Biology subjects

Gao, Q.

Publications and source records attributed to Gao, Q..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Pan-cancer tumor classification by a holistic tumor microenvironment atlas

The tumor microenvironment (TME) heterogeneity presents a major bottleneck to effective cancer immunotherapies. We address this by establishing a pan-cancer tumor classification system based on the holistic TME cellular components. First, using single-cell transcriptomes from 1,271 patients across 26 cancer types, we compile a TME cellular atlas, leading to the identification of recurrent cell states and multicellular modules across cancer types. Among these, we highlight a type I interferon (IFN-I)-related multicellular module, including IFIT1+ tumor-associated macrophages, as a critical contributor to immune-activation TMEs. From a holistic perspective, pan-cancer TMEs exhibit trichotomous patterns predominantly driven by T, myeloid, and stromal compartments. Leveraging fine-grained TME cellular composition, we further stratify all tumors into 10 stable groups. These groups display varying responses to immune checkpoint blockade (ICB), and each rationally selected therapeutic strategy specifically perturbs the corresponding expression signature. Our pan-cancer tumor classification scheme reveals the underlying patterns of TME heterogeneity and provides a framework for stratifying patients, guiding treatment selection, and developing novel therapeutic options.

cancer biology↗

bioRxiv2025

STEAP4+ neutrophils: a promising circulating biomarker for lung metastasis

As the leading contributor to cancer-related mortality, metastasis often evades detection until advanced stages, underscoring the critical need for early predictive biomarkers. Neutrophils are naturally circulating sentinels that have been implicated in pioneering pre-metastatic niche formation in distant organs. Nevertheless, their heterogeneity within evolving metastatic microenvironments remains poorly characterized. Here, through dynamically delineating neutrophil subsets via single-cell transcriptomics, we identified a conserved feature of lung metastasis in breast cancer and other cancer models. Among the core genes, a cell surface marker, STEAP4, was selected and validated to indicate lung metastases at both RNA and protein levels. In both humans and mice, these STEAP4+ neutrophils were detectable not only in lung metastatases but also in the circulation. Clinically, the abundance of circulating STEAP4+ neutrophils robustly discriminates patients with lung metastasis from those with localized primary tumor. Our findings uncover STEAP4+ neutrophils as a promising biomarker and lay the groundwork for a non-invasive, blood-based diagnostic strategy for metastatic disease.

cancer biology↗

bioRxiv2025

Directed evolution of a compact TranC11a system for efficient genome editing

The recently discovered TranC systems represent programmable RNA-guided DNA endonucleases of transposon origin with compact protein sizes ideal for therapeutic delivery. However, their editing efficiency in human and plant cells is limited. Here, we evolved TranC11a and engineered its sgRNA to enhance overall editing efficiencies. TranC11a systems exhibit up to 9.2-fold higher editing activity than its parent and achieves efficiency comparable to SpCas9 across multiple human genome endogenous sites, significantly outperforming compact editors NovaIscB and enTnpB1c. TranC11a enables efficient editing of disease-relevant genes in human cells and breeding traits in maize. With its high editing activity and compact size (574 aa), TranC11a demonstrates strong potential for future in vivo genome editing and crop engineering.

synthetic biology↗

bioRxiv2025

Moderate-Intensity Intermittent Training Inhibits miR-34a-5p to Reduce Prefrontal Cortex Apoptosis and Improve Cognitive Ability in Aging Rats Reduced by D-galactose

Changes in microRNA (miRNA) play a role in brain aging. They are considered potential therapeutic targets. Regular long-term exercise benefits brain health. However, its exact mechanism is not fully understood. This study explored how moderate-intensity intermittent training (MIIT) improves cognitive function and reduces apoptosis in the aging brain. This study induced aging in rats by giving them D-gal injections (150 mg/kg/day) for 6 weeks. After confirming the model, the rats underwent MIIT. They exercised 45 minutes a day, 5 days a week, for 8 weeks. The results from behavioral, morphological, and molecular tests showed that 8 weeks of MIIT significantly slowed the decline in spatial learning and memory in D-gal aging rats. The exercise also improved the structure of the prefrontal cortex (PFC) and reduced apoptosis. Aging caused an overexpression of miR-34a-5p in the prefrontal cortex. MIIT reduced this overexpression. It also up-regulated Notch1 and inhibited excessive apoptosis by regulating Bcl-2 and Bax expression. In conclusion, MIIT may improve brain health by targeting miR-34a-5p and regulating apoptosis-related pathways.

