Biology subjects

Dubois, L.

Publications and source records attributed to Dubois, L..

10 recordsLinked to original sources

bioRxiv2026

FET fusion proteins reshape splicing factor networks to drive oncogenic alternative splicing

Gene fusions involving the FET gene family (FUS, EWSR1, and TAF15) act as drivers of numerous cancer subtypes. The resulting chimeric proteins are widely viewed as aberrant transcriptional regulators that promote malignant transformation through chromatin and enhancer reprogramming. Here, we show that FET fusion oncoproteins also function as regulators of alternative splicing across multiple sarcoma subtypes. Transcriptomic analyses revealed extensive but largely non-overlapping splicing programs driven by the EWSR1::FLI1, EWSR1::WT1, EWSR1::ATF1 and FUS::DDIT3 fusions that nevertheless converged on common oncogenic functions. Fusion-dependent splicing regulation was mechanistically separable from canonical transcriptional activity and was associated with extensive remodeling of cooperative RNA-binding protein (RBP) assemblies on target transcripts. Despite regulating distinct exons, different FET fusions engaged highly similar RBP interaction networks, consistent with a conserved mode of splicing regulation. Transcriptome-wide mapping of RBP occupancy revealed extensive reorganization of local RNA regulatory landscapes following fusion depletion. The requirement of RNA for FET fusion condensate formation, together with the inability of condensation-defective mutants to restore splicing regulation, further supported a role for higher-order assemblies in fusion-dependent alternative splicing (AS) control. Fusion-driven splicing programs stratified Ewing sarcoma patients independently of established clinical covariates, thereby underscoring their clinical relevance. AS of TFDP1 emerged as a common fusion-regulated splicing event required for sarcoma cell fitness and therapeutically actionable using antisense oligonucleotides. Together, our findings establish AS regulation as a conserved function of FET fusion oncoproteins that is mechanistically separable from their canonical transcriptional activity. More broadly, they support a model in which oncogenic fusion proteins can drive malignant phenotypes through large-scale remodeling of RNA regulatory networks.

molecular biology↗

bioRxiv2026

Proximity-Aware Graph Attention Networks for Spatially Resolved Cell-Cell Inference

Cell-cell inference is a fundamental mechanism driving tissue homeostasis, immune regulation, and disease progression. Existing CCC inference tools operate on dissociated single-cell RNA-seq data, discarding the spatial constraints that govern short-range paracrine and juxtacrine signaling. We present SO_SCPLOWPAC_SCPLOWGNN, a proximity-aware graph attention network that jointly encodes physical cell adjacency and ligand-receptor co-expression from spatial transcriptomics data to infer spatially resolved CCC interactions. A heterogeneous cell communication graph is constructed by combining spatial proximity edges with molecular ligand-receptor edges, and a distance-modulated attention mechanism enforces the locality constraint of cell-to-cell signaling. The model is trained with a composite self-supervised objective that integrates spatial co-localization enrichment and downstream target gene activation. We evaluate SO_SCPLOWPAC_SCPLOWGNN on four spatial transcriptomics datasets spanning 10X Visium, MERFISH, and Slide-seq platforms. Compared with state-of-the-art methods including COMMOT, SpaOTsc, CellChat, and NicheNet, our method achieves superior interaction AUROC (0.871 vs. 0.831 for COMMOT), a 3.42x spatial enrichment score, and an F1 of 0.681 in communication hotspot detection. Ablation studies confirm that spatial distance modulation is the single most impactful component, contributing a 0.030 AUROC improvement over a non-spatial baseline.

