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

Nottet Nicolas

 nottet@ipmc.cnrs.fr
 04 93 95 77 91
 660 route des lucioles 06560 Valbonne - Sophia-Antipolis

8 publications found

1. 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

2. A root-knot nematode small glycine and cysteine-rich secreted effector, MiSGCR1, is involved in plant parasitism.
New Phytol. 2018 Jan;217(2):687-699. doi: 10.1111/nph.14837
Nguyen CN, Perfus-Barbeoch L, Quentin M, Zhao J, Magliano M, Marteu N, Da Rocha M, Nottet N, Abad P, Favery B
INRA, Université Côte d'Azur, CNRS, ISA, 400 route des Chappes, 06903, Cedex Sophia-Antipolis, France. Department of Plant Pathology and Key Laboratory of Plant Pathology of Ministry of Agriculture, China Agricultural University, Beijing, 100193, China.

Root-knot nematodes, Meloidogyne spp., are obligate endoparasites that maintain a biotrophic relationship with their hosts. They infect roots as microscopic vermiform second-stage juveniles, and establish specialized feeding structures called 'giant-cells', from which they withdraw water and nutrients. The nematode effector proteins secreted in planta are key elements in the molecular dialogue of parasitism. Here, we compared Illumina RNA-seq transcriptomes for M. incognita obtained at various points in the lifecycle, and identified 31 genes more strongly expressed in parasitic stages than in preparasitic juveniles. We then selected candidate effectors for functional characterization. Quantitative real-time PCR and in situ hybridizations showed that the validated differentially expressed genes are predominantly specifically expressed in oesophageal glands of the nematode. We also soaked the nematodes in siRNA to silence these genes and to determine their role in pathogenicity. The silencing of the dorsal gland specific-Minc18876 and its paralogues resulted in a significant, reproducible decrease in the number of mature females with egg masses, demonstrating a potentially important role for the small glycine- and cysteine-rich effector MiSGCR1 in early stages of plant-nematode interaction. Finally, we report that MiSGCR1 suppresses plant cell death induced by bacterial or oomycete triggers of plant defense.
Pubmed link : 29034957

3. A new long noncoding RNA (LncRNA) is induced in cutaneous squamous cell carcinoma and downregulates several anticancer and cell-differentiation genes in mouse.
J Biol Chem. 2017 Jun 8. pii: jbc.M117.776260. doi: 10.1074/jbc.M117.776260. [Epub ahead of print]
Ponzio G, Rezzonico R, Bourget I, Allan R, Nottet N, Popa A, Magnone V, Rios G, Mari B, Barbry P
Université Côte d’Azur, CNRS, IPMC, France. Université Côte d'Azur, CNRS, INSERM, IRCAN, France.

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Although some of the early events involved in this pathology have been identified, the subsequent steps leading to tumor development are poorly defined. We demonstrate here that the development of mouse tumors induced by the concomitant application of a carcinogen and a tumor promoter (7,12 dimethylbenz[a]anthracene [DMBA] and 12-O-tetradecanoylphorbol-13-acetate [TPA], respectively) is associated with the upregulation of a previously uncharacterized long noncoding RNA (lncRNA), termed AK144841. We found that AK144841 expression was absent from normal skin and was specifically stimulated in tumors and highly tumorigenic cells. We also found that AK144841 exists in two variants, one consisting of a large 2-kb transcript composed of four exons and one of a 1.8-kb transcript lacking the second exon. Gain- and loss-of-function studies indicated that AK144841 mainly inhibited gene expression, specifically downregulating the expression of genes of the late-cornified-envelope-1 (Lce1) family involved in epidermal terminal differentiation and of anticancer genes such as Cgref1, Brsk1, Basp1, Dusp5, Btg2, Anpep, Dhrs9, Stfa2, Tpm1, SerpinB2, Cpa4, Crct1, Cryab, Il24, Csf2, and Rgs16. Interestingly, the lack of the second exon significantly decreased AK144841's inhibitory effect on gene expression. We also noted that high AK144841 expression correlated with a low expression of the aforementioned genes and with the tumorigenic potential of cell lines. These findings suggest that AK144841 could contribute to the dedifferentiation program of tumor-forming keratinocytes and to molecular cascades leading to tumor development.
Pubmed link : 28596382

4. Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition
Nucleic Acids Res. 2016 Dec 19. pii: gkw1284
Zangari J, Ilie M, Rouaud F, Signetti L, Ohanna M, Didier R, Roméo B, Goldoni D, Nottet N, Staedel C, Gal J, Mari B, Mograbi B, Hofman P, Brest P
Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France. Université Côte d'Azur, CHU-Nice, Hospital-related Biobank (BB-0033-00025), FHU-OncoAge, 06000 Nice, France. Université Côte d'Azur, INSERM, C3M, 06200 Nice, France. Université Côte d'Azur, CNRS, INSERM, IPMC, FHU-OncoAge, 06560 Valbonne, France. Université de Bordeaux, INSERM, ARNA, 33076 Bordeaux, France. Antoine Lacassagne Cancer Center, Epidemiology and Biostatistics Unit, 06189 Nice, France.

Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA through EVs has been extensively studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by a recipient cell remains to be determined. Here, we identify the ex-miRNA-directed phenotype to be transient due to the rapid decay of ex-miRNA. We demonstrate that the ex-miR-223-3p transferred from polymorphonuclear leukocytes to cancer cells were functional, as demonstrated by the decreased expression of its target FOXO1 and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within 8 h. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. In conclusion, we showed that the 'steady step' level of engulfed miRNA and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNA.
Pubmed link : 27994032

5. Membrane-bound ICAM-1 contributes to the onset of proinvasive tumor stroma by controlling acto-myosin contractility in carcinoma-associated fibroblasts
Oncotarget. 2016 Nov 25. doi: 10.18632/oncotarget.13610.
Bonan S, Albrengues J, Grasset E, Kuzet SE, Nottet N, Bourget I, Bertero T, Mari B, Meneguzzi G, Gaggioli C
INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, F-06107, Nice, France. Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, Sophia-Antipolis, France.

Acto-myosin contractility in carcinoma-associated fibroblasts leads to assembly of the tumor extracellular matrix. The pro-inflammatory cytokine LIF governs fibroblast activation in cancer by regulating the myosin light chain 2 activity. So far, however, how LIF mediates cytoskeleton contractility remains unknown. Using phenotypic screening assays based on knock-down of LIF-dependent genes in fibroblasts, we identified the glycoprotein ICAM-1 as a crucial regulator of stroma fibroblast proinvasive matrix remodeling. We demonstrate that the membrane-bound ICAM-1 isoform is necessary and sufficient to promote inflammation-dependent extracellular matrix contraction, which favors cancer cell invasion. Indeed, ICAM-1 mediates generation of acto-myosin contractility downstream of the Src kinases in stromal fibroblasts. Moreover, acto-myosin contractility regulates ICAM-1 expression by establishing a positive feedback signaling. Thus, targeting stromal ICAM-1 might constitute a possible therapeutic mean to counteract tumor cell invasion and dissemination.
Pubmed link : 27901489

6. Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis.
Stem Cells. 2016 Sep 24. doi: 10.1002/stem.2505.
Khalfallah O, Jarjat M, Davidovic L, Nottet N, Cestèle S, Mantegazza M, Bardoni B
Université Côté d'Azur - Nice, France. CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, Valbonne Sophia-Antipolis, France. CNRS, LIA « NEOGENEX », Valbonne Sophia-Antipolis, France. Université Côté d'Azur - Nice, France. bardoni@ipmc.cnrs.fr. CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, Valbonne Sophia-Antipolis, France. bardoni@ipmc.cnrs.fr. CNRS, LIA « NEOGENEX », Valbonne Sophia-Antipolis, France. bardoni@ipmc.cnrs.fr.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, βIII-tubulin, p27kip1 , NeuN and NeuroD1 were up-regulated, leading to an accelerated neuronal differentiation, that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout (KO) mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. This article is protected by copyright. All rights reserved.
Pubmed link : 27664080

