Biology subjects

Petit, A.

Publications and source records attributed to Petit, A..

13 recordsLinked to original sources

bioRxiv2026

Fragmented landscapes of mobile transposable element families bolster the diversity of large-effect alleles in Arabidopsis

Transposable elements (TEs) are powerful endogenous mutagens, but our understanding of the 'mobilome' - the set of mobile TEs at the species level - has largely been shaped by the study of a single reference genome. To overcome this reference-centric view, we produced long-read genome assemblies for 91 Arabidopsis thaliana strains and performed a reference-free pangenomic graph analysis of structural variants. Our analysis revealed the presence of twice as many TE families with recent mobilization activity as previously described. These >200 newly identified TE families are ancestral, with a third experimentally shown to be mobile and although they are often characterized by the presence of full-length copies in only a few rather than in most strains, they nonetheless contribute significantly to the generation of large-effect alleles. These findings uncover a much more fragmented and impactful mobilome than previously documented and highlight how pangenome approaches dramatically improve the study of genetic diversity.

genomics↗

bioRxiv2026

Ventral anterior foregut endoderm cells as progenitors for airway epithelial cell replacement in primary ciliary dyskinesia

BackgroundLung transplantation remains the ultimate treatment option for patients with end-stage lung disease, but has many limitations. This underlines the urgent need of developing alternative approaches to treat lung disorders. Among the emergent strategies, gene therapy holds great potential for the treatment of monogenic lung diseases. However, so far, aerosolized viral vector-based delivery for gene therapy has failed likely because of difficulties in accessing the target cells. Combined gene and cell therapy approaches could be a promising alternative. Trials using basal cell transplantation already showed encouraging results. Moreover, the induced pluripotent stem cell (iPSC) technology broadens the scope of personalized therapies by paving the way for autologous approaches. Our group previously derived iPSC lines from patients with Primary Ciliary Dyskinesia (PCD) and found that their correction by gene conversion allows functional recovery. This study aimed to identify the best progenitors and airway conditioning technique to develop an autologous cell replacement strategy for PCD. MethodsAirway epithelial cells were differentiated from induced pluripotent stem cell (iPSC) lines from a healthy donor (parental Hy03) and Hy03 in which MCIDAS was knocked out (PCD model) and maintained in air-liquid interface (iALI). The engraftment of GFP+ ventral Anterior Foregut Endoderm (vAFE) cells, differentiated from GFP-expressing Hy03 iPSCs, was assessed after conditioning of the recipient iALI. The efficacy (epithelial cell shedding) and toxicity (cell death) of different conditioning strategies were compared. Cilia functional repair was assessed using microbead motion tracking. ResultsGFP+ vAFE cells can successfully integrate and repair trypsin- or EDTA-conditioned airway epithelia derived from the parental and MCIDAS-/- Hy03 iPSC lines. EDTA showed optimal efficacy/safety balance. Progenitor integration and differentiation were confirmed by E-cadherin, tubulin-IV, KRT5 and MUC5AC co-expression in GFP+ engrafted cells at day 35 post-graft (immunofluorescence analysis). The engrafted GFP+ population reached 35-45% of the total epithelial population, as indicated by flow cytometry quantification of EpCAM+/GFP+ cells. Functional analysis demonstrated cilia motion restoration after GFP+ cell engraftment onto MCIDAS-/- iALI. ConclusionsOur study shows that vAFE cells can integrate and differentiate to repair epithelial models of PCD. EDTA conditioning is promising for the clinical application of this therapeutic strategy.

