La mémoire à long terme chez la drosophile (un cadre d'étude des retards mentaux non syndromiques)

Le retard mental est une pathologie qui affecte de 1 à 3% de la population. II se caractérise par un quotient intellectuel inférieur à 70 associé à des déficits comportementaux. De nombreux gènes connus pour leur implication dans ce désordre neurologique sont bien conservés chez la drosophile. La drosophile se présente comme un système modèle très attractif pour mieux comprendre les mécanismes moléculaires et cellulaires impliqués dans l'apprentissage et la mémoire. Malgré la simplicité de son système nerveux, elle est capable d'associer une odeur à un choc électrique et de stocker cette information à long terme. Les homologues de trois gènes impliqués dans le retard mental non syndromique chez l'Homme ont été étudiés chez la drosophile : tequila, DPak et dpix. Grâce à la technique du RNAi, l'expression des gènes d'intérêt a été diminuée au niveau des corps pédoncules, le centre de la mémoire olfactive. Les mouches ont présenté un défaut de mémoire à long terme et une mémoire à court terme normale. De plus, nous avons montré que tequila et DPak sont spécifiquement requis à l'état adulte pour une mise en place correcte de la mémoire à long terme. En revanche, la diminution d'expression de ces gènes n'a aucune conséquence sur la morphologie des corps pédonculés, suggérant un rôle essentiel dans les mécanismes de plasticité synaptique nécessaires à la mise en place de la mémoire. Le gène tequila montre une augmentation d'expression lors de la mise en place de la mémoire à long terme. Ce travail de thèse a permis de montrer que la drosophile peut servir de modèle pour une étude approfondie des mécanismes impliqués dans le retard mental non syndromique.Mental retardation affects 1 to 3% of the population of the industrialized contries. People affected by this pathology have a intellectual quotient less than 70. A lot of genes are known to be implicated in this neurological disorder, they are well conserved in Drosophila genome. Drosophila seems to be a very attractive animal system to better understand the cellular and molecular mechanisms underlying learning and memory. Despite his relatively simple nervous system, drosophila is able to make the association between an odour and a electric shock and to retrieve this information later. Three genes implicated in non syndromic mental retardation were studied in drosophila : tequila, DPak and dpix. With RNAi, these three genes were silenced in the mushroom bodies, the olfactory memory center. Flies have a soecific long term memory defect and a normal short term memory. Tequila and DPak are required specifically in the long term memory establishment. The silencing of these genes does not affect the morphology of the mushroom bodies suggesting a essential role in pathways underlying neuronal plasticity who is required for long term memory. Teq expression is upregulated during the establishment of long term memory. This work has shown that drosophila could be a useful organism to better understand the non syndromic mental retardation.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

NF-kappaB modulation and ionizing radiation: mechanisms and future directions for cancer treatment.

NF-kappaB transcription factor regulates important cellular processes ranging from establishment of the immune and inflammatory responses to regulation of cell proliferation or apoptosis, through the induction of a large array of target genes. NF-kappaB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-kappaB is triggered by chimio- and radio-therapeutic strategies that are intended to eliminate cancerous cells through induction of apoptosis. Numerous studies have demonstrated that inhibition of NF-kappaB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFalpha or chemo- or radio-therapies. From these studies as emerged the concept that NF-kappaB blockade could be associated to conventional therapies in order to increase their efficiency. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy.Journal ArticleReviewSCOPUS: sh.jinfo:eu-repo/semantics/publishe

Robust Antibody–Antigen Complexes Prediction Generated by Combining Sequence Analyses, Mutagenesis, In Vitro Evolution, X-ray Crystallography and In Silico Docking

International audienc

Expression changes and chromatin architecture modifications in WBS cells.

<p>Changes in expression and chromatin structure in WBS (GM13472) versus Ctrl (GM07006) cells. Changes in histone marks are presented as the log2-fold ratio between WBS and Ctrl cells. Statistical analysis was performed by a 2-sample t-Test. Values in italics are not statistically different.</p><p>AREL  =  average relative expression level, BDL  =  below detection line, NS  =  no regions within gene were defined as significantly changed,</p><p>*most significant block according to SICER within the gene (FDR<1%).</p

Extensive chromatin interactions of seven genes flanking the WBSCR on human chromosome 7 (HSA7) in cells from a healthy control individual.

<p>(<b>A</b>) Windowed and normalized 4C signal of each of the seven viewpoints along the entire HSA7. The black ticks below each graph show the location of the Bricks (Blocks of Regulators In Chromosomal Kontext). The gene density across HSA7, as well as the windowed profiles of H4K20me1 and H3K27me3 marks in the same cell line are shown below. Some examples of strong correlation of gene-dense regions and high density of H4K20me1 marks with highly interacting regions are highlighted in blue. The mapping of the assessed genes/viewpoints and of the WBSCR is indicated at the bottom. The red box specifies the close-up shown in panel B. (<b>B</b>) Close-up of the windowed 4C signal of the seven viewpoints around the WBSCR for the region indicated with a red box on HSA7 (top panel). The windowed 4C signal is shown in grey, while the profile corrected 4C signal (after removal of the highly interacting neighboring background signal) is overlaid in black. The position of all genes are displayed at the bottom, and the mapping of the assessed viewpoints is highlighted by red and green arrows indicating if the corresponding genes are down- or upregulated in cells from WBS patients, respectively. Black arrows underscore the mapping of the viewpoint that is not modified in gene expression (<i>ZNF107</i>) and the newly identified interacting partners <i>AUTS2</i> and <i>CALN1</i>. The location of the WBSCR is indicated by a purple horizontal bar. A close-up of interactions within this WBSCR is provided in <b>Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079973#pone.0079973.s004" target="_blank">Figure S4</a></b>.</p

Structural variation-associated expression changes are paralleled by chromatin architecture modifications.

Copy number variants (CNVs) influence the expression of genes that map not only within the rearrangement, but also to its flanks. To assess the possible mechanism(s) underlying this "neighboring effect", we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. Using chromosome conformation capture (4C-seq), we observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together. The newly identified interacting genes include AUTS2, mutations of which are associated with autism and intellectual disabilities. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We also pinpointed concomitant changes in histone modifications between samples. We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype. GEO SERIES ACCESSION NUMBER: GSE33784, GSE33867

Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

Contains fulltext : 88508.pdf (publisher's version ) (Closed access)Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.1 september 201

A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs

A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved