Tip60 is a key histone acetyltransferase (HAT) enzyme that plays essential roles in diverse chromatin- mediated biological processes, including gene regulation, apoptosis, cell-cycle regulation, DNA recombination and repair. Tip60 is part of a multi-protein complex that is recruited by transcription factors to the promoters of certain genes where it generally acetylates surrounding histones to activate gene expression. Thus, Tip60 recruitment is involved in epigenetic gene regulation. While it is evident that Tip60 plays a central role in transcriptional control, it remains unclear as to the tissue and cell type-specific developmental pathways and target genes that require Tip60 to function. To investigate the role of TIP60 in multicellular development, our laboratory has identified and cloned the human TIP60 homolog in Drosophila (Dmel TIP60). We have developed a system in transgenic flies that allows for targeted and inducible overexpression of wild-type or dominant negative HAT defective Dmel TIP60 and Dmel TIP60 knockdown in specific tissues, cell types and developmental stages of choice. Using this system, we have determined that Dmel TIP60 is essential for nervous system formation during early development. We show that loss of Dmel TIP60 in the fly brain leads to substantial neuronal loss and lethality. Consistent with our finding, other groups have documented an essential role for Tip60 HAT activity in the transcriptional activation of target genes via amyloid precursor protein (APP) mediated cell signaling pathways proposed to be involved in neuronal development. Intriguingly, TIP60 levels dramatically increase in the brains of young Alzheimer's disease (AD) model mice overproducing APP long before they acquire the A2 plaques, neurotoxicity and behavioral abnormalities representative of the disease. These findings provide the basis for our central hypothesis that APP perturbation causes upregulation of endogenous TIP60, leading to misregulation of both TIP60/APP and exclusive TIP60 chromatin-mediated neuronal pathways that is relevant in both development and neurodegeneration. To test this hypothesis, the following specific aims will be carried out.
Aim 1 will identify TIP60 epigenetically regulated target genes that participate in distinct neuronal developmental processes and Aim 2 will determine the extent to which TIP60 chromatin-mediated neuronal processes and target genes are affected by overexpression of APP, in vivo. Such knowledge has important implications for the development of novel chromatin-based therapeutics in TIP60 associated disorders.

Public Health Relevance

Our goal of deciphering the role of Tip60 and APP in neuronal development should profoundly enhance our understanding of nervous system development and neurodegenerative disorders. Such knowledge has important implications for the development of novel epigenetic-based therapeutics. ? ?

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Oster-Granite, Mary Lou
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Drexel University
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Panikker, Priyalakshmi; Xu, Song-Jun; Zhang, Haolin et al. (2018) Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition. J Neurosci 38:4569-4583
Xu, Songjun; Panikker, Priyalakshmi; Iqbal, Sahira et al. (2016) Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration. PLoS One 11:e0159623
Xu, Songjun; Elefant, Felice (2015) Tip off the HAT- Epigenetic control of learning and memory by Drosophila Tip60. Fly (Austin) 9:22-8
Xu, Songjun; Wilf, Rona; Menon, Trisha et al. (2014) Epigenetic control of learning and memory in Drosophila by Tip60 HAT action. Genetics 198:1571-86
Pirooznia, Sheila K; Elefant, Felice (2013) A HAT for sleep?: epigenetic regulation of sleep by Tip60 in Drosophila. Fly (Austin) 7:99-104
Johnson, Ashley A; Sarthi, Jessica; Pirooznia, Sheila K et al. (2013) Increasing Tip60 HAT levels rescues axonal transport defects and associated behavioral phenotypes in a Drosophila Alzheimer's disease model. J Neurosci 33:7535-47
Pirooznia, Sheila K; Chiu, Kellie; Chan, May T et al. (2012) Epigenetic regulation of axonal growth of Drosophila pacemaker cells by histone acetyltransferase tip60 controls sleep. Genetics 192:1327-45
Pirooznia, Sheila K; Sarthi, Jessica; Johnson, Ashley A et al. (2012) Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model. PLoS One 7:e41776
Lorbeck, Meridith; Pirooznia, Keerthy; Sarthi, Jessica et al. (2011) Microarray analysis uncovers a role for Tip60 in nervous system function and general metabolism. PLoS One 6:e18412
Sarthi, Jessica; Elefant, Felice (2011) dTip60 HAT activity controls synaptic bouton expansion at the Drosophila neuromuscular junction. PLoS One 6:e26202

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