physiology↗

bioRxiv2025

DeepHalo: Deep Learning-Powered Exploration of Halogenated Metabolites Uncovering Antibacterial Depsipeptides

In the omics era, confident high-throughput analytical tools are crucial for the efficient identification of metabolites. Here, we present DeepHalo, a deep learning-integrated and hierarchically optimized workflow designed for high-throughput exploration of halogenated metabolites from high-resolution mass spectrometry-based metabolomics. DeepHalo leverages deep learning models combined with a comprehensive scoring to enhance the reliability of halogen predictions. It integrates PyOpenMS for fast isotope pattern detection and incorporates a halogen-based dereplication algorithm with GNPS molecular networking to efficiently exploit and annotate halogenates from complex biological matrices. To validate its performance, DeepHalo was applied to explore halogenated metabolites from 1,296 microbial culture crude, leading to the discovery of six families of structurally diverse halogenated molecules. This included a new class of cyclic depsipeptides, aglomycins A-E, featuring rare 3-chloroanthranilic acid and/or epoxyvaline blocks. Additionally, a plausible biosynthetic pathway of aglomycins was proposed through bioinformatics analyses and targeted gene knockout experiments. Bioassays revealed that aglomycin A exhibits synergistic antibacterial activity with linezolid against vancomycin-resistant Enterococcus faecium (VRE) both in vitro and in vivo. We envision that DeepHalo (freely available at https://github.com/xieyying/DeepHalo) will become a powerful tool for accelerating the discovery of halogenated "dark matter".

biochemistry↗

bioRxiv2025

Zinc-Enhanced Activity of an Antimicrobial Halogenated Phenazine Against Streptococcus mutans and Other Gram-positive Bacteria

Halogenated phenazine (HP) compounds have shown promise as antimicrobial agents, particularly against biofilm-associated Gram-positive pathogens. Among these compounds, HP-29 demonstrates potent activity against methicillin-resistant Staphylococcus aureus by inducing rapid iron starvation. As maintenance of trace metals homeostasis is critical for the survival of Streptococcus mutans, this study investigated the antimicrobial efficacy of HP-29 and the impact of metal supplementation on this major oral and occasional systemic pathogen. As anticipated, HP-29 inhibited S. mutans growth in a dose-dependent manner, with iron supplementation alleviating the antimicrobial effect. Cobalt, manganese, or nickel supplementation also mitigated the inhibitory activity of HP-29 but, unexpectedly, the addition of zinc greatly enhanced HP-29 antimicrobial activity. This zinc-driven potentiation of HP-29 extended to other Gram-positive pathogens, including Enterococcus faecalis and S. aureus. Inductively coupled plasma mass spectrometry analysis revealed that intracellular iron content decreased significantly following exposure to HP-29. At the same time, exposure to HP-29 led to a slight increase in intracellular zinc, mirroring the increase observed in cells exposed to excess zinc. When combined with zinc, HP-29 triggered a 5-fold increase in intracellular zinc and reduced manganese levels by [~]50%. Transcriptome analysis showed that HP-29, with or without zinc, altered expression of genes linked to iron and manganese uptake as well as zinc efflux, suggesting broad disruption of metal ion regulation. These findings highlight HP-29 as a potent antimicrobial that broadly impairs metal homeostasis. The unexpected synergy of HP-29 with zinc points toward a promising dual-agent therapeutic strategy against Gram-positive pathogens. IMPORTANCEWidespread development of antibiotic resistance has created a constantly moving target when combating infectious microbes. Here, we further explore an antimicrobial halogenated phenazine, HP-29, which is effective against Gram-positive bacteria through disruption of intracellular trace metal equilibrium. We showed that HP-29 inhibits growth of the oral and systemic pathogen Streptococcus mutans and that its antimicrobial effect is greatly potentiated by the addition of zinc. The zinc-mediated enhancement of HP-29s efficacy was also observed in other Gram-positive pathogens, including Enterococcus faecalis and Staphylococcus aureus. Intracellular trace metal quantifications and transcriptome analysis confirmed that HP-29 treatment impairs trace metal homeostasis, an outcome that is exacerbated when S. mutans is treated with both HP-29 and zinc. The observed synergy of HP-29 with zinc supports the development of a dual-agent therapeutic strategy against Gram-positive pathogens.

