Biology subjects

Xu, J.

Publications and source records attributed to Xu, J..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

Visual Regularities Underlie Hierarchical Object Representations in the Human Brain and Self-supervised DNN

NeuroAI develops the interplay of neuroscience and artificial intelligence, especially on visual processing. Human visual system organizes objects based on a representational hierarchy. However, it remains unclear whether this hierarchy arises from visual or semantic information. One hypothesis posits that the visual system is structured around statistical regularities of visual information. Here, we test this hypothesis using the THINGS datasets and pure-visual deep neural networks (DNN). We constructed a low-dimensional object space based on multiple abstract object properties, reflecting statistical patterns of visual regularities. By applying voxelwise encoding models, we identified clusters in the higher visual cortex based on their property tuning, and they were found to support specific object categories. These clusters serve as the middle level to reveal a property-cluster-object hierarchical organization. Subsequently, we investigated whether this hierarchical structure could be captured by a self-supervised DNN. Through activity similarity analysis, we mapped the brain clusters onto the DNN and independently found that the DNNs clusters exhibited distinct property tuning and influenced the classification accuracy of corresponding object categories, mirroring the effects observed in the human brain. Our results demonstrate similar hierarchical structures in the human brain and self-supervised DNN, suggesting that the visual regularities shape neural architecture of visual system. This study highlights the great potential of neural computational model in neuroscience study. Index Terms Visual Processing, Abstract Property, Hierarchical Representation, Self-supervised Visual DNN

neuroscience↗

bioRxiv2025

MBOAT7 and CDS2 coordinate lipid droplet dynamics and cholesterol metabolism in liver

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent disorder worldwide characterized by the accumulation of hepatic lipid droplets (LDs). However, the mechanisms by which hepatocytes adapt to the dynamic changes in LD morphology to maintain metabolic homeostasis remains incompletely understood. Here, we show that MBOAT7, a known MASLD-associated protein, cooperates with CDS2 to regulate lipid droplet dynamics and lipid metabolism. Under physiological conditions, their interaction in the endoplasmic reticulum (ER) maintains metabolic homeostasis. Disruption of this interaction, such as through CDS2 knockdown or loss of function, triggers an adaptive response wherein MBOAT7 translocates to ER-LD contact sites in a RAB1-dependent manner. This redistribution inhibits DGAT2-mediated LD growth and promotes lipolysis. Our findings highlight the redistribution of MBOAT7 to ER-LD contacts serves as a critical mechanism for adaptive control LD size and lipid metabolic homeostasis.

cell biology↗

bioRxiv2025

Dual inhibition of sEH and COX-2 Improved Cognition in Alzheimer's Disease via Enhanced Myogenic Response and Cerebral Artery Distensibility

Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimers disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the Novel Object Recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 M) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Vehicle-treated AD rats displayed impaired functional hyperemia, whereas PTUPB (1 M) significantly restored this response. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats indicated that PTUPB influences genes related to contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD, likely by enhancing myogenic response and increasing cerebral artery distensibility. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.

neuroscience↗

bioRxiv2025

Ginkgolic acid attenuates e chinococcus granulosus infection-induced hepatic fibrosis by inhibiting Smad4 SUMOylation

