Biology subjects

Zhu, Q.

Publications and source records attributed to Zhu, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Epigenetic regulation of cilia stability and kidney by the chromatin remodeling SWI/SNF complexes

Cilia are important subcellular organelles, whose assembly are regulated by master regulator transcription factors including Foxj1 and Rfx proteins. However, whether and how cilia are regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Notably, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes led to ciliopathy-like phenotypes in zebrafish embryos. Specifically, loss of Actl6a, an essential components of the SWI/SNF complexes, resulted in cilia disassembly and cystic kidney, without affectting cilia motility. Omics analyses revealed that in Actl6a-depleted pronephros or embryos, a set of cilia genes--including master regulators foxj1a and rfx2--were downregulated at transcriptional level, chromatin accessibility level and SWI/SNF binding level. Depletion of foxj1a or rfx2 in zebrafish also caused cilia disassembly and cystic kidney. Furthermore, overexpression of foxj1a or rfx2 mRNA partially rescued the cystic kidney and cilia disassembly phenotypes in actl6a mutants. Taken together, our study reveals that the SWI/SNF complexes maintain cilia stability and kidney homeostasis by directly modulating the expression of foxj1a or rfx2.

developmental biology↗

bioRxiv2025

Emergent Leadership Driven by Asymmetric Stability Shapes Learning in Dyadic Motor Coordination

Coordinated actions are fundamental to human behavior. Even without explicit communication, stable coordination patterns and implicit leadership roles can emerge. This study examines the dynamic nature of leadership and its impact on perceptuomotor learning in a dyadic coordination task. Paired participants (dyads) controlled targets using joysticks to produce a novel coordination pattern, which was learned using visual feedback without direct communication over multiple sessions. Results showed that leadership was an emergent property of the system, dynamically shaped by the interplay between individual and system-level stability. At the system level, leadership role transitions modulated the dyads learning, characterized by distinct learning models. At the individual level, leaders maintained overall stability but exhibited occasional bursts of instability to assert control and reinforce coordination. These findings highlight the role of leader-follower dynamics in learning and performance, showing that leadership is both a limiting factor and a facilitator for coordination.

animal behavior and cognition↗

bioRxiv2025

Widespread distribution of the BpfA-carrying bacteria involved in the bisphenol F degradation in Pseudomonadota and Actinomycetota

The global use of bisphenol F (BPF) has led to widespread environmental contamination, posing significant threats to ecosystems and human health. However, the genes involved in BPF degradation remained unknown. In this study, a novel oxidase gene, bpfA, was obtained from strain Microbacterium sp. F2 through a four-step purification strategy. BpfA is classified as a member of the 4-phenol oxidizing (4PO) subfamily and contains a conserved FAD-binding domain (Asp152 and His393) as well as a Tyr-Tyr-Arg triad (Tyr93, Tyr474, Arg475). BpfA catalyzes the conversion of BPF to 4,4-dihydroxydibenzophenone (DHBP) through a series of three consecutive reactions. In addition, BpfA exhibits catalytic activity towards 4-alkylphenols, such as vanillyl alcohol (VA), 4-n-propylguaiacol (4PG), and 4-(methoxymethyl)phenol (4MOP). BpfA homologs are widely distributed in the environment, particularly in soil. Bioinformatics-based taxonomic profiling revealed that BpfA homologs are widely distributed in metagenomes from cultivated land and forests, mainly belonging to Pseudomonadota and Actinomycetota. This study enhances our understanding of the microbial degradation mechanism of BPF, elucidates the catalytic function of the novel oxidase gene bpfA and its distribution pattern in the environment, and provides important insights into the evolutionary origin of BPF degradation genes and the targeted mining of environmental microbial resources.

microbiology↗

bioRxiv2025

CD163+/Dab2+ Macrophages Alleviate Cardiac Hypertrophy via Nrg2/ErbB4-Mediated Mitochondrial Reprogramming