microbiology↗

bioRxiv2025

Analysis of Wheat Spike Morphological Traits Using 2D Imaging

The morphological structure of wheat spikes plays a central role in wheat yield. Wheat spike morphology, closely associated with crop yield, has attracted considerable attention in the fields of genetics and breeding. However, traditional measurement methods can only measure simple traits, and precise phenotypes remain difficult to obtain, constraining the study and improvement of complex spike-related traits. This study utilized deep learning technologies to develop a pipeline, called SpikePheno, for the acquisition of precise wheat spike phenotypes. Our pipeline demonstrated high accuracy in spike segmentation, achieving a mean Intersection over Union (mIoU) of 0.948. Additionally, our method accurately identified spikelet counts, achieving an R2 of 0.9923. Using experimental data of 221 wheat cultivars from various regions of China grown in Zhao County, Hebei Province, our pipeline extracted 45 different phenotypes and studied their correlations with thousand grain weight (TGW) and spike yield. Our findings indicate that precise measurement of spike area, spikelet area, and other phenotypic traits enables a clearer understanding of the correlation between spike morphology and wheat yield. Through hierarchical clustering based on spike morphology, we categorized wheat spikes into six classes and identified phenotypic differences between these classes and their impact on TGW and yield. Furthermore, this study revealed phenotypic differences between wheat cultivars from different geographical regions and over different decades, with an increase in large-spike cultivars over time, especially in southern China. This research may help breeders understand the relationship between wheat spike morphology and yield, providing an important basis for future wheat breeding efforts.

plant biology↗

bioRxiv2025

OriGene: A Self-Evolving Virtual Disease Biologist Automating Therapeutic Target Discovery

Here, we present OriGene, a self-evolving multi-agent system that functions as a virtual disease biologist, systematically identifying original and mechanistically grounded therapeutic targets at scale. OriGenes architecture integrates over 600 specialized tools through a Model Context Protocol (MCP), enabling it to reason across diverse data modalities including genomics, protein networks, pharmacology, clinical records and literature evidence, to generate and prioritize target discovery hypotheses. We implemented a strategy combining a knowledge graph-based Tool RAG with an advanced agent selection mechanism to enable dynamic, context-aware tool deployment. Through a self-evolving framework, OriGene continuously integrates human and experimental feedback to iteratively refine its core thinking templates, tool composition, and analytical protocols, thereby enhancing both accuracy and adaptability over time. To comprehensively evaluate its performance, we established TRQA, an original benchmark comprising over 1,900 expert-level question-answer pairs spanning a wide range of diseases and target classes. OriGene consistently outperforms human experts, leading research agents, and state-of-the-art large language models in accuracy, recall, and robustness, particularly under conditions of data sparsity or noise. Critically, OriGene nominated previously underexplored therapeutic targets for liver (GPR160) and colorectal cancer (ARG2), which demonstrated significant anti-tumor activity in patient-derived organoid and tumor fragment models mirroring human clinical exposures. These findings demonstrate OriGenes potential as a scalable and adaptive platform for AI-driven discovery of mechanistically grounded therapeutic targets, offering a new paradigm to accelerate drug development.

bioinformatics↗

bioRxiv2025

The genomic and transcriptional landscape of the spinal cord H3K27-altered diffuse midline glioma suggests the potential therapeutic strategy

Diffuse midline glioma with H3K27-altered (DMG) is a lethal pediatric malignancy that primarily occurs in the brainstem of children. In adults, DMG arising in the spinal cord is rarely reported and remains poorly understood. The cellular architecture and clinical outcomes of DMG vary depending on the tumors location. To dissect the genomic and transcriptional architecture of a cohort of spinal cord DMG patients, we conducted whole-exome sequencing and single-cell RNA sequencing on 19 tumor samples from 7 patients. We identified previously underappreciated stem-like cells associated with hypoxia in malignant tumor cells, which were present in all samples of spinal cord DMG but absent in published intracranial DMG, corroborating cellular heterogeneity based on tumor location. We discovered that tumor-associated myeloid cells constituted the largest population of non-malignant cells in adult spinal cord DMG. Our research revealed a transition from microglia to macrophages, characterized by enhanced cell-to-cell interactions mediated through the VEGF signaling pathway network. Notably, we found that epigenetic agents can repress the expression of hypoxia-related gene programs in patient-derived spinal cord DMG cultures and inhibit cell proliferation in vitro. Collectively, our study reveals a crucial anatomical dimension that DMG exhibits a location-specific genomic and transcriptional landscape despite shared H3K27 alterations, providing the paradigm for developing precision therapeutic strategies that extend beyond DMG to other molecularly defined yet anatomically divergent malignancies.

