Résumé
In eukaryotes, the spatial and temporal organization of genome duplication gives rise to distinctive profiles of replication origin usage along the chromosomes. While it has become increasingly clear that these programs are important for cellular physiology, the mechanisms by which they are determined and modulated remain elusive. Replication initiation requires the function of cyclin-dependent kinases (CDKs), which associate with various cyclin partners to drive cell proliferation. Surprisingly, although we possess detailed knowledge of the CDK regulators and targets that are crucial for origin activation, little is known about whether CDKs play a critical role in establishing the genome-wide pattern of origin selection. We have addressed this question in the fission yeast, taking advantage of a simplified cell cycle network in which cell proliferation is driven by a single cyclin-CDK module. This system allows us to precisely control CDK activity in vivo using chemical genetics. First, in contrast to previous reports, our results clearly show that distinct cyclin-CDK pairs are not essential for regulating specific subsets of origins and for establishing a normal replication program. Importantly, we then demonstrate that the timing at which CDK activity reaches the S phase threshold is critical for the organization of replication in distinct efficiency domains, while the level of CDK activity at the onset of S phase is a dose-dependent modulator of overall origin efficiencies. Our study therefore implicates these different aspects of CDK regulation as versatile mechanisms for shaping the architecture of DNA replication across the genome.
Auteurs, date et publication :
Auteurs Anthony Perrot , Christopher Lee Millington , Blanca Gómez-Escoda , Diane Schausi-Tiffoche , Pei-Yun Jenny Wu
Publication : PLOS Genetics
Date : 2025
Volume : 14
Issue : 2
Pages : e1007214
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular and cellular functions of CD90 remain unclear.Experimental Design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells.Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion in vivo and killed CD90high primary GSC lines.Conclusions: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients. Clin Cancer Res; 23(23); 7360-74. ©2017 AACR.
Auteurs, date et publication :
Auteurs Tony Avril , Amandine Etcheverry , Raphaël Pineau , Joanna Obacz , Gwénaële Jegou , Florence Jouan , Pierre-Jean Le Reste , Masumeh Hatami , Rivka R. Colen , Brett L. Carlson , Paul A. Decker , Jann N. Sarkaria , Elodie Vauléon , Dan Cristian Chiforeanu , Anne Clavreul , Jean Mosser , Eric Chevet , Véronique Quillien
Publication : Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Date : 2017
Volume : 23
Issue : 23
Pages : 7360-7374
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Primary consumers in freshwater ecosystems, such as the zooplankton organism Daphnia magna, are highly affected by cyanobacteria, both as they may use it as a food source but also by cyanobacterial metabolites present in the water. Here, we investigate the impacts of cyanobacterial metabolites focussing on the environmental realistic scenario of the naturally released mixture without crushing cyanobacterial cells or their uptake as food. Therefore, D. magna were exposed to two concentrations of cell free cyanobacterial spent medium from Microcystis aeruginosa PCC 7806 to represent higher and lower ecologically-relevant concentrations of cyanobacterial metabolites. Including microcystin-LR, 11 metabolites have been detected of which 5 were quantified. Hypothesising concentration and time dependent negative impact, survival, gene expression marking digestion and metabolism, oxidative stress response, cell cycle and molting as well as activities of detoxification and antioxidant enzymes were followed for 7 days. D. magna suffered from oxidative stress as both catalase and glutathione S-transferase enzyme activities significantly decreased, suggesting enzyme exhaustibility after 3 and 7 days. Moreover, gene-expressions of the 4 stress markers (glutathione S-transferase, glutathione peroxidase, catalase and thioredoxin) were merely downregulated after 7 days of exposure. Energy allocation (expression of Glyceraldehyde-3-phosphate dehydrogenase) was increased after 3 days but decreased as well after 7 days exposure. Cell cycle was impacted time dependently but differently by the two concentrations, along with an increasing downregulation of myosin heavy chain responsible for cell arrangement and muscular movements. Deregulation of nuclear hormone receptor genes indicate that D. magna hormonal steering including molting seemed impaired despite no detection of microviridin J in the extracts. As a consequence of all those responses and presumably of more than investigated molecular and physiological changes, D. magna survival was impaired over time, in a concentration dependent manner. Our results confirm that besides microcystin-LR, other secondary metabolites contribute to negative impact on D. magna survival and stress response.
