UCAGenomiX related publications

Du to our strong expertise in "omics" experiments and in microRNAs topics we decided to separate into 3 categories the related publications into which the Functional genomics Platform of Nice-Sophia-Antipolis is involved :
  1. Expression studies (DNA microarrays and high-throughput sequencing experiments)
  2. MicroRNA studies
  3. Miscellaneous

Pottier Nicolas

 pottier@ipmc.cnrs.fr
 04 93 95 77 90
 660 route des lucioles 06560 Valbonne - Sophia-Antipolis

9 publications found

1. The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia.
Leukemia. 2018 Aug 8. doi: 10.1038/s41375-018-0227-5.
Duployez N, Marceau-Renaut A, Villenet C, Petit A, Rousseau A, Ng SWK, Paquet A, Gonzales F, Barthélémy A, Leprêtre F, Pottier N, Nelken B, Michel G, Baruchel A, Bertrand Y, Leverger G, Lapillonne H, Figeac M, Dick JE, Wang JCY, Preudhomme C, Cheok M
Laboratory of Hematology, CHU Lille, Lille, France. nicolas.duployez@chru-lille.fr.

Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64-6.82), P < 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38-8.92), P = 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63-7.16), P = 0.001; OS HR = 3.02 (95%CI = 1.16-7.85), P = 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.
Pubmed link : 30089916

2. Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation
Arch Toxicol. 2018 Jan 23. doi: 10.1007/s00204-018-2158-3
Vandenbussche C, Van der Hauwaert C, Dewaeles E, Franczak J, Hennino MF, Gnemmi V, Savary G, Tavernier Q, Nottet N, Paquet A, Perrais M, Blum D, Mari B, Pottier N, Glowacki F, Cauffiez C
EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Faculté de Médecine/Pôle Recherche, Univ. Lille, 1, place de Verdun, 59045, Lille Cedex, France. Centre Hospitalier de Valenciennes-Service de Néphrologie, Médecine Interne et Vasculaire, 59300, Valenciennes, France. Département de la Recherche en Santé, CHU Lille, 59000, Lille, France. UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Univ. Lille, 59000, Lille, France. UMR-S 1172, Inserm, 59000, Lille, France. Service d'Anatomopathologie, CHU Lille, 59000, Lille, France. CNRS, IPMC, FHU-OncoAge, Université Côte d'Azur, 06560, Valbonne, France. Service de Toxicologie et Génopathies, CHU Lille, 59000, Lille, France. Service de Néphrologie, CHU Lille, 59000, Lille, France. EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Faculté de Médecine/Pôle Recherche, Univ. Lille, 1, place de Verdun, 59045, Lille Cedex, France. christelle.cauffiez@univ-lille2.fr.

Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1 mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Tacrolimus also affected renal miRNA expression, including miRNAs previously involved in fibrotic and inflammatory processes as "fibromirs" such as miR-21-5p, miR-199a-5p and miR-214-3p. In agreement with in vivo data, Renal Proximal Tubular Epithelial cells exposed to Tacrolimus (25 and 50 µM) showed upregulation of miR-21-5p and the concomitant induction of epithelial phenotypic changes, inflammation and oxidative stress. In conclusion, this study suggests for the first time that miRNAs, especially fibromiRs, participate to Tacrolimus-induced nephrotoxic effects. Therefore, targeting miRNAs may be a new therapeutic option to counteract Tacrolimus deleterious effects on kidney.
Pubmed link : 29362864

3. Copy-number analysis identified new prognostic marker in acute myeloid leukemia.
Leukemia. 2016 Nov 4. doi: 10.1038/leu.2016.265.
Nibourel O, Guihard S, Roumier C, Pottier N, Terre C, Paquet A, Peyrouze P, Geffroy S, Quentin S, Alberdi A, Abdelali RB, Renneville A, Demay C, Celli-Lebras K, Barbry P, Quesnel B, Castaigne S, Dombret H, Soulier J, Preudhomme C, Cheok MH
CHU Lille University Hospital, Department of Hematology, Lille, France. INSERM UMR-S1172, Institute for Cancer Research of Lille, Factors of Leukemia Cell Persistance, Lille Cedex, France. CHU Lille University Hospital, Department of Biochemistry and Molecular Biology, Lille, France. Hospital of Versailles, Department of Hematology, Chesnay, France. University Côte d'Azur, CNRS Institute of Molecular and Cellular Pharmacology, Sophia-Antipolis, Nice, France. University Paris Diderot, INSERM U944 Saint-Louis Hospital, Department of Hematology, Paris, France. 7University Paris 7, Department of Hematology, Paris, France.