BackgroundPathological cardiac hypertrophy is a hallmark of numerous cardiovascular diseases, yet effective targeted therapies remain elusive in current clinical practice. Cardiac macrophages contribute to disease progression, but the underlying mechanisms have not been fully elucidated. MethodsSingle-nucleus RNA-sequencing, bulk RNA-sequencing, proteomics, metabolomics, and a mouse model of pressure overload were employed to investigate cardiac remodeling. We identified a macrophage subset co-expressing CD163 and Dab2 and examined its role using immunofluorescence, flow cytometry, and functional assays. We further assessed the Nrg2/ErbB4 signaling axis through genetic and pharmacological modulation. ResultsCD163/Dab2 macrophages were reduced in hypertrophic hearts and positively correlated with Nrg2 expression. These macrophages alleviated cardiomyocyte hypertrophy in vitro, an effect abolished by Nrg2 knockdown. In vivo, recombinant Nrg2 treatment mitigated cardiac hypertrophy, preserved mitochondrial structure, and restored bioenergetics via the ErbB4 receptor. Transcriptomic analyses confirmed enhanced expression of genes involved in mitochondrial oxidative phosphorylation. Furthermore, CD163+/Dab2+ macrophages improved mitochondrial dysfunction by the Nrg2/ErbB4 pathway in vitro. ConclusionsWe identified a CD163/Dab2 macrophage subset that protects against pathological cardiac hypertrophy by promoting mitochondrial function through Nrg2/ErbB4 signaling. This axis may offer a promising therapeutic target for interventions in pathological cardiac hypertrophy.

cell biology↗

bioRxiv2025

A Multimodal Spatial and Epigenomic Atlas of Human Adult Lung Topography

Developing high-resolution reference maps of disease-susceptible spatial niches is a critical step to mitigating the profound effects of lung disease. Here, we present an integrated multimodal single-nucleus human lung atlas (snHLA) profiling 746,047 nuclei from 49 mapped lung blocks spanning clinically relevant distal airways, alveoli, and interstitium across 11 healthy adults. Integrating snRNA-seq and SNARE-seq2, which co-assays chromatin accessibility and gene expression from the same nucleus, we resolved 70 molecularly distinct populations and captured 332,846 accessible chromatin regions, nominating new transcriptional regulators of human lung cell diversity. Spatial transcriptomics using MERFISH mapped 25 cell populations across 7 structural neighborhoods and multiplexed immunofluorescence localized cell subtypes and distal airway-defining protein markers, expanding and validating distinct lung structure-specific cell populations. This open access snHLA and companion Cell Type and Marker Gene Dictionary with anatomically aligned nomenclature delivers a foundational resource at an unprecedented resolution to interrogate the origins of lung pathophysiology.

cell biology↗

bioRxiv2025

An aphid-resistant plant metabolite as a candidate aphicide: Insight into the bioactivity and action mode of betulin against aphids

Pest-resistant plants usually utilize secondary metabolites to cope with insect infestation. Betulin, a key bioactive compound in aphid-resistant wild peach, possesses promising applications in crop protection. Here, betulin, in both greenhouse and field experiments, displayed excellent control efficacy against Myzus persicae. RNA-seq, qRT-PCR, and western blotting revealed that betulin significantly inhibited the expression of MpGABR (encoding a GABAA receptor). Besides, RNAi-mediated silencing of MpGABR markedly increased aphid sensitivity to betulin. Furthermore, MST (microscale thermophoresis) and voltage-clamp assays indicated that betulin bound to MpGABR (Kd = 2.24 {micro}M) and acted as an inhibitor of MpGABR. Molecular docking, mutagenesis and genome editing suggested that THR228 is a critical and highly conserved site in MpGABR that betulin binds to specifically, causing aphid death. Overall, the activity of betulin depends on specific targeting and inhibition of MpGABR. Elucidating the mechanism of action of this peach-derived insecticide may offer a sustainable green strategy for aphid control.

molecular biology↗

bioRxiv2025

Circular RNA profiling revealed an evolutionarily conserved circACACA promotes liver lipid metabolism, oxidative stress, and autophagy disorder in a ceRNA manner