cancer biology↗

bioRxiv2025

DeepAden: an explainable machine learning for substrate specificity prediction in nonribosomal peptide synthetases

Microbial non-ribosomal peptides (NRPs) exhibit remarkable structural diversity and serve as valuable sources of lead compounds for clinical drug development. The biosynthesis of NRPs relies on non-ribosomal peptide synthetases (NRPSs), in which adenylation (A) domains play a pivotal role in defining the core structure by selectively recognizing and activating amino acid substrates. Accurately predicting the substrate specificities of A-domains is thus essential for understanding the core structural and biosynthetic logic of NRPs. Here, we present DeepAden, a two-stage deep learning framework. In the first stage, a graph attention network (GAT)-based model localizes 27-residue binding pockets within 6 [A] of bound substrates and convert these into pocket representations. In the second stage, pocket representations are then encoded alongside substrate information using pretrained language models, and aligned using contrastive learning. In addition, we introduce a SHapley Additive exPlanations (SHAP)-guided data augmentation strategy to mitigate class imbalance and improve robustness, particularly for nonproteinogenic substrates. DeepAden achieves competitive performance compared with state-of-the-art tools on a benchmark dataset, and enabled the identification of two Streptomyces NRPS gene clusters through accurate A-domain substrates specificity predictions. DeepAden offers a powerful tool for precise pocket localization and robust substrate prediction, accelerating the discovery and characterization of novel NRP natural products for future work. The DeepAden web server is available at https://deepnp.site/.

bioinformatics↗

bioRxiv2025

Conformal Bioprinting of Bi-phasic Jammed Bioinks, Independent of Gravity, Orientation, and Curvature

Rapid in situ bioprinting on complex, human-scale anatomical surfaces remain a key challenge for clinical translation. Here, we present a gravity-independent, conformal bioprinting strategy using bi-phasic granular bioink and multinozzle printheads capable of adapting to arbitrary surface curvatures. The bioink comprised of jammed gelatin microgels suspended in a fibrinogen matrix exhibits yield-stress behavior to maintain shape fidelity after extrusion while supporting cell viability and proliferation. Two monolithic multinozzle printhead architectures with identical bioink delivery networks were evaluated: (1) a rigid configuration for handheld bioprinting and (2) a soft robotic variant capable of real-time curvature adaptation via pneumatic actuation. Microgravity experiments aboard a parabolic flight confirmed successful bioink deposition under [~]0 g conditions. A ladder-rung microfluidic architecture ensured uniform bioink delivery across printhead nozzles, improving deposition consistency. In situ bioprinting on anatomical facial phantoms confirmed conformal, high-throughput (deposition at 20 mm{middle dot}s-1) deposition of bioink over physiologically relevant curvatures, both with and without cells. Cell-laden constructs retained >85% cell viability post-printing and supported proliferation. This work introduces a scalable bioprinting platform suitable for clinical, remote, and deep-space environments, enabling autonomous tissue fabrication. The curvature-adaptive printhead advances current in situ bioprinting capabilities, facilitating the generation of personalized grafts with complex anatomical geometries.

bioengineering↗

bioRxiv2025

β-Glucan Modulates Monocyte Plasticity and Differentiation Capacity to Mitigate DSS-Induced Colitis

Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this proinflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with {beta}-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from {beta}-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1 macrophages derived from Ly6Chi monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how {beta}-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/653036v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1b969c2org.highwire.dtl.DTLVardef@1ce603dorg.highwire.dtl.DTLVardef@10582forg.highwire.dtl.DTLVardef@10d7de6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Interleukin-6 is critical in the development of gcn2-mutation associated pulmonary vascular disease in mice