BackgroundThe SUMOylation modification is closely linked to the progression of fibrotic diseases, yet its role in hepatic fibrosis associated with cystic echinococcosis (CE) remains unclear. This study aimed to investigate the function of SUMOylation in CE-related hepatic fibrosis and evaluate the anti-fibrotic effects and mechanisms of ginkgolic acid (GA) via regulation of the SUMOylation pathway. MethodologyPeri-lesional (PL) and adjacent normal (AN) liver tissues from CE patients were collected to examine histopathology and SUMO pathway proteins. A CE-infected mouse model was established and treated with GA to assess cyst burden, serum TGF-{beta}1 levels, hepatic fibrosis markers, and SUMO-related proteins. In vitro, macrophages and hepatic stellate cells (HSCs, LX-2 line) were stimulated with Echinococcus granulosus cyst fluid (EgCF) or TGF-{beta}1 to evaluate GAs effects on macrophage polarization (CD206/CD86), HSC activation (-SMA/PCNA), Smad4 SUMOylation, and nuclear translocation. Macrophage-HSC crosstalk was investigated via conditioned medium co-culture assays. ResultFibrosis was exacerbated in peri-lesional liver tissues of CE patients, accompanied by SUMO pathway activation. GA significantly alleviated hepatic fibrosis in CE mice and reversed SUMO pathway dysregulation. Mechanistically, GA inhibited EgCF-induced pro-fibrotic M2 macrophage polarization and blocked Smad4 SUMOylation and nuclear translocation by modulating SUMOylation. Furthermore, GA directly suppressed HSC activation and bidirectionally disrupted the pro-fibrotic crosstalk between macrophages and HSCs under EgCF stimulation, ultimately alleviating fibrosis. ConclusionThis study reveals the critical role of SUMOylation modification in CE-associated hepatic fibrosis and elucidates a novel anti-fibrotic mechanism whereby GA targets the SUMOylation-Smad4 axis to regulate the immune microenvironment. Author summaryThis study demonstrates aberrant activation of the SUMOylation pathway during hepatic fibrosis progression in cystic echinococcosis (CE), characterized by upregulated SUMO1/Ubc9 expression and downregulated SENP1 in peri-cystic liver tissue. Ginkgolic acid (GA) intervention significantly attenuated CE-associated liver fibrosis in mice, evidenced by reduced cyst volume, decreased TGF-{beta}1 levels, and suppressed expression of fibrotic markers (-SMA/COL1A1). GA concurrently reversed dysregulated SUMO pathway protein expression. Mechanistically, GA upregulates the deSUMOylating enzyme SENP1, thereby inhibiting Echinococcus granulosus cyst fluid (EgCF)-induced SUMOylation and nuclear translocation of Smad4. This blockade impedes macrophage polarization toward the pro-fibrotic M2 phenotype (CD206{downarrow}) and suppresses hepatic stellate cell (HSC) activation (-SMA/PCNA{downarrow}). Furthermore, GA disrupts the pro-fibrotic bidirectional crosstalk between HSCs and macrophages. Collectively, these findings indicate that GA ameliorates CE-induced hepatic fibrosis by targeting the SUMO-Smad4 axis to modulate the immune microenvironment, providing a novel therapeutic strategy.

molecular biology↗

bioRxiv2025

StrainFacts accurately quantifies both endogenous and live biotherapeutic product strain abundances in simulated and clinical vaginal microbiota samples

Live biotherapeutic products (LBPs) deliver microbial strains to modulate the host microbiota in order to promote health or treat and prevent disease. Since endogenous strains are already present, accurately evaluating LBP efficacy and mechanism of action requires distinguishing administered from endogenous strains. Although computational tools exist for inferring strains from short-read metagenomic data, few have been rigorously tested in the context of LBP treatment. Here, we assess the ability of StrainFacts, a computational tool for inferring strains from short-read metagenomic data, to estimate strain abundances and genotypes of endogenous and administered strains. We performed a simulation study of a single-strain LBP trial, modeling serial samples across a range of administered strain abundance, co-occurring endogenous strains, and sequencing depths. We found that StrainFacts accurately estimated both LBP and endogenous strain abundances and genotypes within simulated samples. We further validated methods using human vaginal microbiota samples spiked with CTV-05, the Lactobacillus crispatus strain contained in the LBP LACTIN-V, which has been shown to reduce recurrent bacterial vaginosis. Our findings demonstrate that StrainFacts can robustly assess LBP and endogenous strain colonization, abundance, and dynamics in simulated and experimental microbiota samples, supporting its utility as an analysis tool for vaginal LBP therapeutic trial data.

bioinformatics↗

bioRxiv2025

SpatialFinder: A Human-in-the-Loop Vision-Language Framework for Prioritizing High-Value Regions in Spatial Transcriptomics