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized primarily by hepatocellular steatosis and lipid accumulation, which leads to hepatocyte apoptosis, autophagy, inflammation, and intracellular oxidative stress. NAFLD is recognized as one of the most prevalent and complex chronic liver diseases globally, with its occurrence and associated mortality rates rising swiftly each year. Due to the high similarity between chicken fatty liver syndrome (FLS) and NAFLD, as well as the easy availability of diseased chickens, the chicken is considered an ideal model for studying the pathogenesis of NAFLD. Previous studies have pinpointed several circular RNAs (circRNAs) implicated in the pathogenesis of NAFLD, yet the underlying functions and mechanisms of numerous circRNAs continue to remain elusive. In this experiment, we utilized circRNA sequencing of chicken livers to identify a novel circRNA, named circACACA, and discovered that it disrupts the metabolic homeostasis of lipids within hepatocytes. Consequently, this disruption leads to oxidative stress and the induction of autophagy, ultimately exerting an adverse effect on chicken liver health. Mechanistically, circACACA functions as a molecular sponge for miR-132b-5p and miR-101-2-5p to modulate the expression of the downstream CBFB/PIM1 complex. Consequently, it influenced the activity of the AKT/mTOR and PPAR-{gamma} signaling pathways to perform its physiological functions. Crucially, we noticed substantial sequence similarity of circACACA across diverse species by comprehensively searching databases. Further, our research with a mouse model confirmed that the functional conservation of circACACA across livers of different species. Overall, this study built a mechanistic network for circACACA and confirmed its sequence conservation and functional relevance across various species. Our results not only provide new targets for the prevention and treatment of NAFLD but also present fresh perspectives for progress in healthy production of laying hens.

cell biology↗

bioRxiv2025

Anti-CSF-1R therapy with combined immuno- chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched Triple Negative Breast Cancers

Patients diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory metronomic Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic syngeneic Trp53 null TNBC genetically engineered mouse models (GEMMs) that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-15 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.

cancer biology↗

bioRxiv2025

Single-Cell Epigenomics Uncovers Heterochromatin Instability and Transcription Factor Dysfunction during Mouse Brain Aging

The mechanisms regulating transcriptional changes in brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight brain regions in the mouse brain at 2, 9, and 18 months of age. In addition to a significant decline in progenitor cell populations involved in neurogenesis and myelination, we observed widespread and concordant changes of transcription and chromatin accessibility during aging in glial and neuronal cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-responsive programs driven by AP-1, indicating a progressive loss of cell identity with aging. We also identify region- and cell-type-specific heterochromatin decay, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long non-coding RNAs, particularly in glutamatergic neurons. Together, these results reveal age-related disruption of heterochromatin maintenance and transcriptional programs, identify vulnerable brain regions and cell types, and pinpoint key molecular pathways altered in brain aging. HighlightsO_LISingle-cell multimodal profiling across eight brain regions reveals coordinated chromatin and transcriptional shifts during aging C_LIO_LIAge-related depletion of progenitor cells coincides with dysregulation of key developmental transcription factors C_LIO_LICell identity maintenance is compromised with the decline of master transcription factors C_LIO_LIHeterochromatin destabilization accompanied by activation of AP-1, transposable elements, pseudogene families, and long non-coding RNAs C_LI

genomics↗

bioRxiv2025

An integrated landscape of mRNA and protein isoforms

Alternative splicing and proteolytic processing expand the functional diversity of the human proteome by generating distinct protein isoforms from a single gene. However, the extent to which transcript isoforms give rise to distinct protein products remains unclear, in part due to technical limitations in proteomic workflows. Here, we combine full-length mRNA sequencing with SDS-PAGE-based protein fractionation and quantitative mass spectrometry to construct an integrated landscape of mRNA and protein isoforms in human RPE-1 cells. To overcome the inherent ambiguity of bottom-up proteomics in isoform detection, we developed IsoFrac, a computational pipeline that resolves protein isoforms based on their migration profiles across gel fractions. This approach enabled the identification of [~]45,000 full-length transcripts, [~]32,000 ORFs, and [~]16,000 distinct protein isoforms. Comparative analyses revealed widespread translation of alternative transcripts and uncovered proteolytic processing as a major, underappreciated source of proteome complexity. Our results establish a scalable framework for isoform-resolved proteogenomics and provide a reference resource for studying the molecular diversity encoded by the human genome.