bioinformatics↗

bioRxiv2026

Adrenergic signaling induces a pro-tumorigenic B cell state in colorectal cancer

The importance of neuron-tumor crosstalk has gained increasing attention, yet its influence on the cellular and molecular landscape of colorectal cancer (CRC) remains largely unexplored. Here, we show that colonic innervation shapes the tumor immune microenvironment in a murine model of colitis-associated CRC. Although neuronal density does not affect tumor number, size, or overall burden, transcriptomic profiling of cells isolated from the tumor of hypo-innervated mice revealed extensive differential gene expression, including genes involved in immunoglobulin (Ig) signaling and the cancer-relevant hallmark avoiding immune destruction. Flow cytometry analysis of leukocyte populations demonstrated a significant reduction of B cells in the cancerous colon of hypo-innervated mice, notably a decrease in germinal center B cells and an altered class-switching profile, characterized by reduced IgA and increased IgD expression. Fluorescence and transmission electron microscopy showed that colonic B cells are primarily localized in the submucosa near neuronal processes containing varicose release sites, suggesting direct neuron-B cell interactions. Functional assays revealed that adrenergic stimulation of B cells promotes their proliferation and maturation, enhances IL-10 secretion, and alters immunoglobulin profiles. Strikingly, the transcriptome of epinephrine-treated B cells closely mirrors that of plasma cells from human CRC tissues, and the transcriptomic signature of these epinephrine-stimulated B cells associates with poorer patient survival. Together, these findings uncover an adrenergic neuron - B cell axis in CRC, providing evidence for direct neuroimmune interactions that affect B cell maturation and may influence tumor progression and therapeutic responses.

cancer biology↗

bioRxiv2025

Cut-Detector: A Tool for Automated Temporal Analysis of Late Cytokinetic Events

Cytokinesis is the final step of cell division, resulting in the physical separation of the two daughter cells. Despite its fundamental importance in cell biology, biologists currently lack automatic tools for large-scale profiling of cytokinesis dynamics. In particular, the timing of the first microtubule cut in the intercellular bridge connecting the daughter cells is crucial, as it marks a critical step preceding abscission. Here, we introduce Cut-Detector, an open-source tool for the automatic analysis of late cytokinesis timing from time-lapse microscopy movies. Cut-Detector employs an AI approach to carry out the multiple tasks required to monitor cytokinesis: cell segmentation and tracking, detection of cell division events, localization of the intercellular bridge, and detection of the microtubule cuts. Cut-Detector will facilitate large-scale analyses to uncover new cytokinetic genes, a task that would be impractical without automation.

bioinformatics↗

bioRxiv2023

Control of intestinal stemness and cell lineage by histone variant H2A.Z isoforms

The histone variant H2A.Z plays important functions in the regulation of gene expression. In mammals, it is encoded by two genes, giving raise to two highly related isoforms named H2A.Z.1 and H2A.Z.2, which can have similar or antagonistic functions depending on the promoter. Knowledge of the physiopathological consequences of such functions emerges, but how the balance between these isoforms regulates tissue homeostasis is not fully understood. Here, we investigated the relative role of H2A.Z isoforms in intestinal epithelial homeostasis. Through genome-wide analysis of H2A.Z genomic localization in differentiating Caco-2 cells, we uncovered an enrichment of H2A.Z isoforms on the bodies of genes which are induced during enterocyte differentiation, stressing the potential importance of H2A.Z isoforms dynamics in this process. Through a combination of in vitro and in vivo experiments, we further demonstrated the two isoforms cooperate for stem and progenitor cells proliferation, as well as for secretory lineage differentiation. However, we found that they antagonistically regulate enterocyte differentiation, with H2A.Z.1 preventing terminal differentiation and H2A.Z.2 favoring it. Altogether, these data indicate that H2A.Z isoforms are critical regulators of intestine homeostasis and may provide a paradigm of how the balance between two isoforms of the same chromatin structural protein can control physiopathological processes.

cell biology↗

bioRxiv2022

Extending and improving metagenomic taxonomic profiling with uncharacterized species with MetaPhlAn 4

Metagenomic assembly enables novel organism discovery from microbial communities, but from most metagenomes it can only capture few abundant organisms. Here, we present a method - MetaPhlAn 4 - to integrate information from both metagenome assemblies and microbial isolate genomes for improved and more comprehensive metagenomic taxonomic profiling. From a curated collection of 1.01M prokaryotic reference and metagenome-assembled genomes, we defined unique marker genes for 26,970 species-level genome bins, 4,992 of them taxonomically unidentified at the species level. MetaPhlAn 4 explains [~]20% more reads in most international human gut microbiomes and >40% in less-characterized environments such as the rumen microbiome, and proved more accurate than available alternatives on synthetic evaluations while also reliably quantifying organisms with no cultured isolates. Application of the method to >24,500 metagenomes highlighted previously undetected species to be strong biomarkers for host conditions and lifestyles in human and mice microbiomes, and showed that even previously uncharacterized species can be genetically profiled at the resolution of single microbial strains. MetaPhlAn 4 thus integrates the novelty of metagenomic assemblies with the sensitivity and fidelity of reference-based analyses, providing efficient metagenomic profiling of uncharacterized species and enabling deeper and more comprehensive microbiome biomarker detection.