Sequencing an entire spatial transcriptomics slide can cost thousands of dollars per assay, making routine use impractical. Focusing on smaller regions of interest (ROIs) based on adjacent routine H&E slides offers a practical alternative, but there is (i) no reliable way to identify the most informative areas from standard H&E images alone; and (ii) limited solutions for clinicians to prioritize the microenvironment of their own interests. Here we introduce SpatialFinder, a framework that combines a biomedical vision-language model (VLM) with a human-in-the-loop optimization pipeline to predict gene expression heterogeneity and rank high-value ROIs across routine H&E tissue slides. Evaluated across four Visium HD tissue types, SpatialFinder consistently outperforms baseline VLMs in selecting regions with high cellular diversity and tumor presence, achieving up to 89% correlation with ground truth rankings. These results demonstrate the potential of human-AI collaboration to make spatial transcriptomics more cost-effective and clinically actionable.

bioinformatics↗

bioRxiv2025

Genomic Evidence for a-α Heterothallic and α-α Unisexual Mating and Recombination in an Environmental Cryptococcus deneoformans Population

Cryptococcus deneoformans is a human fungal pathogen capable of both a- and - mating and sexual reproduction in laboratory settings. However, the extent of a- and - sexual reproductions in natural populations remain unexplored. Here we analyzed the whole-genome sequences of 24 environmental strains of C. deneoformans from western Saudi Arabia, including one MATa and 23 MAT isolates, with 15 MAT isolates belonging to multi-locus sequence type ST160 as defined by their combined DNA sequences at seven loci. To identify signatures for a- and - reproduction, three samples were analyzed: total, MAT, and ST160. For each subpopulation, single nucleotide polymorphisms (SNPs) were identified for both the nuclear and mitochondrial genomes and subjected to four-gamete tests. In the total population and the MAT subpopulation, variable proportions of SNP pairs within as well as between the nuclear and the mitochondrial genomes showed evidence for recombination. Though no mitogenome SNPs were found among the 15 strains of ST160, the nuclear genome showed clear evidence for recombination, including among SNPs within the mating type region. In addition, the nuclear genome SNP pairs located further apart on the same chromosome showed a greater frequency of recombination in all three sample types. In contrast, mitogenome recombination breakpoints were mainly located in two genomic regions. Together, these results provide robust evidence for both a- and - sexual reproduction within this environmental population of C. deneoformans. Article SummaryThis study compares conclusions drawn from multilocus sequence data and whole-genome SNP data regarding genetic diversity and reproduction in an environmental population of Cryptococcus deneoformans. By analyzing bi-allelic SNPs across 24 strains isolated from western Saudi Arabian soils, evidence of both a- and - recombination was found, suggesting the occurrence of both a- and - sexual reproduction in nature. This provides strong support for these reproductive modes and indicates diverse mechanisms of genetic exchange in fungal pathogens in nature. Additionally, our results suggest that multi-locus sequence typing underestimates genetic diversity, potentially confounding interpretations of population structure and evolutionary history.

microbiology↗

bioRxiv2025

Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis

Isocitrate dehydrogenase (IDH) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2, a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.

cancer biology↗

bioRxiv2025

GIN-CRC-Pareto: A graph-based Pareto-optimal multi-task learning framework to identify miRNA-target interactions in colorectal cancer

Colorectal cancer (CRC) ranks as the third highest incidence among malignancies in humans and the second most common cause of cancer-related mortality in the United States. Accumulating evidence has established microRNAs (miRNAs) as critical regulators of cancer development and therapeutic response. Understanding miRNA-mRNA interactions is critical for elucidating the molecular mechanisms driving CRC and other malignancies. In this study, we proposed GIN-CRC-Pareto, a graph-based, Pareto-optimal multi-task learning framework that simultaneously predicts miRNA-mRNA binding pairs, identifies seed match pairings, and classifies seed match subtypes. By leveraging the power of graph neural networks and Pareto-optimal gradient balancing strategy, GIN-CRC-Pareto dynamically adjusted the task weights during training to optimize each task without compromising the others. Experimental results demonstrated that our framework consistently outperforms traditional deep learning models and existing state-of-the-art tools across multiple evaluation metrics, with 0.909 in accuracy, 0.909 in precision and 0.968 in AUC in the miRNA-mRNA binding pairs prediction task. Additionally, we further validated the generalizability of the framework in combination with transfer learning techniques to identify miRNA-target interactions across other cancers. These findings highlight the effectiveness of the proposed framework to comprehensively identify the miRNA-target interactions in CRC, with the potential to serve as a scalable and generalizable tool across diverse cancer types, ultimately facilitating the development of miRNA-based therapeutics for cancer treatment.

