Biology subjects

Tual-Chalot, S.

Publications and source records attributed to Tual-Chalot, S..

5 recordsLinked to original sources

bioRxiv2026

Pharmacologic METTL3 inhibition attenuates TGF-beta-driven profibrotic signature in systemic sclerosis

Systemic sclerosis (SSc) is a devastating fibrosing disorder affecting the skin and internal organs, associated with the highest mortality among all rheumatic diseases. The mechanisms underlying excessive fibrogenesis in SSc are incompletely defined and treatment options are limited. N6-methyladenosine (m6A), the most abundant internal mRNA modification, is a reversible and pharmacologically tractable determinant of RNA fate. Here we mapped the m6A epitranscriptome of peripheral blood mononuclear cells (PBMCs) from patients with SSc using two orthogonal single-nucleotide-resolution platforms, a MazF-based m6A microarray and nanopore direct RNA sequencing. SSc PBMCs showed coordinated upregulation of the m6A writer complex (METTL3, METTL14, WTAP), a two-fold increase in global m6A, and redistribution of m6A marks from 3' untranslated regions toward coding sequences. Both platforms converged on TGF-b signaling as the most enriched pathway among differentially methylated transcripts, with hypermethylation of TGFB1, JUNB and KLF10 transcripts. Pharmacologic inhibition of METTL3 with STM2457 significantly reversed TGF-b-induced transcriptomic changes in skin fibroblasts preventing their transformation into pathological myofibroblasts. Together, these findings uncover an epitranscriptomic signature driving profibrotic transcriptional alterations in SSc, including enhanced TGF-b signaling, which can be effectively reversed by clinically available enzymatic m6A inhibitors. Our data suggest that targeting m6A methylation may offer a novel therapeutic strategy to mitigate fibrosis in SSc.

molecular biology↗

bioRxiv2025

STExplorer: Navigating the Micro-Geography of Spatial Omics Data

Spatial transcriptomics (ST) has the potential to provide unprecedented insights into gene expression across tissue architecture, but existing analytical methods often overlook the full complexity of the spatial dimension. We present STExplorer, an R package that adapts well-established computational geography (CG) methods to explore the micro-geography of spatial omics data. By incorporating techniques like Geographically Weighted Principal Component Analysis (GWPCA), Fuzzy Geographically Weighted Clustering (FGWC), Geographically Weighted Regression (GWR), and analyses of observation Spatial Autocorrelation (SA), STExplorer enables the uncovering of spatially resolved patterns that capture the spatial heterogeneity of biological data. STExplorer provides a complete suite of functions for spatial analyses and visualisations, supporting deeper biological understanding and inference. Built on the Bioconductor ecosystem, the package integrates with SpatialFeatureExperiment objects, ensuring compatibility with existing pipelines. It includes preprocessing capabilities such as data import, quality control, gene count normalisation, and variable gene selection, alongside tools for downstream analysis and detailed visualisations that quantify and map spatial heterogeneity and relationships. We demonstrate the utility of STExplorer through applications to spatial transcriptomics datasets, revealing that spatially varying gene expression and relationships are often masked by standard analyses. By bridging bioinformatics and CG, STExplorer provides a novel and informed approach to spatial transcriptomics analysis, with robust tools to address spatial heterogeneity and its associated underlying biology, thereby advancing our understanding of complex tissue biology without reinventing the wheel.

bioinformatics↗

bioRxiv2023

Exogenous TGFβ1 and its mimic HpTGM attenuate the heart's inflammatory response to ischaemic injury and improve long term cardiac outcomes

RationaleSuccessful and timely coronary reperfusion following acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage transiently ischaemic heart muscle. However, the subsequent inflammatory response within the infarct can lead to further loss of viable myocardium. Robust interventions are required in the acute MI setting to minimise cardiac injury and reduce risk of further detrimental progression. ObjectiveTGF{beta}1 is an anti-inflammatory cytokine released endogenously in response to infection or tissue injury. The goal of this study was to investigate its protective effects when given exogenously following myocardial infarction. Methods and ResultsTGF{beta}1 is found at increased levels in the blood of STEMI patients immediately following myocardial infarction. We observe a significant correlation (p=0.003) between higher circulating TGF{beta}1 levels at 24h post MI and a reduction in infarct size over the following 3 months, suggesting that an early increase in circulating TGF{beta}1 is protective in these patients. Using a mouse model of cardiac ischaemia-reperfusion we demonstrate that additional exogenous TGF{beta}1 delivered in the acute setting has multiple beneficial outcomes. At 24 hours post-reperfusion It leads to a significantly smaller infarct size (30% reduction, p=0.025), reduced inflammatory infiltrate (28% reduction, p=0.015), lower intra-cardiac expression of inflammatory cytokines IL1{beta} and CCL2 (>50 % reduction, p=0.038 and 0.0004, respectively) and reduced scar size at 4 weeks (21% reduction, p=0.015). Furthermore exogenous delivery of an equivalent dose of HpTGM, a recently described low-fibrogenic mimic of TGF{beta}1, secreted by a helminth parasite to evade immune rejection, has an almost identical protective effect on injured mouse hearts. Furthermore using a genetic approach we show the benefit is mediated by the vascular endothelium. ConclusionsThis work reveals the potential of exogenous TGF{beta}1 and HpTGM delivered in the acute MI setting to provide protective anti-inflammatory effects and reduce infarct size, leading to a smaller scar and reduced detrimental progression.

pathology↗

bioRxiv2020

Clearance of senescent cells during cardiac ischemia-reperfusion injury improves heart recovery following myocardial infarction

A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS based proteomics reveal that biological processes associated with fibrosis and inflammation, that were increased following ischemia-reperfusion, were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of proinflammatory, profibrotic and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-{beta}3, interleukin-11, interleukin-16 and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI senescent cells play a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.

cell biology↗

bioRxiv2018

Length-independent telomere damage drives cardiomyocyte senescence

Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

cell biology↗