systems biology↗

bioRxiv2025

Augmenting microbial phylogenomic signal with tailored marker gene sets

Phylogenetic marker genes are traditionally selected from a fixed collection of whole genomes evenly distributed across major microbial phyla, covering only a small fraction of gene families. And yet, most microbial diversity is found in metagenome-assembled genomes that are unevenly distributed and harbor gene families that do not fit the criteria of universal orthologous genes. To address these limitations, we systematically evaluate the phylogenetic signal of gene families annotated from KEGG and EggNOG functional databases for deep microbial phylogenomics. We show that markers selected from an expanded pool of gene families and tailored to the input genomes improve the accuracy of phylogenetic trees across simulated and real-world datasets of whole genomes and metagenome-assembled genomes. The improved accuracy of trees compared to previous markers persists even when metagenome-assembled genomes lack a fraction of open reading frames. The selected markers have functional annotations related to metabolism, cellular processes, and environmental information processing, in addition to replication, translation, and transcription. We introduce TMarSel, a software tool for automated, systematic, free-from-expert opinion, and tailored marker selection that provides flexibility in the number of markers and annotation databases while remaining robust against uneven taxon sampling and incomplete genomic data.

bioinformatics↗

bioRxiv2025

Revealing a coherent cell state landscape across single cell datasets with CONCORD

Revealing the underlying cell-state landscape from single-cell data requires overcoming the critical obstacles of batch integration, denoising, and dimensionality reduction. Here, we present CONCORD, a unified framework that simultaneously addresses these challenges within a single self-supervised model. At its core, CONCORD implements a unified probabilistic sampling strategy that corrects batch effects via dataset-aware sampling and enhances biological resolution through hard-negative sampling. Remarkably, using only a minimalist neural network with a single hidden layer and contrastive learning, CONCORD surpasses state-of-the-art performance without relying on deep architectures, auxiliary losses, or external supervision. It seamlessly integrates data across batches, technologies, and even species to generate high-resolution cell atlases. The resulting latent representations are denoised and biologically meaningful--capturing gene co-expression programs, revealing detailed lineage trajectories, and preserving both local geometric relationships and global topological structures. We demonstrate CONCORDs broad applicability across diverse datasets, establishing it as a general-purpose framework for learning unified, high-fidelity representations of cellular identity and dynamics.

bioinformatics↗

bioRxiv2025

APC loss promotes intestinal transformation through induction of bistable stem cell states

Colorectal cancer (CRC) is a leading cause of cancer deaths, predominantly initiated by genetic inactivation of the APC tumor suppressor. Current dogma holds that APC inactivation promotes tumorigenesis via hyperactivation of the WNT pathway transcriptional effector, {beta}-CATENIN. Although {beta}-CATENIN activation is required for tumor initiation, activating mutations in {beta}-CATENIN are infrequent. Here, we ask what underlies the selective pressure for APC inactivation by comparing the oncogenic effects of APC loss to {beta}-CATENIN hyperactivation. We find that APC loss activates a {beta}-CATENIN-independent fetal intestinal transcriptional program driven by dysregulation of GSK-3 activity upon the LIM-domain protein AJUBA, a positive regulator of YAP. This results in AJUBA stabilization and downstream transcriptional activation of the YAP-driven fetal intestinal gene expression program. We find that {beta}-CATENIN- and YAP-driven transcriptional states are mutually exclusive, existing in an interchangeable bistable balance among APC-null cells. This results in more robust tumor initiation and metastatic progression downstream of APC loss relative to {beta}-CATENIN activation. Taken together, our findings explain the preferential selection for APC inactivation in CRC development and illuminate how {beta}-CATENIN- and YAP-driven gene expression programs coexist to promote tumorigenesis.

