Journal article
Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action
Genetics (Austin), v 198(4), pp 1571-1586
01 Dec 2014
PMID: 25326235
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action
- Creators
- Songjun Xu - Drexel Univ, Dept Biol, Philadelphia, PA 19104 USARona Wilf - Drexel UniversityTrisha Menon - Drexel UniversityPriyalakshmi Panikker - Drexel UniversityJessica Sarthi - Drexel UniversityFelice Elefant - Drexel University
- Publication Details
- Genetics (Austin), v 198(4), pp 1571-1586
- Publisher
- Genetics Society America
- Number of pages
- 23
- Grant note
- R01HD057939 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HD057939 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000346059300018
- Scopus ID
- 2-s2.0-84915814913
- Other Identifier
- 991019169590304721
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- Web of Science research areas
- Genetics & Heredity