Auteurs, date et publication :
Auteurs Gorenka Bojadzija Savic , Hervé Colinet , Myriam Bormans , Christine Edwards , Linda A. Lawton , Enora Briand , Claudia Wiegand
Publication : Toxicon
Date : 2021
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
This study presents the occurrence and abundance of Aeromonas antibiotic-resistant bacteria (ARB) and genes (ARGs) isolated from water, biofilm and fish in two commercial trout farms before and one week after flumequine treatment. Wild (WT) and non-wild (NWT) strains were determined for quinolones (flumequine, oxolinic acid and enrofloxacin), oxytetracycline (OXY), florfenicol (FFN), trimethoprim-sulfamethoxazole (TMP) and colistin (COL), and pMAR (presumptive multi-resistant) strains were classified. Forty-four ARGs for the mentioned antibiotics, β-lactams and multi-resistance were quantified for 211 isolates. BlaSHV-01, mexF and tetE were the dominant ARGs. A greater occurrence and abundance of tetA2, sul3, floR1, blaSHV-01 and mexF were observed for NWT compared to WT. The occurrence of pMAR and NWT Aeromonas for quinolones, OXY, FFN, TMP, COL and ARGs depended on the Aeromonas origin, antibiotic use and the presence of upstream activities. Our results revealed the impact of a flumequine treatment on Aeromonas present on a fish farm through an increase in NWT and pMAR strains. The link between fish and their environment was shown by the detection of identical ARB and ARGs in the two types of samples. There appears to be a high risk of resistance genes developing and spreading in aquatic environments.
Auteurs, date et publication :
Auteurs Niki Hayatgheib , Ségolène Calvez , Catherine Fournel , Lionel Pineau , Hervé Pouliquen , Emmanuelle Moreau
Publication : Microorganisms
Date : 2021
Volume : 9
Issue : 6
Pages : 1201
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Intrahepatic cholangiocarcinoma (iCCA) is a deadly liver primary cancer associated with poor prognosis and limited therapeutic opportunities. Active transforming growth factor beta (TGFβ) signaling is a hallmark of the iCCA microenvironment. However, the impact of TGFβ on the transcriptome of iCCA tumor cells has been poorly investigated. Here, we have identified a specific TGFβ signature of genes commonly deregulated in iCCA cell lines, namely HuCCT1 and Huh28. Novel coding and noncoding TGFβ targets were identified, including a TGFβ-induced long noncoding RNA (TLINC), formerly known as cancer susceptibility candidate 15 (CASC15). TLINC is a general target induced by TGFβ in hepatic and nonhepatic cell types. In iCCA cell lines, the expression of a long and short TLINC isoform was associated with an epithelial or mesenchymal phenotype, respectively. Both isoforms were detected in the nucleus and cytoplasm. The long isoform of TLINC was associated with a migratory phenotype in iCCA cell lines and with the induction of proinflammatory cytokines, including interleukin 8, both in vitro and in resected human iCCA. TLINC was also identified as a tumor marker expressed in both epithelial and stroma cells. In nontumor livers, TLINC was only expressed in specific portal areas with signs of ductular reaction and inflammation. Finally, we provide experimental evidence of circular isoforms of TLINC, both in iCCA cells treated with TGFβ and in resected human iCCA. Conclusion: We identify a novel TGFβ-induced long noncoding RNA up-regulated in human iCCA and associated with an inflammatory microenvironment. (Hepatology Communications 2018;2:254-269)
Auteurs, date et publication :
Auteurs Aude Merdrignac , Gaëlle Angenard , Coralie Allain , Kilian Petitjean , Damien Bergeat , Pascale Bellaud , Allain Fautrel , Bruno Turlin , Bruno Clément , Steven Dooley , Laurent Sulpice , Karim Boudjema , Cédric Coulouarn
Publication : Hepatology Communications
Date : 2025
Volume : 2
Issue : 3
Pages : 254-269
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Aims We aimed to identify a clinically useful biomarker using DNA methylation-based information to optimize individual treatment of patients with glioblastoma (GBM). Methods A six-CpG panel was identified by incorporating genome-wide DNA methylation data and clinical information of three distinct discovery sets and was combined using a risk-score model. Different validation sets of GBMs and lower-grade gliomas and different statistical methods were implemented for prognostic evaluation. An integrative analysis of multidimensional TCGA data was performed to molecularly characterize different risk tumors. Results The six-CpG risk-score signature robustly predicted overall survival (OS) in all discovery and validation cohorts and in a treatment-independent manner. It also predicted progression-free survival (PFS) in available patients. The multimarker epigenetic signature was demonstrated as an independent prognosticator and had better performance than known molecular indicators such as glioma-CpG island methylator phenotype (G-CIMP) and proneural subtype. The defined risk subgroups were molecularly distinct; high-risk tumors were biologically more aggressive with concordant activation of proangiogenic signaling at multimolecular levels. Accordingly, we observed better OS benefits of bevacizumab-contained therapy to high-risk patients in independent sets, supporting its implication in guiding usage of antiangiogenic therapy. Finally, the six-CpG signature refined the risk classification based on G-CIMP and MGMT methylation status. Conclusions The novel six-CpG signature is a robust and independent prognostic indicator for GBMs and is of promising value to improve personalized management.
Auteurs, date et publication :
Auteurs An-An Yin , Nan Lu , Amandine Etcheverry , Marc Aubry , Jill Barnholtz‐Sloan , Lu-Hua Zhang , Jean Mosser , Wei Zhang , Xiang Zhang , Yu-He Liu , Ya-Long He
Publication : CNS Neuroscience & Therapeutics
Date : 2025
Volume : 24
Issue : 3
Pages : 167-177
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Plants are colonized by a great diversity of microorganisms which form a microbiota and perform additional functions for their host. This microbiota can thus be considered a toolbox enabling plants to buffer local environmental changes, with a positive influence on plant fitness. In this context, the transmission of the microbiota to the progeny represent a way to ensure the presence of beneficial symbionts within the habitat. Examples of such transmission have been mainly described for seed transmission and concern a few pathogenic microorganisms. We investigated the transmission of symbiotic partners to plant progeny within clonal plant network.
Auteurs, date et publication :
Auteurs Nathan Vannier , Cendrine Mony , Anne-Kristel Bittebiere , Sophie Michon-Coudouel , Marine Biget , Philippe Vandenkoornhuyse
Publication : Microbiome
Date : 2018
Volume : 6
Issue : 1
Pages : 79
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
Aims DNA methylation has been found to regulate microRNAs (miRNAs) expression, but the prognostic value of miRNA-related DNA methylation aberration remained largely elusive in cancers including glioblastomas (GBMs). This study aimed to investigate the clinical and biological feature of miRNA methylation in GBMs of non-glioma-CpG island methylator phenotype (non-G-CIMP). Methods Prognostic miRNA methylation loci were analyzed, with TCGA and Rennes cohort as training sets, and independent datasets of GBMs and low-grade gliomas (LGGs) were obtained as validation sets. Different statistical and bioinformatic analysis and experimental validations were performed to clinically and biologically characterize the signature. Results We identified and validated a risk score based on methylation status of five miRNA-associated CpGs which could predict survival of GBM patients in a series of training and validation sets. This signature was independent of age and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. The risk subgroup was associated with angiogenesis and accordingly differential responses to bevacizumab-contained therapy. MiRNA target analysis and in vitro experiments further confirmed the accuracy of this signature. Conclusion The five-CpG signature of miRNA methylation was biologically relevant and was of potential prognostic and predictive value for GBMs. It might be of help for improving individualized treatment.
Auteurs, date et publication :
Auteurs En-Ming Kang , An-An Yin , Ya-Long He , Wei-Jun Chen , Amandine Etcheverry , Marc Aubry , Jill Barnholtz‐Sloan , Jean Mosser , Wei Zhang , Xiang Zhang
Publication : CNS Neuroscience & Therapeutics
Date : 2025
Volume : 25
Issue : 9
Pages : 937-950
Catégorie(s)
#CNRS #EcoGenO #Université de RennesRésumé
The induction of general plant defense responses following the perception of external elicitors is now regarded as the first level of the plant immune response. Depending on the involvement or not of these molecules in pathogenicity, this induction of defense is called either Pathogen-Associated Molecular Pattern (PAMP) Triggered Immunity or Pattern Triggered Immunity—both abbreviated to PTI. Because PTI is assumed to be a widespread and stable form of resistance to infection, understanding the mechanisms driving it becomes a major goal for the sustainable management of plant-pathogen interactions. However, the induction of PTI is complex. Our hypotheses are that (i) the recognition by the plant of PAMPs vs non-PAMP elicitors leads to specific defense profiles and (ii) the responses specifically induced by PAMPs target critical life history traits of the pathogen that produced them. We thus analyzed, using a metabolomic approach coupled with transcriptomic and hormonal analyses, the defense profiles induced in potato foliage treated with either a Concentrated Culture Filtrate (CCF) from Phytophthora infestans or two non-PAMP preparations, β-aminobutyric acid (BABA) and an Ulva spp. Extract, used separately. Each elicitor induced specific defense profiles. CCF up-regulated sesquiterpenes but down-regulated sterols and phenols, notably α-chaconine, caffeoyl quinic acid and rutin, which decreased spore production of P. infestans in vitro. CCF thus induces both defense and counter-defense responses. By contrast, the Ulva extract triggered the synthesis of a large-spectrum of antimicrobial compounds through the phenylpropanoid/flavonoid pathways, while BABA targeted the primary metabolism. Hence, PTI can be regarded as a heterogeneous set of general and pathogen-specific responses triggered by the molecular signatures of each elicitor, rather than as a uniform, non-specific and broad-spectrum set of general defense reactions.
Auteurs, date et publication :
Auteurs Rafaela Lopes Martin , Pauline Le Boulch , Pauline Clin , Adrián Schwarzenberg , Jean-Claude Yvin , Didier Andrivon , Eric Nguema-Ona , Florence Val
Publication : PLOS ONE
Date : 2025
Volume : 15
Issue : 8
Pages : e0236633