Epigenetic Control of Learning and Memory inDrosophilaby 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.

Mating and Memory: An Educational Primer for Use with “Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action”

“…In Xu et al (2014), the authors investigate whether epigenetic modifications can affect memory-mediated behaviors. "Epigenetics" broadly refers to information in the genome that is not coded by the DNA but refers to certain genomic states and how these states can be influenced by the environment.…”

“…There are three main families of nuclear HATs (Hodawadekar and Marmorstein 2007;Bannister and Kouzarides 2011). The Tip60 protein investigated in Xu et al (2014) is a member of the MYST family, named for the initial members MOX, Ybf2/Sas3, Sas2, and Tip60. The human Tip60 complex is thought to be involved in DNAdamage responses (Grant 2001).…”

“…Certain familial mutations increase the risk of amyloid-b plaque formation from the secreted C terminus due to minor differences in cleavage sites and misfolding of the processed peptide fragment. In this study by Xu et al (2014), the effects of loss-of-Tip60 and gain-of-Tip60 function are compared in the context of mutant flies that are also transgenic for the human APP protein, either with or without the disease-associated C terminus.…”

“…KEYWORDS Tip60; histone acetylation; courtship memory; Drosophila; amyloid precursor protein; mushroom body; epigenetic modification Background I N a recent article published in GENETICS, Xu et al (2014) use the fruit fly Drosophila melanogaster to study the effect of epigenetic modification by the Tip60 histone acetyl transferase on learning and memory. Using reverse genetic gainof-function and loss-of-function transgenic techniques, Xu et al (2014) relate changes in Tip60 expression to anatomical changes in the fly brain and to alterations in memory related to courtship behavior.…”

“…Using reverse genetic gainof-function and loss-of-function transgenic techniques, Xu et al (2014) relate changes in Tip60 expression to anatomical changes in the fly brain and to alterations in memory related to courtship behavior. The role of Tip60 in learning and memory is further connected to a Drosophila model of Alzheimer's disease.…”