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, la séquence cible de 20 paires de base correspondante constituée en 5' de 2 paires de bases GG et en fin de séquence, du motif PAM 5'-NGG-3' (colonne « Target sequence »), la localisation de la séquence cible au niveau du génome du poisson zèbre (colonne « Genomic location »), la localisation de la séquence cible au niveau des exons du gène HSF1 (colonne « Exon »), le brin d'ADN sur lequel la séquence cible va être complémentaire (colonne « Strand »), le pourcentage de guanine (G) et de cytosine (C) présent dans la séquence cible qui doit se trouver entre 40 et 70% pour être efficace (colonne « GC(%) ») le nombre de régions complémentaires de plus de 3 nts pouvant inhiber l'efficacité du sgARN (colonne « Self-complementarity »), le nombre de sites hors cibles si la séquence cible subit 0 (« MM0 »), 1 (« MM1 »), 2 (« MM2 »), 3 (« MM3 ») mésappariements pouvant entraîner des mutations non prévues dites « off-target, Ce tableau permet de connaître le classement des meilleures séquences établi par l'algorithme CHOCHOP pour réaliser un knock-out du gène HSF1 (Exon en bleu et intron en rouge) via la technique CRISPR/Cas9 (colonne « ranking »)

, En cliquant sur un résultat spécifique, on accède à une nouvelle page contenant le locus zoomé avec le site de coupure prédit surligné en rouge, les options de primers en violet et les sites de restriction codés par couleur selon qu'ils sont uniques ou non dans la région

C. , For microinjection, sgRNA (300 ng/?l) was mixed with Cas9 Nuclease protein NLS (600ng/?l

S. Diagenode, RNA was extracted using RNAeasy Mini Kit (Qiagen) and transcribed to cDNA using the Maxima First Strand cDNA Synthesis Kit for RT-qPCR (Thermo Fisher). Quantitative real-time PCR (qPCR) was performed using the Maxima SYBR Green/ROX qPCR Master Mix 2X

P. Real-time and . System, For each sample, expression levels were normalized by hprt1b

, All RT-qPCR experiments were performed in biological triplicates. The primers are listed in

N. O-dianisidine and . Staining, Embryos were anaesthetized with Benzocaine solution. Detection of hemoglobin by o-dianisidine (Sigma Aldrich) was performed as described 22 . The staining of macrophages with neutral red

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, Annexe, vol.3

, Étude des anomalies génétiques des érythrocytoses inexpliquées -GenRED

. Coordinateur and . Projet,

. Monsieur-françois-girodon,

, HIF? est ainsi stabilisée, capable de transloquer dans le noyau et de former un complexe transcriptionnel actif avec HIF? et CBP/p300, induisant la transcription de gènes qui possèdent une séquence consensus « Hypoxia Responsive Element, 2005.

, Figure 1 Régulation de HIF dans l'hypoxie d'après McMullin, 2009.

. Ainsi, une mutation d'un gène codant une protéine impliquée dans la régulation de la voie de l'hypoxie pourra entrainer le développement d'une érythrocytose idiopathique (McMullin, 2009) via une surexpression d'EPO. A ce jour, des mutations dans trois gènes principaux de la voie de régulation de et al, 2011.

. Gordeuk, , 2004.

, Plus récemment, des mutations germinales du gène EGLN1 codant la protéine PHD2 sont retrouvées à l'état hétérozygote et sont de type « perte de fonction ». L'étude fonctionnelle (Percy et al, 2006) de (Ladroue et al, 2012) : cela se traduit par une moindre efficacité de l'enzyme PHD2, sont composées d'érythrocytes, de granulocytes, de monocytes, de lymphocytes et de thrombocytes, 2008.

, De plus, la voie de régulation de l'hypoxie est très conservée chez le poisson zèbre et ce modèle in vivo a déjà été validé pour l'étude des érythrocytoses : l'invalidation de vhl entraine le développement

, Chuvash développée chez les patients porteurs de la mutation VHL-R200W (van Rooijen et al, 2007.

, Contexte de l'étude

. Actuellement, . De-nantes, and . De-dijon, en partenariat avec des centres de recherche associés, est en cours, dont l'objectif est de rechercher de nouveaux bio-marqueurs diagnostiques pour les 80% d'érythrocytoses inexpliquées, afin de permettre une meilleure prise en charge thérapeutique. Ainsi, un séquençage de nouvelle génération (NGS) de gènes candidats sera complété à Nantes par une analyse de l'exome (partie du génome constituée par les exons, c'est-à-dire les parties des gènes codants les protéines) pour les patients sans anomalie détectée, afin de mettre en évidence de nouvelles mutations qui, une fois identifiées, seront testées in vitro à Nantes et secondairement

, Ce travail correspond au 5ème groupe de travail de cette étude (WP5), groupe qui valide les résultats scientifiques des étapes précédentes

. Le-travail-de-gerri, Ces résultats ont tous été validés en triplica biologique et technique. Néanmoins, une telle diminution n'a pas été observée dans, 2018.

, Néanmoins, après deux ans de travail, nous n'avons plus retrouvé le phénotype observé suite à

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