cell biology↗

bioRxiv2026

Graph-based Drug Decomposition for Anticancer Response Modeling

This paper studies the molecular effects on ex vivo drug response in pediatric acute myeloid leukemia (AML). We firstly estimate dose-response relationships through linear and mixed-effects models, capturing both patient-specific heterogeneity and drug-level effects. Then, drug identifiers are decomposed into curated molecular descriptors and their higher-order interactions, yielding a structured, interpretable representation of chemical properties. To handle the resulting high-dimensional system, we introduce a specialized graph-based drug decomposition and selection, enabling a computationally tractable estimation of the molecular effects on ex vivo drug response. This strategy uncovers the molecular features most strongly associated with cellular viability, providing a biologically grounded and transparent alternative to black-box predictive methods. By directly linking molecular structure to therapeutic outcomes, our framework supports a novel mathematical-programming-based drug-combination selection and cost-efficient compound prioritization in pre-clinical leukemia research.

bioinformatics↗

bioRxiv2024

T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including Hepatocyte Growth factor

BackgroundT-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. MethodsTwo mouse T-ALL cell models were injected into immunocompetent mice. We used anti-Ly6G, and clodronate liposomes to suppress neutrophils and phagocytes, respectively. 5- (N-ethylcarboxamido)adenosine (NECA), an agonist of adenosine receptors was used to decrease inflammatory molecules secretion. FindingsWe show that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils or resident monocytes does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. InterpretationAltogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF as a new potential therapeutic target. FundingsThe work was supported by CEA, Inserm, Universite Paris-Saclay and Universite Paris-Cite, la Recherche contre le Cancer (ARC) and Hope of Princess Manon charity. The LSHL team is labellised by Ligue Nationale Contre le Cancer. Research in contextO_ST_ABSEvidence before this studyC_ST_ABST-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and lethal hematologic malignancy accounting for about 15% of pediatric and 25% of adult ALL. T-ALL originates from a block of differentiation and uncontrolled proliferation of immature T cells. Current chemotherapies provide an overall 5 years survival higher than 90% in children and of about 50% in adults. Both pediatric and adult relapses have a very poor outcome with resistance to treatment. Therefore, the identification of molecular targets and the development of new specific therapies are major goals to improve treatment success, and one way to reach this goal is to have a better understanding the dialog between T-ALL cells and their microenvironment. Cellular and molecular actors in the microenvironment have been identified to impact several types of leukemia. Recently, the supportive role of myeloid cells has been described in T-ALL. Moreover, interactions between receptors and ligands such as DL1, IL-18, IL-7, IGF1 and CXCL12 sustain proliferation, survival or initiation of T-ALL. However, the composition and the contribution of the inflammatory microenvironment that may broadly help T-ALL progression still remains poorly explored. Added value of this studyThe study, utilizing NOTCH1 and TAL1/LMO1-driven mouse T-ALL models, reveals that T-ALL induces an inflammatory microenvironment characterized by increased levels of blood neutrophils, resident monocytes, and plasmatic inflammatory molecules. Targeting molecular microenvironment with the non-selective adenosine receptor agonist NECA drastically decreases T-ALL progression and prolongs mice survival. This study further identifies hepatocyte growth factor (HGF), a known regulator of proliferation and migration of tumor cells, as a putative supportive and targetable factor in T-ALL. Implications of all the available evidenceIn this study, evidence linking T-ALL and inflammatory microenvironment is provided. These data extend our understanding of the biological function of inflammatory microenvironment in T-ALL progression, and open to the targeting of the inflammatory microenvironment, and more specifically HGF/cMet signaling in T-ALL. Such targeted therapeutic approach could be added to current treatments to improve patient outcome.

cancer biology↗

bioRxiv2024

Exploration of a European-centered strawberry diversity panel provides markers and candidate genes for the control of fruit quality traits