bioinformatics↗

bioRxiv2025

On the Utility of Virtual Staining for Downstream Applications as it relates to Task Network Capacity

Virtual staining, or in-silico-labeling, has been proposed to computationally generate synthetic fluorescence images from label-free images by use of deep learning-based image-to-image translation networks. In most reported studies, virtually stained images have been assessed only using traditional image quality measures such as structural similarity or signal-to-noise ratio. However, in biomedical imaging, images are typically acquired to facilitate an image-based inference, which we refer to as a downstream biological or clinical task. This study systematically investigates the utility of virtual staining for facilitating clinically relevant downstream tasks (like segmentation or classification) with consideration of the capacity of the deep neural networks employed to perform the tasks. Comprehensive empirical evaluations were conducted using biological datasets, assessing task performance by use of label-free, virtually stained, and ground truth fluorescence images. The results demonstrated that the utility of virtual staining is largely dependent on the ability of the segmentation or classification task network to extract meaningful task-relevant information, which is related to the concept of network capacity. Examples are provided in which virtual staining does not improve, or even degrades, segmentation or classification performance when the capacity of the associated task network is sufficiently large. The results demonstrate that task network capacity should be considered when deciding whether to perform virtual staining.

bioinformatics↗

bioRxiv2025

Human hippocampal ripples prioritise model-based learning

Humans often learn optimally, inferring the value of options they have never directly experienced by leveraging internal models of the world, a process known as model-based learning. Yet how the brain decides which unexperienced options to update first remains unclear. Here we recorded intracranial EEG from 34 epilepsy patients performing a reinforcement-learning task that required using task structure to infer the value of unvisited (non-local) paths. After each reward, brief hippocampal "ripple" events signalled which indirect experience was most valuable, thereby encoding that paths priority. Longer ripples carried the strongest priority signals, allowing the brain to update high-value, unvisited options first and thereby optimise learning. Ripple events also coincided with selective cortical reactivation of these high-priority paths, consistent with prioritised replay. Crucially, when hippocampal ripples were precisely synchronised with activity in the lateral frontopolar cortex (LFPC), individuals showed greater model-based learning: stronger ripple-LFPC coupling predicted more effective use of task structure and more accurate learning of non-local values. Our findings establish hippocampal ripple-centred prefrontal coordination as a fundamental mechanism that prioritises valuable experiences for model-based learning, explaining how the human brain learns so efficiently.

neuroscience↗

bioRxiv2025

TopoLa: A Universal Framework to Enhance Cell Representations for Single-cell and Spatial Omics through Topology-encoded Latent Hyperbolic Geometry

Recent advances in cellular research demonstrate that scRNA-seq characterizes cellular heterogeneity, while spatial transcriptomics reveals the spatial distribution of gene expression. Cell representation is the fundamental issue in the two fields. Here, we propose Topology-encoded Latent Hyperbolic Geometry (TopoLa), a computational framework enhancing cell representations by capturing fine-grained intercellular topological relationships. The framework introduces a new metric, TopoLa distance (TLd), which quantifies the geometric distance between cells within latent hyperbolic space, capturing the networks topological structure more effectively. With this framework, the cell representation can be enhanced considerably by performing convolution on its neighboring cells. Performance evaluation across seven biological tasks, including scRNA-seq data clustering and spatial transcriptomics domain identification, shows that TopoLa significantly improves the performance of several state-of-the-art models. These results underscore the generalizability and robustness of TopoLa, establishing it as a valuable tool for advancing both biological discovery and computational methodologies.

bioinformatics↗

bioRxiv2025

A trade-off mechanism underpins the evolution of a young two-gene sex-determining system in plants

