Etude de la régulation épigénétique de l'allèle Abr du gène Agouti chez la race bovine normande

Le travail décrit dans ce mémoire est une contribution apportée aux recherches axées sur les mécanismes épigénétiques. Plus particulièrement, ont été étudiées les mécanismes épigénétiques qui régissent l'expression du promoteur LINE porté par l'allèle Abr. La couleur de robe de la race bovine Normande se caractérise par un mélande de poils noirs et de poils rouges (bringeure) dont la proportion est variable entre les animaux et au niveau des différentes régions de la peau du même animal. Notre équipe a identifié l'allèle Abr du gène Agouti qui est responsable de ce paron de coloration complexe. Dans la première partie de ce travail nous démontrons que le promoteur du LINE possède une activité transcriptionnelle en utilisant différents gènes rapporteurs. Par ailleurs nous avons démontré que les sites d'initiation de la transcription sont influencés par les séquences adjacentes au promoteur. Dans la deuxième partie nous montrons que la méthylation du promoteur du LINE est l'une des facettes du processus épigénétique qui régule son expression variable entre les animaux et au sein du même animal. En effet, nous avons montré que l'expression variable du gène Agouti est proportionnelle au degré de méthylation du promoteur du LINE. Par ailleurs, nous montrons que cette régulation épigénétique dépend du fond génétique des animaux à l'instar des données acquises pour un allèle similaire chez la souris.The work describeb in this manuscript is a contribution to the comprehension of the epigenetic mechanisms that control the variable expression ot the LINE promoter of the Abr allele. The coat color of the Normande cattle breed is characterized by a mixture of black and red hairs (brindle) whose proportion varies between animals and a different regions of the skin of the same animal. Our team has identified the Abr allele Agouti gene which is responsible for this coat color pattern. In the first part of this work we demonstrate, using different reporter genes, that the LINE promoter has a transcriptional activity. By RACE experiments wa have been able to determine the initiation sites of transcription which are influenced by adjacent sequences of the promoter. In the second part we show the methylation of the LINE promoter is one facet of epigenetic process that regulates its variable expression between animals and within the same animal. Indeed we have shown the the variable expression of Agouti gene is proportionnal to the degree of promoter methylation of the LINE. Furthermore, we show that this epigenic regulation depends on the genetic background of animals as reported for the allele of Agouti homologous in mice.LIMOGES-BU Sciences (870852109) / SudocSudocFranceF

Evaluation of children with Psoriasis from the BiPe Cohort: are patients using biotherapies in real life eligible for phase III clinical studies?

International audienceBackground Phase III clinical trials of biotherapies for childhood psoriasis are designed for a selected population, which can differ from real-life patients. Objective Our objective was to assess the proportion of children with psoriasis that received biotherapy in the biological treatments for pediatric psoriasis (BiPe) cohort that would be excluded from phase III clinical trials of these treatments. Methods Data concerning initiation of the first biotherapy from all patients included in the BiPe cohort were analyzed. Ineligibility was assessed after applying the exclusion criteria used in the principal phase III trials of etanercept, adalimumab, and ustekinumab for childhood psoriasis. Results Of the 134 patients included, 73 (54.5%) were ineligible for at least one randomized controlled trial based on one or more exclusion criteria. Amongst the 63 children treated with etanercept, 35 (55.5%) were ineligible: 22 because of the type of psoriasis, 12 because of concomitant treatment, and six because of psoriasis severity based on psoriasis assessment severity index (PASI) and physician global assessment (PGA) scores (PASI < 12 and PGA < 3). Amongst the 44 children treated with adalimumab, 32 (72.7%) were ineligible: 17 because of the clinical type of psoriasis, 12 because of psoriasis severity (PASI < 20 and PGA < 4), and seven because of concomitant treatment. Amongst the 27 children patients treated with ustekinumab, 12 (44.4%) were ineligible: eight because of psoriasis severity (PASI < 12 and PGA < 3), five because of the clinical type of psoriasis, and one because of concomitant treatment. Drug survival and the frequency of serious adverse events did not differ between eligible and ineligible patients. Conclusion The majority of children treated with biotherapies in real-life practice differ from those in phase III trials, most commonly because of the clinical type of their psoriasis, the disease severity being lower than required and the use of prior or concomitant psoriasis treatment. Efficacy and safety results from phase III clinical trials in selected populations may not sufficiently reflect what is seen in real life, thus results from real-life cohort studies are necessary