Fruit quality traits are major breeding targets in cultivated strawberry (Fragaria x ananassa). Taking into account the requirements of both growers and consumers when selecting high quality cultivars is a real challenge. Here, we used an original diversity panel enriched with unique European accessions and the 50K FanaSNP array to highlight the evolution of strawberry diversity over the past 160 years, investigate the molecular basis of 12 major fruit quality traits by GWAS, and provide genetic markers for breeding. Results show that considerable improvements of key breeding targets including fruit weight, firmness, composition and appearance occurred simultaneously in European and American populations. Despite the high genetic diversity of our panel, we observed a drop in nucleotide diversity in certain chromosome regions, revealing the impact of selection. GWAS identified 71 associations with 11 quality traits and, while validating known associations (firmness, sugar), highlighted the predominance of new QTL, demonstrating the value of using untapped genetic resources. Three of the six selective sweeps detected are related to glossiness or skin resistance, two little-studied traits important for fruit attractiveness and, potentially, postharvest shelf-life. Moreover, major QTL for firmness, glossiness, skin resistance and susceptibility to bruising are found within a low diversity region of chromosome 3D. Stringent search for candidate genes underlying QTL uncovered strong candidates for fruit color, firmness, sugar and acid composition, glossiness and skin resistance. Overall, our study provides a potential avenue for extending shelf-life without compromising flavor and color as well as the genetic markers needed to achieve this goal.

genetics↗

bioRxiv2023

High CD44 expression identifies rare chemoresistant leukemic cells endowed with enhanced E-Selectin binding in T-ALL

T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy characterized by an increased proliferation and incomplete maturation of T-cell progenitors. Despite therapeutic improvements, relapses are often of bad prognosis. Therapeutic vulnerabilities and chemoresistance mechanisms arising from cell plasticity induced by the bone marrow (BM) microenvironment remain an important field of investigation. Employing single cell RNA sequencing (scRNAseq) of human T-ALL cells recovered from adipocyte-rich and -poor BM, a distinct leukemic stem cell (LSC) population defined by quiescence and elevated CD44 level (Ki67neg/lowCD44high) expression is identified in both territories. In vivo chemotherapy demonstrated that the LSC population evades drug treatment. Patient sample analyses confirmed the presence of Ki67neg/lowCD44high LSC both at diagnosis and relapse that displayed a specific transcriptomic signature. Interestingly, the intense expression of CD44 in T-ALL Ki67neg/lowLSC was associated with E-selectin binding. Importantly, when 39 human T-ALL samples were analyzed, the E-selectin binding ability was found significantly higher in Relapse/Refractory compared to drug-sensitive patients. These findings characterize a T-ALL LSC population with chemoresistant properties and shade light on new strategies for prognostic stratification while opening avenues for novel therapeutic options.

cancer biology↗

bioRxiv2023

Strawberry phenotypic plasticity in flowering time is driven by interaction between genetic loci and temperature

The flowering time, which determines when the fruits or seeds can be harvested, is known to be sensitive to plasticity, i.e. the ability of a genotype to display different phenotypes in response to environmental variations. In the context of climate change, strawberry breeding can take advantage of phenotypic plasticity to create high-performing varieties adapted either to local conditions or to a wide range of climates. To decipher how the environment affects the genetic architecture of flowering time in cultivated strawberry (Fragaria xananassa) and modify its QTL effects, we used a bi-parental segregating population grown for two years at widely divergent latitudes (5 European countries) and combined climatic variables with genomic data (Affymetrix(R) SNP array). We detected 10 unique flowering time QTL and demonstrated that temperature modulates the effect of plasticity-related QTL. We propose candidate genes for the three main plasticity QTL, including FaTFL1 which is the most relevant candidate in the interval of the major temperature-sensitive QTL (6D_M). We further designed and validated a genetic marker for the 6D_M QTL which offers great potential for breeding programs, for example for selecting of early-flowering strawberry varieties well adapted to different environmental conditions. HighlightsA GXE study of a segregating strawberry population in Europe showed that temperature is the main driver of flowering time plasticity. A genetic marker was designed for the main QTL.

genetics↗

bioRxiv2021

RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and a therapeutic target in patient-derived xenografts