Biallelic mutations in eukaryotic translation initiation factor 2 kinase 4, EIF2AK4 (which encodes general control nonderepressible 2, GCN2) underpin heritable forms of pulmonary veno-occlusive disease (PVOD), a rare and fatal form of pulmonary hypertension. The mechanisms linking these are mostly uncharacterised. We demonstrate for the first time that homozygous loss of gcn2 is sufficient to cause mild pulmonary hypertension in mice. Single-cell transcriptomics of mouse lungs identified adventitial fibroblasts as having the greatest GCN2-dependent transcriptional differences, implicating them as key players in this model of PVOD. The most significantly upregulated pathways in gcn2-/- adventitial fibroblasts were inflammatory. Therefore, we went on to demonstrate a pro-inflammatory phenotype in gcn2-/- mouse embryonic fibroblasts and gcn2-/- mice. In a novel murine model of pulmonary hypertension induced by exposure to mitomycin C, deletion of interleukin-6 rescued the pulmonary vascular phenotype. When chronically exposed to lipopolysaccharide, the pulmonary hypertensive phenotype of gcn2-/- mice is exaggerated. Genetic ablation of interleukin-6 completely rescues both the baseline and LPS-exaggerated pulmonary hypertensive phenotype. Targeting Il6-dependent pathways may be useful in treating this deadly disease.

pathology↗

bioRxiv2025

FveTRM5 plays a critical role in regulating fruit shape in woodland strawberry

Cultivated strawberry is a globally important fruit crop with high economic value. Fruit shape contributes to fruit quality and diversity and is a target for breeding, but very few regulatory genes have been reported in strawberry. Here, we identified an ethyl methanesulfonate (EMS) round fruit (rf) mutant that produces round or flat fruits in woodland strawberry. The primary candidate point mutation is located in the second exon of FvH4_2g22810, causing a premature stop codon at residue 266. This gene encodes a protein with a high similarity to TON1 RECRUITING MOTIF 5 (TRM5) and has therefore been named FveTRM5. Transformation of FveTRM5pro:FveTRM5 into rf could rescue the round fruit phenotype, suggesting that FveTRM5 is responsible for rf. Overexpression of FveTRM5 produced elongated organs in both Arabidopsis and woodland strawberry, suggesting a conserved role in different species. FveTRM5 is ubiquitously expressed with higher levels in developing organs. Observation of cell shape showed that FveTRM5 promotes cell elongation and inhibits cell division in the medial-lateral direction in the receptacle. The FveTRM5 protein localized to microtubules. In conclusion, our results suggest that FveTRM5 plays an essential role in regulating strawberry fruit shape by influencing cell elongation and cell division, providing an excellent target gene for breeding new fruit shape cultivars.

plant biology↗

bioRxiv2025

Hyperactivity of the Amygdala Mediates Depressive-Like Phenotypes and Decreased Serotonin Release

Clinical and preclinical studies have consistently demonstrated a correlation between hyperactivity of the amygdala and the onset of depression. However, the underlying mechanisms influencing serotonin levels a critical neurotransmitter implicated in depression and a primary target for selective serotonin reuptake inhibitors (SSRIs) remain inadequately understood. In this study, we employed a restrained inescapable shock (RIS) model to investigate these mechanisms in mice. The RIS paradigm elicited depressive-like phenotypes, increased c-Fos expression in the amygdala, diminished serotonin levels, and elevated corticosterone concentrations. Notably, chemogenetic inhibition of the amygdala mitigated depressive symptoms, reduced neuronal activity in this region, and restored serotonin levels. Anatomical analyses revealed a significant connectivity between the central amygdala (CeA) and the dorsal raphe nucleus (DRN). Fiber photometry recordings indicated that serotonergic neuronal activity in the DRN decreased in response to aversive stimuli, accompanied by amygdala activation following RIS, with no notable alterations in DRN GABAergic activity. These findings suggest that chronic stress may exacerbate amygdala hyperactivity, which subsequently inhibits serotonin release in the brain, potentially intensifying depressive states. Therefore, targeting amygdala hyperactivity may represent a novel therapeutic strategy for the management of stress-related depressive and anxiety disorders.