cancer biology↗

bioRxiv2025

Context-Dependent and Gene-Specific Role of Chromatin Architecture Mediated by Histone Modifiers and Loop-extrusion Machinery

Loop-extrusion machinery, comprising the cohesin complex and CCCTC-binding factor CTCF, organizes the interphase chromosomes into topologically associating domains (TADs) and loops, but acute depletion of components of this machinery results in variable transcriptional changes in different cell types, highlighting the complex relationship between chromatin organization and gene regulation. Here, we systematically investigated the role of 3D genome architecture in gene regulation in mouse embryonic stem cells under various perturbation conditions. We found that acute depletion of cohesin or CTCF disrupts the formation of TADs, but affects gene regulation in a gene-specific and context-dependent manner. Furthermore, the loop extrusion machinery was dispensable for transcription from most genes in steady state, consistent with prior results, but became critical for a large number of genes during transition of cellular states. Through a genome-wide CRISPR screen, we uncovered multiple factors that can modulate the role of loop extrusion machinery in gene regulation in a gene-specific manner. Among them were the MORF acetyltransferase complex members (Kat6b, Ing5, Brpf1), which could antagonize the transcriptional insulation mediated by CTCF and cohesin complex at developmental genes. Interestingly, inhibition of Kat6b partially rescues the insulator defects in cells lacking the cohesin loader Nipbl, mutations of which are responsible for the developmental disorder Cornelia de Lange syndrome. Taken together, our findings uncovered interplays between the loop extrusion machinery and histone modifying complex that underscore the context-dependent and gene-specific role of the 3D genome.

genomics↗

bioRxiv2025

Reducing batch effects in single cell chromatin accessibility measurements by pooled transposition with MULTI-ATAC

Large-scale scATAC-seq experiments are challenging because of their costs, lengthy protocols, and confounding batch effects. Several sample multiplexing technologies aim to address these challenges, but do not remove batch effects introduced when performing transposition reactions in parallel. We demonstrate that sample-to-sample variability in nuclei-to-Tn5 ratios is a major cause of batch effects and develop MULTI-ATAC, a multiplexing method that pools samples prior to transposition, as a solution. MULTI-ATAC provides high accuracy in sample classification and doublet detection while eliminating batch effects associated with variable nucleus-to-Tn5 ratio. We illustrate the power of MULTI-ATAC by performing a 96-plex multiomic drug assay targeting epigenetic remodelers in a model of primary immune cell activation, uncovering tens of thousands of drug-responsive chromatin regions, cell-type specific effects, and potent differences between matched inhibitors and degraders. MULTI-ATAC therefore enables batch-free and scalable scATAC-seq workflows, providing deeper insights into complex biological processes and potential therapeutic targets.

molecular biology↗

bioRxiv2025

A Sensitive Soma-localized Red Fluorescent Calcium Indicator for Multi-Modality Imaging of Neuronal Populations In Vivo

Recent advancements in genetically encoded calcium indicators, particularly those based on green fluorescent proteins, have optimized their performance for monitoring neuronal activities in a variety of model organisms. However, progress in developing red-shifted GECIs, despite their advantages over green indicators, has been slower, resulting in fewer options for end-users. In this study, we explored topological inversion and soma-targeting strategies, which are complementary to conventional mutagenesis, to re-engineer a red genetically encoded calcium indicator, FRCaMP, for enhanced in vivo performance. The resulting sensors, FRCaMPi and soma-targeted FRCaMPi (SomaFRCaMPi), exhibit up to 2-fold higher dynamic range and peak {Delta}F/F0 per single AP compared to widely used jRGECO1a in neurons in culture and in vivo. Compared to jRGECO1a and FRCaMPi, SomaFRCaMPi reduces erroneous correlation of neuronal activity in the brains of mice and zebrafish by two- to four-fold due to diminished neuropil contamination without compromising the signal-to-noise ratio. Under wide-field imaging in primary somatosensory and visual cortex in mice with high labeling density (80-90%), SomaFRCaMPi exhibits up to 40% higher SNR and decreased artifactual correlation across neurons. Altogether, SomaFRCaMPi improves the accuracy and scale of neuronal activity imaging at single-neuron resolution in densely labeled brain tissues due to a 2-3-fold enhanced automated neuronal segmentation, 50% higher fraction of responsive cells, up to 2-fold higher SNR compared to jRGECO1a. Our findings highlight the potential of SomaFRCaMPi, comparable to the most sensitive soma-targeted GCaMP, for precise spatial recording of neuronal populations using popular imaging modalities in model organisms such as zebrafish and mice.