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.Leukemia advance online publication, 4 November 2016; doi:10.1038/leu.2016.265.
Pubmed link : 27686867

4. MicroRNA target identification: lessons from hypoxamiRs.
Antioxid Redox Signal. 2014 Sep 10;21(8):1249-68. doi: 10.1089/ars.2013.5648. Epub 2014 Feb 3.
Bertero T, Robbe-Sermesant K, Le Brigand K, Ponzio G, Pottier N, Rezzonico R, Mazure NM, Barbry P, Mari B
Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) , Centre National de la Recherche Scientifique, CNRS UMR 7275, Sophia Antipolis, France .

SIGNIFICANCE: MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as key regulators of many physiological and pathological processes, including those relevant to hypoxia such as cancer, neurological dysfunctions, myocardial infarction, and lung diseases. RECENT ADVANCES: During the last 5 years, miRNAs have been shown to play a role in the regulation of the cellular response to hypoxia. The identification of several bona fide targets of these hypoxamiRs has underlined their pleiotropic functions and the complexity of the molecular rules directing miRNA::target transcript pairing. CRITICAL ISSUES: This review outlines the main in silico and experimental approaches used to identify the targetome of hypoxamiRs and presents new recent relevant methodologies for future studies. FUTURE DIRECTIONS: Since hypoxia plays key roles in many pathophysiological conditions, the precise characterization of regulatory hypoxamiRs networks will be instrumental both at a fundamental level and for their future potential therapeutic applications.
Pubmed link : 24111877

5. FibromiRs: translating molecular discoveries into new anti-fibrotic drugs.
Trends Pharmacol Sci. 2014 Mar;35(3):119-26. doi: 10.1016/j.tips.2014.01.003. Epub 2014 Feb 19.
Pottier N, Cauffiez C, Perrais M, Barbry P, Mari B
1EA4483, Department of Biochemistry and Molecular Biology, Lille 2 University School of Medicine, Lille, France. Electronic address: nico_pottier@yahoo.fr. 2EA4483, Department of Biochemistry and Molecular Biology, Lille 2 University School of Medicine, Lille, France. 3INSERM U837, Jean-Pierre Aubert Research Center, Lille, France. 4CNRS, Institute of Molecular and Cellular Pharmacology, Sophia Antipolis, France; University of Nice Sophia Antipolis, Nice, France.

Fibrosis, or tissue scarring, is defined as excessive and persistent accumulation of extracellular matrix components in response to chronic tissue injury. Fibrosis is a pathological feature characterizing nearly all forms of chronic organ failure. Fibroproliferative disorders of liver, kidney, heart, and lung are frequently associated with considerable morbidity and mortality worldwide. Limited therapeutic options are available; none is yet effective in stopping the ultimate progression of the disease. This has prompted investigations for new molecular targets. Recent studies have shown aberrant expression of miRNAs (fibromiRs) during the development of fibrosis. The challenge now is to understand how these aberrantly expressed miRNAs collaborate to drive fibrogenesis. Progress in understanding how fibromiRs contribute to tissue fibrosis is necessary to translate molecular discoveries into new therapeutics for fibroproliferative diseases.
Pubmed link : 24560301

6. miR-199a-5p in idiopathic pulmonary fibrosis
Med Sci (Paris). 2013 May;29(5):461-3. doi: 10.1051/medsci/2013295006. Epub 2013 May 28.
Henaoui IS, Cauffiez C, Aubert S, Buscot M, Dewaeles E, Copin MC, Marquette CH, Barbry P, Perrais M, Pottier N, Mari B
UMR-7275 CNRS, université de Nice Sophia-Antipolis, institut de pharmacologie moléculaire et cellulaire, 660, route des Lucioles Sophia-Antipolis, 06560 Valbonne, Nice, France.


Pubmed link : 23732092

7. miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1.
PLoS Genet. 2013 Feb;9(2):e1003291. doi: 10.1371/journal.pgen.1003291. Epub 2013 Feb 14.
Lino Cardenas CL, Henaoui IS, Courcot E, Roderburg C, Cauffiez C, Aubert S, Copin MC, Wallaert B, Glowacki F, Dewaeles E, Milosevic J, Maurizio J, Tedrow J, Marcet B, Lo-Guidice JM, Kaminski N, Barbry P, Luedde T, Perrais M, Mari B, Pottier N
EA4483, Faculté de Médecine de Lille, Pole Recherche, Lille, France.

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
Pubmed link : 23459460

8. Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions.
PLoS One. 2009 Aug 24;4(8):e6718.
Pottier N, Maurin T, Chevalier B, Puissegur MP, Lebrigand K, Robbe-Sermesant K, Bertero T, Lino Cardenas CL, Courcot E, Rios G, Fourre S, Lo-Guidice JM, Marcet B, Cardinaud B, Barbry P, Mari B
CNRS, Institut de Pharmacologie Moleculaire et Cellulaire, UMR6097, Sophia Antipolis, France.

BACKGROUND: Epithelial-mesenchymal interactions are critical in regulating many aspects of vertebrate embryo development, and for the maintenance of homeostatic equilibrium in adult tissues. The interactions between epithelium and mesenchyme are believed to be mediated by paracrine signals such as cytokines and extracellular matrix components secreted from fibroblasts that affect adjacent epithelia. In this study, we sought to identify the repertoire of microRNAs (miRNAs) in normal lung human fibroblasts and their potential regulation by the cytokines TNF-alpha, IL-1beta and TGF-beta. METHODOLOGY/PRINCIPAL FINDINGS: MiR-155 was significantly induced by inflammatory cytokines TNF-alpha and IL-1beta while it was down-regulated by TGF-beta. Ectopic expression of miR-155 in human fibroblasts induced modulation of a large set of genes related to "cell to cell signalling", "cell morphology" and "cellular movement". This was consistent with an induction of caspase-3 activity and with an increase in cell migration in fibroblasts tranfected with miR-155. Using different miRNA bioinformatic target prediction tools, we found a specific enrichment for miR-155 predicted targets among the population of down-regulated transcripts. Among fibroblast-selective targets, one interesting hit was keratinocyte growth factor (KGF, FGF-7), a member of the fibroblast growth factor (FGF) family, which owns two potential binding sites for miR-155 in its 3'-UTR. Luciferase assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Site-directed mutagenesis revealed that only one out of the 2 potential sites was truly functional. Functional in vitro assays experimentally validated that miR-155 can efficiently target KGF 3'-UTR. Furthermore, in vivo experiments using a mouse model of lung fibrosis showed that miR-155 expression level was correlated with the degree of lung fibrosis. CONCLUSIONS/SIGNIFICANCE: Our results strongly suggest a physiological function of miR-155 in lung fibroblasts. Altogether, this study implicates this miRNA in the regulation by mesenchymal cells of surrounding lung epithelium, making it a potential key player during tissue injury.
Pubmed link : 19701459

9. Relationships Between Early Inflammatory Response to Bleomycin and Sensitivity to Lung Fibrosis.
Am J Respir Crit Care Med. 2007 Aug 2;
Pottier N, Chupin C, Defamie V, Cardinaud B, Sutherland R, Rios G, Gauthier F, Wolters PJ, Berthiaume Y, Barbry P, Mari B
Institut de Pharmacologie Moleculaire et Cellulaire, UMR6097, CNRS and University of Nice Sophia Antipolis, Sophia Antipolis, France.

RATIONALE. Different sensitivities to pro-fibrotic compounds such as bleomycin are observed among mouse strains. OBJECTIVES. To identify genetic factors contributing to the outcome of lung injury. METHODS. Physiological comparison of C57BL/6 sensitive and Balb/C resistant mice challenged with intra tracheal bleomycin instillation revealed several early differences: global gene expression profiles were thus established from lungs derived from the two strains, in the absence of any bleomycin administration. MEASUREMENTS AND MAIN RESULTS. Expression of 25 genes differed between the two strains. Among them, two molecules, not previously associated with pulmonary fibrosis, were identified. The first one corresponds to dipeptidyl peptidase I (DPPI), a cysteine dipeptidyl peptidase (also known as cathepsin C) essential for the activation of serine proteinases produced by immune/inflammatory cells. The second corresponds to TIMP-3, an inhibitor of matrix metalloproteases and of ADAMs such as the TNFconverting enzyme. In functional studies performed in the bleomycin induced lung fibrosis model, the level of expression of these two genes was closely correlated with specific early events associated with lung fibrosis, namely activation of PMN-derived serine proteases and TNFalpha-dependent inflammatory syndrome. Surprisingly, genetic deletion of DPPI in the context of a C57BL/6 genetic background did not protect against bleomycin-mediated fibrosis, suggesting additional function(s) for this key enzyme. CONCLUSIONS. This study highlights the importance of the early inflammatory events that follow bleomycin instillation in the development of lung fibrosis, and describes for the first time the roles that DPPI and TIMP-3 may play in this process.
Pubmed link : 17673693