Sexual systems in animals and plants are remarkably diverse, with dioecy having evolved independently in numerous lineages. In plants, dioecy often evolved more recently than in the best-studied animal systems, making plants especially important for understanding how separate sexes evolved independently from functionally hermaphrodite ancestors. Despite long-standing theories of developmental trade-offs in sex allocation, the underlying genetic mechanisms remain elusive. Here, we show that the XY sex determination system in the dioecious plant species Eurycorymbus cavaleriei in Sapindaceae involves two Y-linked mutations that act jointly within the developmental male-female trade-off: YUN{Delta}, a truncated allele that lowers the dosage of the D-class MADS-box gene YUN, and SUNMAO, a novel sRNA locus that silences the X-linked SUN allele. In females, SUN stabilizes the HD-ZIP transcription factor KUN, which is a known sex determinant in another dioecious plant, thereby promoting femaleness by increasing YUN expression; loss of SUN expression, together with the effect of YUN{Delta}, shifts development toward males. Two interlocking regulatory loops in this "SKY" module (SUN-KUN-YUN) fine-tunes YUN dosage. This dioecious system in E. cavaleriei likely evolved by sequential mutations in genes acting in the predicted male-female trade-off system, with their close linkage reflecting a translocation, and later recombination-suppressing inversions.

plant biology↗

bioRxiv2025

A high-quality bread wheat genome unravels adaptive evolution of wheat end-use quality

Understanding the genetics of superior dough performance is essential for improving wheat end-use quality. Here, we presented a de novo assembly of the genome of JM44, a Chinese wheat cultivar known for its exceptional end-use quality. The JM44 genome achieved reference-level quality (QV = 66.74), depicting a complete picture of complex regions containing gluten genes. Our microsynteny analysis across the Triticum-Aegilops complex showed that high-molecular-weight glutenin subunits (HMW-GSs) loci are highly conserved, while low-molecular-weight glutenin subunits (LMW-GSs) and -/{beta}-gliadins exhibited greater structural variation. These variable loci appear to have been preferentially selected by humans and contributed substantially to the evolution of wheat quality traits. Moreover, we observed that epistatic interactions between gluten genes are strong in modern cultivars, but markedly weaker in landraces, indicating the importance of epistatic selection during modern breeding. Our findings shed light on the genomics and evolution of wheat quality traits, providing valuable guidance for future breeding efforts.

genomics↗

bioRxiv2025

Genomic selection for accelerated heartwood formation in Pedunculate oak (Quercus robur L.) using whole-genome sequencing

Heartwood traits in trees are critical for timber quality but are notoriously difficult to phenotype due to their late expression and the need for destructive sampling. In this proof-of-concept study, we demonstrate that combining genome-wide association studies (GWAS) with Bayesian genomic prediction models provides an effective strategy to overcome these challenges. By using GWAS to preselect trait associated SNPs and integrating them into predictive models, we substantially improve the accuracy of genomic predictions for heartwood related traits in oaks. Our approach allows for reliable selection of superior genotypes at the seedling stage, long before heartwood traits can be directly measured, thus enabling early and cost-effective breeding decisions. We also identify the number of rings in sapwood as a genetically controlled, easily measured proxy trait that enhances selection strategies for heartwood content. Together, these findings provide a scalable framework for integrating genomics into operational tree breeding programs and demonstrate how combining GWAS and genomic prediction can accelerate the improvement of complex wood traits in long lived forest tree species.

genetics↗

bioRxiv2025

Engineering circular guide RNA and CRISPR-Cas13d-encoding mRNA for the RNA editing of Adar1 in triple-negative breast cancer immunotherapy

Clustered regularly interspaced short palindromic repeat Cas endonuclease (CRISPR-Cas) systems, such as RNA-editing CRISPR-Cas13d, are poised to advance the gene therapy of various diseases. However, their clinical development has been challenged by 1) the limited biostability of linear guide RNAs (lgRNAs) susceptible to degradation, 2) the immunogenicity of prokaryotic microorganism-derived Cas proteins in human that restrains their long-term therapeutic efficacy, and 3) off-targeting gene editing caused by the prolonged Cas expression from DNA vectors. Here, we report the development of highly stable circular gRNAs (cgRNAs) and transiently-expressing Cas13d-encoding mRNA for efficient CRISPR-Cas13d editing of target mRNA. We first optimized cgRNA for CRISPR-Cas13d editing of adenosine deaminase acting on RNA type I (Adar1) transcript for the combination immunotherapy of triple negative breast cancer (TNBC). cgRNAs were synthesized by enzymatic ligation of lgRNA precursors. cgRNAs enhanced biostability with comparable Cas13d-binding affinity relative to lgRNA. Next, using ionizable lipid nanoparticles (LNPs), we co-delivered the resulting Adar1-targeting cgRNA with an mRNA encoding RfxCas13d (mRNA-RfxCas13d), a widely used Cas13d variant, to TNBC cells. As a result, relative to lgRNA, cgRNA significantly enhanced the efficiency of Adar1 knockdown with minimal collateral activity, which sensitized the cancer cells for cytokine-mediated cell apoptosis. In a 4T1 murine TNBC tumor model in syngeneic mice, Adar1-targeting cgRNA outperformed lgRNA for tumor immunotherapy in combination with immune checkpoint blockade (ICB). Collectively, these results demonstrate the great potential of cgRNA and mRNA-RfxCas13d for RNA-targeted gene editing.