neuroscience↗

bioRxiv2025

High-speed mapping of whole-mouse peripheral nerves at subcellular resolution

In contrast to the rapid advancements in mesoscale connectomic mapping of the mammalian brain, similar mapping the peripheral nervous system has remained challenging due to the bodys size and complexity. Here, we present a high-speed blockface volumetric imaging system with an optimized workflow of whole-body clearing, capable of imaging the entire adult mouse at micrometer resolution within 40 hours. Three-dimensional reconstruction of individual spinal fibers in Thy1-EGFP mice reveals distinct morphological features of sensory and motor projections along the ventral and dorsal rami. Immunostaining facilitates body-wide mapping of sympathetic nerves and their branches, highlighting their perivascular patterns in limb muscles, bones, and most visceral organs. Viral tracing elucidates the fine architecture of vagus nerves and individual vagal fibers, revealing unexpected projection routes to various organs. Our approach offers an effective means to achieve a holistic understanding of cellular-level interactions among different systems that underlie body physiology and disease. HighlightsO_LIImaging of whole adult mouse at uniform subcellular resolution within 40 hours C_LIO_LIReconstruction of 191 thoracic spinal neuron projections for Thy1-EGFP mice C_LIO_LIMapping of immunolabeled sympathetic projections and their perivascular patterns C_LIO_LIResolving virus-labeled architecture of vagus nerves and complex single-fiber routes C_LI

neuroscience↗

bioRxiv2024

Distribution of contezolid in different tissues of mice and human patients infected with Mycobacterium abscessus

BackgroundLinezolid (LZD), while effective against Mycobacterium abscessus (MAB), can cause myelosuppression and peripheral neuropathy. Contezolid (CZD) shares a similar antimicrobial profile with improved safety, but biodistribution data remain limited. This study evaluated CZDs biodistribution in MAB-infected mice and humans and its therapeutic potential across infection sites. MethodsMICs of CZD and LZD against 32 clinical MAB isolates and three reference strains were determined. In MAB-infected mice, drug concentrations were quantified in plasma and pulmonary and cerebral tissues at 2, 4, and 8 hours post-administration. In MAB-infected patients, CZD concentrations in bone, plasma, and cerebrospinal fluid were measured at multiple time points and MAB counts in sputum cultures were assessed daily over 14 days. ResultsRespective MIC50 and MIC90 values were 8 and 32 {micro}g/mL (LZD) and 16 and 32 {micro}g/mL (CZD). Pharmacokinetic CZD and LZD level comparisons revealed peak CZD plasma levels within 2 hours, higher systemic CZD levels, comparable pulmonary tissue concentrations, and slightly lower CZD cerebral tissue penetration. In patients, CZD levels in ankle joint effusion samples reached 2.0885 {micro}g/mL at 6 hours, peaking in the posterior malleolus. Plasma CZD concentrations peaked at 8.2349 {micro}g/mL at 3 hours and dropped to 6.1065 {micro}g/mL by 6 hours, while CSF levels were 0.9295 and 0.792 {micro}g/mL at 3 and 6 hours, respectively. Sputum bacterial burden decreased rapidly within 24 hours of CZD treatment, with near-complete clearance by day 4. ConclusionCZD and LZD exhibit comparable tissue distribution but different site-specific penetration, supporting their potential for treating diverse MAB infections.

microbiology↗