bioinformatics↗

bioRxiv2022

Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh Syndrome

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological aging process. Rapamycin, a drug that increases lifespan and health during normative aging also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh Syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh Syndrome. Here we show that another drug that extends lifespan and delays normative aging in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression. This study provides the first evidence that alteration of the gut microbiome may impact severe mitochondrial disease and provides further support for the model that biological aging and severe mitochondrial disorders share underlying common mechanisms.

biochemistry↗

bioRxiv2020

Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3

Culture-independent analyses of microbial communities have advanced dramatically in the last decade, particularly due to advances in methods for biological profiling via shotgun metagenomics. Opportunities for improvement continue to accelerate, with greater access to multi-omics, microbial reference genomes, and strain-level diversity. To leverage these, we present bioBakery 3, a set of integrated, improved methods for taxonomic, strain-level, functional, and phylogenetic profiling of metagenomes newly developed to build on the largest set of reference sequences now available. Compared to current alternatives, MetaPhlAn 3 increases the accuracy of taxonomic profiling, and HUMAnN 3 improves that of functional potential and activity. These methods detected novel disease-microbiome links in applications to CRC (1,262 metagenomes) and IBD (1,635 metagenomes and 817 metatranscriptomes). Strain-level profiling of an additional 4,077 metagenomes with StrainPhlAn 3 and PanPhlAn 3 unraveled the phylogenetic and functional structure of the common gut microbe Ruminococcus bromii, previously described by only 15 isolate genomes. With open-source implementations and cloud-deployable reproducible workflows, the bioBakery 3 platform can help researchers deepen the resolution, scale, and accuracy of multi-omic profiling for microbial community studies.

microbiology↗

bioRxiv2020

Predictive Markers of LRRK2 Inhibition in Biofluids

Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, may be critical in the clinical development of successful LRRK2-targeting therapeutics. In this study, three different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360, MLi2, and RA283) were orally administered to groups of cynomolgus macaques at different doses. Biofluid markers with proposed pharmacodynamic properties for assessing LRRK2 inhibition were measured from samples of blood, urine, and cerebral-spinal fluid (CSF). LRRK2 kinase inhibition led to consistent reduced pS935-LRRK2 and pRab10 proteins in blood mononuclear cells, reduced exosome LRRK2 protein and di-docosahexaenoyl (22:6) bis (monoacylglycerol) phosphate in urine, and reduced exosome LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. Incomplete LRRK2 kinase inhibition reduced LRRK2 protein secretion in exosomes whereas high drug exposures may reduce both exosome and tissue levels of LRRK2 protein. These orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics in the brain and periphery.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsPDParkinson’s diseaseLRRK2Leucine-rich repeat kinase 2 NHPs: Non-human primatesdi-22:6-BMPdi-docosahexaenoyl (22:6) bis (monoacylglycerol) phosphate CSF: Cerebrospinal fluidATPadenosine-tri phosphateView Full Text

neuroscience↗

bioRxiv2019

Intrinsic control of muscle attachment sites matching

How a stereotypic muscle pattern is established, and adapted to fit locomotion behaviour is a fascinating question. Here we set up the targeted deletion of cis-regulatory modules (CRMs) controlling the transcription of Drosophila muscle identity transcription factors (iTF) to generate larval muscle identity mutants. By focusing on one muscle transcription and morphology, we show that selection of muscle attachment sites and the precision of muscle/muscle matching is intrinsic to muscle identity. It involves propagation of the iTF expression code from a founder myoblast to the other syncytial nuclei after fusion. Live imaging indicates that the precise staggered muscle attachment pattern involves attraction to tendon cells and homotypic repulsion. Unbalance leads to the formation of abnormal, branched muscles. Single muscle morphology shifts induce subtle locomotor behaviour. Together this work highlights that CRM deletion is an effective setting for creating muscle-specific defects and branched muscles, as new paradigms to study the development of human myopathies affecting subsets of muscles. Highlights- First muscle-identity mutants, via deletion of specific cis-regulatory modules - Reprogramming of syncytial nuclei is key to muscle morphological identity - Selection of muscle attachment sites; attraction and retraction intrinsic to muscle identity - Genetically controlled formation of branched muscles, a new paradigm for functional studies - Single muscle morphology shift induces subtle locomotor behaviour modification

developmental biology↗