neuroscience↗

bioRxiv2025

Lysine Potentiates Insulin Secretion via AASS-Dependent Catabolism and Regulation of GABA Content and Signaling

Background and aimLysine is an essential amino acid with insulinotropic effects in humans. In vitro, lysine also potentiates glucose-stimulated insulin secretion (GSIS) in {beta} cell lines and rodent pancreatic islets. For decades it has been assumed that insulinotropic action of lysine is mediated by plasma membrane depolarization similar to arginine. Aminoadipate-Semialdehyde Synthase (AASS) is a mitochondrial-located bifunctional enzyme engaged in the first two steps of the lysine catabolism. Whether AASS-dependent lysine catabolism occurs in {beta} cells and whether it is required for its insulinotropic action has not been investigated. MethodsmRNA expression of lysine catabolism pathway genes was assessed in human islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects. AASS was silenced in human pancreatic islets and in INS1 832/13 {beta} cells. {beta} cell metabolism and function were investigated by ELISA, extracellular flux analysis, live cell calcium imaging, transcriptomics and metabolomics analyses. ResultsExpression of genes involved in lysine catabolism, including AASS, ALDH7A1, DHTKD1 and HADH, was reduced in pancreatic islets from T2D donors. Silencing of AASS resulted in reduced lysine- and glucose-stimulated insulin secretion in human islets and INS1 832/13 {beta} cells. Surprisingly, transcriptomics and metabolomics analysis in Aass-KD {beta} cells with suppressed lysine catabolism identified reduced {gamma}-aminobutyric acid (GABA)/glutamate ratio as well as altered expression of genes implicated in GABA metabolism. This was accompanied by altered mitochondrial TCA cycle and oxidative phosphorylation (OXPHOS) activity, reflected by elevated lactate/pyruvate and reduced whole-cell ATP/ADP content as well as ATP-linked mitochondrial respiration. Glucose-and GABA-stimulated cytosolic calcium was also altered in Aass-KD {beta} cells. Strikingly, addition of GABA recovered impaired insulin secretion in Aass-KD {beta} cells. ConclusionAASS-dependent lysine catabolism is required to maintain adequate GABA shunt metabolism and signaling. In addition, lysine catabolism supports mitochondrial energy production, calcium uptake and insulin secretion. Reduced AASS-dependent lysine catabolism may contribute to {beta} cell GABA depletion and dysfunction in T2D patients.

cell biology↗

bioRxiv2024

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Moz and Hbo1 impairs NUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML. SIGNIFICANCE STATEMENTMOZ and HBO1 associate with NUP98 fusion oncoprotein condensates to drive leukemogenesis. Inhibition of their histone acetyltransferase activity is an effective therapeutic strategy in NUP98-rearranged leukemias, including those resistant to Menin inhibition. Moreover, combined MOZ/HBO1 and Menin inhibition is synergistic, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.

cancer biology↗

bioRxiv2024

Marker gene fishing for single-cell data with complex heterogeneity

In single-cell studies, cells can be characterized with multiple sources of heterogeneity such as cell type, developmental stage, cell cycle phase, activation state, and so on. In some studies, many nuisance sources of heterogeneity (SOH) are of no interest, but may confound the identification of the SOH of interest, and thus affect the accurate annotate the corresponding cell subpopulations. In this paper, we develop B-Lightning, a novel and robust method designed to identify marker genes and cell subpopulations correponding to a SOH (e.g., cell activation status), isolating it from other sources of heterogeneity (e.g., cell type, cell cycle phase). B-Lightning uses an iterative approach to enrich a small set of trustworthy marker genes to more reliable marker genes and boost the signals of the SOH of interest. Multiple numerical and experimental studies showed that B-Lightning outperforms existing methods in terms of sensitivity and robustness in identifying marker genes. Moreover, it increases the power to differentiate cell subpopulations of interest from other heterogeneous cohorts. B-Lightning successfully identified new senescence markers in ciliated cells from human idiopathic pulmonary fibrosis (IPF) lung tissues, new T cell memory and effector markers in the context of SARS-COV-2 infections, and their synchronized patterns which were previously neglected. This paper highlights B-Lightnings potential as a powerful tool for single-cell data analysis, particularly in complex data sets where sources of heterogeneity of interest are entangled with numerous nuisance factors.

bioinformatics↗