Modélisation du handicap intellectuel chez la drosophile – de la clinique à la régulation épigénétique de l’apprentissage et de la mémoire

Résumé

Epigenetic regulation of cognition is an emerging field in Neuroscience. However, the identity of crucial regulators and underlying molecular mechanisms are poorly understood. Excellent candidates are epigenetic genes that are mutated in intellectual Disability disorders. Using Drosophila as our experimental model, we have investigated the fonction of EHMTI, the euchromatin histone methyltransferase mutated in Kleefstra syndrome. We identified EHMT as an evolutionarily conserved key regulator of cognition that in Drosophila orchestrales an epigenetic program featuring classic learning and memory genes. Drosophila was a Iso successfully used to validate novel Kleefstra Syndrome candidate genes that were identified in single patients by NextGeneration Sequencing, which has allowed us to uncover a novel chromatin modification module that underlies this clinically recognizable form of severe Intellectual Disability. Of note, memory defects in EHMT mutants can be rescued by restoring EHMT expression in adulthood, an exciting finding of potential therapeutic relevance. Our work sheds light on the epigenetic regulation of cognition and aims to establish Drosophila as a tool for personalized next generation diagnostics and drug testing.

Références

Kleefstra T., Kramer J.M., Neveling K., Willemsen M.H., Koemans T.S., Yissers L., Wissink-Lindhout W., Fenckova M., van den Akker W.M.R., Nadif-Kasri N., Nillesen W.M., Prescott T., Clark R.D., Devriendt K., van Reeuwijk J. de Brouwer A.P.M., Gilissen C., Zhou H., Brunner H.G., Yeltman J.A., Schenck A. and van Bokhoven H., "Disruption of a novel EHMT1-associated chromatin modification module causes intellectual disability", Am J Human Genetics, 2012, 91(1):73-82.

Kramer J.M., Kochinke K., Oortveld M.A.W., Marks H., Kramer D., de Jong E.K., Asztalos Z., Westwood J.T., Stun nenberg H.G., Sokolowski M.B., Keleman K., van Bokhoven H. and Schenck A., "Epigenetic regulation of learning & memory by Drosophi/a EHMT/G9a", PLoS Biol., 2011, 9(1): e1000569.