bioengineering↗

bioRxiv2025

A new double reporter strategy reveals a subset of non-migratory hematopoietic stem cells localized in a dynamic bone marrow niche.

Interactions of hematopoietic stem cells (HSCs) with the bone marrow microenvironment are critical to regulate stem cell function in homeostasis, emergency hematopoiesis and ageing. The dynamic behavior of endogenous HSCs in their niches has been challenging to study due to the complexity of markers required to define pure HSCs. Multiple recently developed reporter strategies advanced our capacity to identify HSCs in situ. Yet, they provide different levels of HSC enrichment and are frequently not stable in situations of perturbed hematopoiesis, leading to contradictory observations of HSC migratory behavior. Here we employed a new double reporter strategy by combining the Hoxb5-mKO2 and Vwf-GFP reporters, that are stably expressed in homeostasis, stress and ageing. Hoxb5+Vwf+ cells represent a subset of highly pure and potent long-term HSCs with a platelet-biased pattern of differentiation, that are included in the populations identified by other reporter strategies. Intravital microscopy revealed Hoxb5+Vwf+ cells to be non-migratory in homeostasis, following platelet depletion when these cells are actively proliferating, and during ageing. This non-migratory behavior of HSCs in homeostasis and stress indicates that their activation does not inherently depend on relocation to alternative niches eliciting proliferation, as previously proposed. We found Hoxb5+Vwf+ HSCs in direct contact with vasculature and LepR+ perivascular cells but not preferentially closer to megakaryocytes. Nevertheless, increased megakaryopoiesis following platelet depletion brings megakaryocytes into close proximity of Hoxb5+Vwf+ HSCs, revealing previously unrecognized niche dynamics in HSC regulation during regeneration. DATA SHARING STATEMENTOriginal data will be made available upon reasonable request. The RNA sequencing data used in this study has been published before35 and is available from GEO (GSE81682). The code used for analysis is available from https://github.com/loversaber/Secchi_Paper_RNAseq_Analysis.git. KEY POINTSO_LICombined expression of Hoxb5-mKO2 and Vwf-GFP reporters defines a population of highly enriched long-term HSCs in situ and in vivo. C_LIO_LIHoxb5+Vwf+ HSCs are non-migratory in homeostasis, stress hematopoiesis and ageing, while their niche is highly dynamic. C_LI

cell biology↗

bioRxiv2025

The bladder cancer m6A landscape is defined by methylation dilution and 3'-UTR hypermethylation

N6-Methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNAs and regulates target transcripts throughout the mRNA life cycle. Although changes in m6A have been reported in human cancers, technical limitations have hindered a comprehensive understanding of the cancer-associated m6A landscape. Here, we used GLORI-sequencing to establish the first transcriptome-wide, single-nucleotide resolution maps of m6A in cancer. Differentially methylated transcripts were enriched in oncogenic pathways relevant to UCB. We discovered two key m6A signatures in UCB: a global loss of methylation and a local hypermethylation at 3'-UTRs. Integration of RNA-sequencing data revealed that the global loss resulted from dilution of methylation marks due to increased expression of unmethylated transcripts and decreased expression of highly methylated transcripts. In contrast, local 3'-UTR hypermethylation was associated with the overexpression of VIRMA, a component of the m6A writer complex, which was linked to UCB progression. Our study is the first to describe the m6A epitranscriptomic landscape of cancer at single-base resolution and provides first insights into the processes that generate its characteristic signatures.

cancer biology↗