7. RiboProfiling: a Bioconductor package for standard Ribo-seq pipeline processing.
F1000Res. 2016 Jun 9;5:1309. doi: 10.12688/f1000research.8964.1. eCollection 2016.
Popa A, Lebrigand K, Paquet A, Nottet N, Robbe-Sermesant K, Waldmann R, Barbry P
Institut de Pharmacologie Moleculaire et Cellulaire, University Nice Sophia Antipolis and CNRS, Sophia- Antipolis, 06560, France.

The ribosome profiling technique (Ribo-seq) allows the selective sequencing of translated RNA regions. Recently, the analysis of genomic sequences associated to Ribo-seq reads has been widely employed to assess their coding potential. These analyses led to the identification of differentially translated transcripts under different experimental conditions, and/or ribosome pausing on codon motifs. In the context of the ever-growing need for tools analyzing Ribo-seq reads, we have developed 'RiboProfiling', a new Bioconductor open-source package. 'RiboProfiling' provides a full pipeline to cover all key steps for the analysis of ribosome footprints. This pipeline has been implemented in a single R workflow. The package takes an alignment (BAM) file as input and performs ribosome footprint quantification at a transcript level. It also identifies footprint accumulation on particular amino acids or multi amino-acids motifs. Report summary graphs and data quantification are generated automatically. The package facilitates quality assessment and quantification of Ribo-seq experiments. Its implementation in Bioconductor enables the modeling and statistical analysis of its output through the vast choice of packages available in R. This article illustrates how to identify codon-motifs accumulating ribosome footprints, based on data from Escherichia coli.
Pubmed link : 27347386

8. Identification of novel target genes for safer and more specific control of root-knot nematodes from a pan-genome mining.
PLoS Pathog. 2013 Oct;9(10):e1003745. doi: 10.1371/journal.ppat.1003745. Epub 2013 Oct 31.
Danchin EG, Arguel MJ, Campan-Fournier A, Perfus-Barbeoch L, Magliano M, Rosso MN, Da Rocha M, Da Silva C, Nottet N, Labadie K, Guy J, Artiguenave F, Abad P
INRA, UMR 1355 ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France ; CNRS, UMR 7254 ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France ; Université de Nice Sophia-Antipolis, UMR ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France.

Root-knot nematodes are globally the most aggressive and damaging plant-parasitic nematodes. Chemical nematicides have so far constituted the most efficient control measures against these agricultural pests. Because of their toxicity for the environment and danger for human health, these nematicides have now been banned from use. Consequently, new and more specific control means, safe for the environment and human health, are urgently needed to avoid worldwide proliferation of these devastating plant-parasites. Mining the genomes of root-knot nematodes through an evolutionary and comparative genomics approach, we identified and analyzed 15,952 nematode genes conserved in genomes of plant-damaging species but absent from non target genomes of chordates, plants, annelids, insect pollinators and mollusks. Functional annotation of the corresponding proteins revealed a relative abundance of putative transcription factors in this parasite-specific set compared to whole proteomes of root-knot nematodes. This may point to important and specific regulators of genes involved in parasitism. Because these nematodes are known to secrete effector proteins in planta, essential for parasitism, we searched and identified 993 such effector-like proteins absent from non-target species. Aiming at identifying novel targets for the development of future control methods, we biologically tested the effect of inactivation of the corresponding genes through RNA interference. A total of 15 novel effector-like proteins and one putative transcription factor compatible with the design of siRNAs were present as non-redundant genes and had transcriptional support in the model root-knot nematode Meloidogyne incognita. Infestation assays with siRNA-treated M. incognita on tomato plants showed significant and reproducible reduction of the infestation for 12 of the 16 tested genes compared to control nematodes. These 12 novel genes, showing efficient reduction of parasitism when silenced, constitute promising targets for the development of more specific and safer control means.
Pubmed link : 24204279