responses to UVB (305 nm) and UVC (275 nm) in cacao-infecting Colletotrichum gloeosporioides and Pestalotiopsis sp.

Sustainable control of microbial pathogens requires alternatives to chemicals, but physical methods like Ultraviolet-C (UVC) show variable efficacy linked to poorly understood pathogen-specific responses. Here, we investigate differential UVB/UVC responses in plant pathogenic fungi (Colletotrichum gloeosporioides, Pestalotiopsis sp.). Using hyperspectral imaging and machine learning, we dissect the physiological underpinnings of UV sensitivity. UVC proves more potent than UVB, with Pestalotiopsis sp. showing significantly higher resistance than C. gloeosporioides isolates. Crucially, hyperspectral signatures correlated with resistance, revealing UVC-induced photopigment changes, biochemical disruption, and oxidative stress markers in sensitive isolates, contrasting with minimal perturbation in the resistant isolate. Machine learning accurately decoded these complex phenotypes for classification. This understanding enabled enhanced inactivation via optimized pulsed UVC and synergistic sonication. We link distinct physiological states, non-invasively detected via hyperspectral imaging, to fungal UV resistance, demonstrating how integrating advanced phenotyping and machine learning provides a mechanistic basis for optimizing physical pathogen controls.

microbiology↗

bioRxiv2024

Orchestrating the Acquisition of Oligodendrocyte Precursor Cell versus Olfactory Bulb Interneuron Fates through Olig1/2 during Mammalian Cortical Gliogenesis and Gliomagenesis

The hijacking of developmental gliogenesis programs is a hallmark of glioblastoma (GBM), in which glial precursor cells (GPCs) typically differentiate into both neurons and glial cells. In GBM, this process is disrupted, leading to the overproduction of proliferative glial-like cells. Our study demonstrates that the knockout of Olig1/2 in both normal development and gliomagenesis causes GPCs to shift from generating highly proliferative oligodendrocyte precursor cells to producing non-proliferative olfactory bulb interneurons. Mechanistically, Olig1/2 play dual roles by orchestrating distinct transcriptional programs in GPCs, particularly inhibiting the expression of Gsx2 through direct binding to its multiple enhancers. Additionally, we provide compelling evidence that human H3.3G34R/V-mutant tumors, a subtype of high-grade gliomas, originate from dorsal cortical-derived GPCs rather than from the previously assumed progenitors in the ventral basal ganglia. Collectively, our findings reveal a previously unrecognized role of Olig1/2 in both gliogenesis and gliomagenesis, offering deeper insights into the connections between normal neural development and tumorigenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/623106v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@10ea118org.highwire.dtl.DTLVardef@1725006org.highwire.dtl.DTLVardef@1e3ce25org.highwire.dtl.DTLVardef@f300ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Catalytic-independent functions of INTAC in conferring sensitivity to BET inhibition

Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs with poorly understood mechanisms. Using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary module of the INTAC complex, a global regulator of polymerase pause-release dynamics. This process bypasses a requirement for INTACs catalytic activities and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8-KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.

molecular biology↗

bioRxiv2023

Circulating Microparticles: Optimization and Standardization of Isolation Protocols and Reassessment of Their Characteristics and Functions

Microparticles (MPs) are convenient for clinical diagnosis, and have functional roles in signal transduction. Although the importance of MPs is being increasingly recognized, the diversity of isolated protocols for MPs results in a heterogeneous population of their unknown origins, even expands to uncertain functions. Here we systematically studied the composition of MPs at different centrifugal speed intervals, and found that 3000g was a critical centrifugation speed in determining new MPs composition. The platelet-derived particles accounted for more than 80% under 3000g, while only about 20% in MPs obtained over 3000g. Furthermore, we found that the function of new MPs was significantly different from that of traditional ones, such as procoagulation activity, anti-inflammation and clinical diagnosis etc. Thus, our work optimized the method of MPs isolation, clarified some characteristics and physiological functions that should belong to platelets rather than MPs, which will derive new conceptual MPs for its composition and function.

cell biology↗

bioRxiv2022

H3K4 di- and trimethylation modulate the stability of RNA polymerase II pausing

Modifications of histones are intricately linked with the regulation of gene expression, with demonstrated roles in various physiological processes and disease pathogenesis. Methylation of histone H3 lysine 4 (H3K4), implemented by the COMPASS family, is enriched at promoters and associated cis-regulatory elements, with H3K4 trimethylation (H3K4me3) considered a hallmark of active gene promoters. However, the relative roles of deposition and removal of H3K4 methylation, as well as the extent to which these events contribute to transcriptional regulation have so far remained unclear. Here, through rapid depletion of the transcription regulator SPT5 or either of two shared subunits of COMPASS family members, we reveal a dynamic turnover of H3K4me3 mediated by the KDM5 family of histone demethylases. Loss of H3K4me3 following COMPASS disruption does not impair the recruitment of TFIID and initiating RNA polymerase II (Pol II). Instead, H3K4me3 loss leads to reductions in the paused form of Pol II on chromatin while inducing the relative enrichment of the Integrator-PP2A (INTAC) termination complex, leading to reduced levels of elongating polymerases, thus revealing how H3K4me3 dynamics can regulate Pol II pausing to sustain or attenuate transcription.

molecular biology↗

bioRxiv2022

Spatial cell fate manipulation of human pluripotent stem cells by controlling microenvironment using photocurable hydrogel

Human pluripotent stem cells (hPSCs) dynamically respond to their chemical and physical microenvironment, dictating their behavior. However, conventional in vitro studies predominantly employ plastic culture wares, which offer a simplified representation of the in vivo microenvironment. Emerging evidence underscores the pivotal role of mechanical and topological cues in hPSC differentiation and maintenance. In this study, we cultured hPSCs on hydrogel substrates with spatially controlled stiffness. The use of culture substrates that enable precise manipulation of spatial mechanical properties holds promise for better mimicking in vivo conditions and advancing tissue engineering techniques. We designed a photocurable polyethylene glycol-polyvinyl alcohol (PVA-PEG) hydrogel, allowing for spatial control of surface stiffness and geometry at a micrometer scale. This versatile hydrogel can be functionalized with various extracellular matrix (ECM) proteins. Laminin 511-functionalized PVA-PEG gel effectively supports the growth and differentiation of hPSCs. Moreover, by spatially modulating the stiffness of the patterned gel, we achieved spatially selective cell differentiation, resulting in the generation of intricate, patterned structures. Summary statementA new hydrogel substrate enables spatial control of surface stiffness at the micrometer level, enabling local differentiation of hPSC and facilitating complex pattern formation.

bioengineering↗