title: Epigenetic control of learning and memory in Drosophila by Tip60 HAT action.
abstract: Disruption of epigenetic gene control mechanisms in the brain causes significant cognitive impairment that is a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Histone acetylation is one of the best characterized of these epigenetic mechanisms that is critical for regulating learning- and memory- associated gene expression profiles, yet the specific histone acetyltransferases (HATs) that mediate these effects have yet to be fully characterized. Here, we investigate an epigenetic role for the HAT Tip60 in learning and memory formation using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that Tip60 is endogenously expressed in the Kenyon cells, the intrinsic neurons of the MB, and in the MB axonal lobes. Targeted loss of Tip60 HAT activity in the MB causes thinner and shorter axonal lobes while increasing Tip60 HAT levels cause no morphological defects. Functional consequences of both loss and gain of Tip60 HAT levels in the MB are evidenced by defects in immediate-recall memory. Our ChIP-Seq analysis reveals that Tip60 target genes are enriched for functions in cognitive processes, and, accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, we find that both learning and immediate-recall memory deficits that occur under AD-associated, amyloid precursor protein (APP)-induced neurodegenerative conditions can be effectively rescued by increasing Tip60 HAT levels specifically in the MB. Together, our findings uncover an epigenetic transcriptional regulatory role for Tip60 in cognitive function and highlight the potential of HAT activators as a therapeutic option for neurodegenerative disorders.
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Songjun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Rona
authors.initials: R
authors.lastname: Wilf
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Trisha
authors.initials: T
authors.lastname: Menon
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Priyalakshmi
authors.initials: P
authors.lastname: Panikker
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sarthi
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 fe22@drexel.edu.
authors.forename: Felice
authors.initials: F
authors.lastname: Elefant
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D007858:Learning; D008568:Memory; D024521:Mushroom Bodies / Q000196:embryology / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D051548:Histone Acetyltransferases; C511056:Tip60 protein, Drosophila
keywords: Drosophila; Tip60; cognition; epigenetics; histone acetylation