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor denosumab in BC patients, beyond its bone-related effects, is unclear. Here, we investigated the prognostic value of RANK expression and its functionality in human BC. We analyzed RANK and RANKL expression in more than 1500 BC cases (777 being estrogen receptor-negative (ER-)) from four independent cohorts. We confirmed that RANK is more frequently expressed in ER- tumors, but it is also found in a subset of ER+ tumors. In ER- BC, RANK expression was independently associated with poor outcome, especially in postmenopausal patients and those who received adjuvant chemotherapy. Gene expression analyses unraveled distinct biology associated with RANK in relation to ER expression and menopause, and evidenced enhanced RANK activation in ER- postmenopausal tumors, together with regulation of metabolic pathways. Functional studies and transcriptomic analyses in ER- RANK+ patients-derived orthoxenografts demonstrated that activation of RANK signaling pathway promotes tumor cell proliferation and stemness, and regulates multiple biological processes including tumor immune surveillance and metabolism. Our results demonstrate that RANK expression is an independent poor prognosis biomarker in postmenopausal ER- BC patients and support the rational of using RANK pathway inhibitors in combination with chemotherapy in ER- BC.

cancer biology↗

bioRxiv2021

TWIST1 expression is associated with high-risk Neuroblastoma and promotes Primary and Metastatic Tumor Growth

The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings suggest TWIST1 as novel therapeutic target in NB.

cancer biology↗

bioRxiv2020

Differentiation of human induced pluripotent stem cells into functional airway epithelium

RationaleHighly reproducible in vitro generation of human bronchial epithelium from pluripotent stem cells is an unmet key goal for drug screening to treat lung diseases. The possibility of using induced pluripotent stem cells (hiPSC) to model normal and diseased tissue in vitro from a simple blood sample will reshape drug discovery for chronic lung, monogenic and infectious diseases. MethodsWe devised a simple and reliable method that drives a blood sample reprogrammed into hiPSC subsequently differentiated within 45 days into air-liquid interface bronchial epithelium (iALI), through key developmental stages, definitive-endoderm (DE) and Ventralized-Anterior-Foregut-Endoderm (vAFE) cells. ResultsReprogramming blood cells from one healthy and 3 COPD patients, and from skin-derived fibroblasts obtained in one PCD patient, succeeded in 100% of samples using Sendai viruses. Mean cell purity at DE and vAFE stages was greater than 80%, assessed by expression of CXCR4 and NKX2.1, avoiding the need of cell sorting. When transferred to ALI conditions, vAFE cells reliably differentiated within 4 weeks into bronchial epithelium with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells as found in vivo. Benchmarking all culture conditions including hiPSCs adaptation to single-cell passaging, cell density and differentiation induction timing allowed for consistently producing iALI bronchial epithelium from the five hiPSC lines. ConclusionsReliable reprogramming and differentiation of blood-derived hiPSCs into mature and functional iALI bronchial epithelium is ready for wider use and this will allow better understanding lung disease pathogenesis and accelerating the development of novel gene therapies and drug discovery.

bioengineering↗

bioRxiv2020

The genetic architecture of fruit colour in strawberry (Fragaria x ananassa) uncovers the predominant contribution of the F. vesca subgenome to anthocyanins and reveals underlying genetic variations

Fruit colour, which is central to the sensorial and nutritional quality of the fruit, is a major breeding target in cultivated strawberry (Fragaria x ananassa). Red fruit colour is caused by the accumulation of anthocyanins, which are water-soluble flavonoids. Here, using pseudo F1 progeny derived from the cv. Capitola and the advanced line CF1116 and taking advantage of the available high density SNP array, we delineated fruit flavonoids mQTLs (13 compounds: anthocyanin, flavonols and flavan-3-ols) and colour-related QTLs (total anthocyanins and fruit colour) to narrow genomic regions corresponding to specific subgenomes of the cultivated strawberry. Findings showed that the overwhelming majority of the anthocyanin mQTLs and other colour-related QTLs are specific to F. vesca subgenome but that other subgenomes also contribute to colour variations. We then focused on two major homoeo-mQTLs for pelargonidin-3-glucoside (PgGs) localized on both male and female maps on linkage group LG3a (F. vesca subgenome). Combined high-resolution mapping of PgGs mQTLs and colour QTLs, transcriptome analysis of selected progeny individuals and whole genome sequencing of the parents led to the identification of several INDELS in the cis-regulatory region of a MYB102-like ODORANT gene and of the deletion of a putative MADS box binding motif in the 5UTR upstream region of an anthocyanidin reductase (ANR) gene, which likely underlie significant colour variations in strawberry fruit. The implications of these findings are important for the functional analysis and genetic engineering of colour-related genes and for the breeding by Marker-Assisted-Selection of new strawberry varieties with improved colour and health-benefits.

genetics↗

bioRxiv2020

Metabolite Quantitative Trait Loci for flavonoids provide new insights into the genetic architecture of strawberry (Fragaria x ananassa) fruit quality

Flavonoids are products from specialized metabolism that contribute to fruit sensorial (colour) and nutritional (antioxidant properties) quality. Here, using a pseudo full-sibling F1 progeny previously studied for fruit sensorial quality of cultivated strawberry (Fragaria x ananassa), we explored over two successive years the genetic architecture of flavonoid-related traits using LC-ESI-MS (13 compounds including anthocyanins, flavonols and flavan-3-ols) and colorimetric assays (anthocyanins, flavonoids, phenolics, FRAP and TEAC antioxidant capacity). Network correlation analysis highlighted the high connectivity of flavonoid compounds within each chemical class and low correlation with colorimetric traits except anthocyanins. Mapping onto the female and male linkage maps of 152 flavonoid metabolic QTLs (mQTLs) and of 26 colorimetric QTLs indicated co-localization on few linkage groups of major flavonoid- and taste-related QTLs previously uncovered. These results pave the way for the discovery of genetic variations underlying flavonoid mQTLs and for marker-assisted selection of strawberry varieties with improved sensorial and nutritional quality.

genetics↗

bioRxiv2019

Screening of clustered regulatory elements reveals functional cooperating dependencies in Leukemia.

In the recent years, massively parallel sequencing approaches identified hundreds of mutated genes in cancer(1) providing an unprecedented amount of information about mechanisms of cancer cell maintenance and progression. However, while (it is widely accepted that) transformation processes result from oncogenic cooperation between deregulated genes and pathways, the functional characterization of candidate key players is mostly performed at the single gene level which is generally inadequate to identify these oncogene circuitries. In addition, studies aimed at depicting oncogenic cooperation involve the generation of challenging mouse models or the deployment of tedious screening pipelines. Genome wide mapping of epigenomic modifications on histone tails or binding of factors such as MED1 and BRD4 allowed identification of clusters of regulatory elements, also termed Super-Enhancers (SE)(2). Functional annotation of these regions revealed their high relevance during normal tissue development and cancer ontogeny(3). An interesting paradigm of the tumorigenic function of these SE regions comes from ETO2-GLIS2-driven acute megakaryoblastic leukemia (AMKL) in which the fusion protein ETO2-GLIS2 is sufficient to promote an aberrant transcriptional network by the rewiring of SE regions(4). We thus hypothesized that important regulatory regions could control simultaneously expression of genes cooperating in functional modules to promote cancer development. In an effort to identify such modules, we deployed a genome-wide CRISPRi-based screening approach and nominated SE regions that are functionally linked to leukemia maintenance. In particular, we pinpointed a novel SE region regulating the expression of both tyrosine kinases KIT and PDGFRA. Whereas the inhibition of each kinase alone affected modestly cancer cell growth, combined inhibition of both receptors synergizes to impair leukemia cell growth and survival. Our results demonstrate that genome-wide screening of regulatory DNA elements can identify co-regulated genes collaborating to promote cancer and could open new avenues to the concept of combined gene inhibition upon single hit targeting.

cancer biology↗