Academic journal article Genetics

Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action

Academic journal article Genetics

Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action

Article excerpt

THE ability of living organisms to respond to a constantly changing environment and fine-tune their complex be- haviors accordingly is crucial for their adaptation and sur- vival throughout development (Levenson and Sweatt 2005; Borrelli et al. 2008; West and Greenberg 2011; Al-Saigh et αi. 2012). One of the most important of such experi- ence-driven behavioral changes is learning and memory for- mation, as it directly impacts cognitive ability (Levenson and Sweatt 2005; Carulli et cd. 2011; Nelson and Monteggia 2011; West and Greenberg 2011). In the brain, external stim- uli are converted into intracellular signals that program co- ordinated expression of specific gene sets that promote sustained neuroplasticity and cognitive adaptation (Sweatt 2009; Riccio 2010; Carulli et cd. 2011). Disruption of these response programs results in significant cognitive impairment disorders (West and Greenberg 2011; Ebert and Greenberg 2013; Pirooznia and Elefant 2013a). Epigenetic post-translational modifications (PTMs) of histone proteins that control nuclear chromatin packaging and gene expression profiles are emerg- ing as a fundamental mechanism by which neurons adapt their transcriptional response to environmental cues (Feng et al. 2007; Sweatt 2009; Bousiges et al. 2010; Meaney and Ferguson-Smith 2010; Riccio 2010; Nelson and Monteggia 2011; Pirooznia and Elefant 2012). One of the best-characterized forms of epigenetic chromatin modification in the learning and memory field is histone acetylation (Peixoto and Abel 2013), which is regulated by the antagonistic activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Legube and Trouche 2003). Blocking histone acet- ylation has been reported to impair both long-lasting synaptic plasticity and behavioral performance (Korzus et al. 2004). Notably, inhibition of histone deacetylase activity reverses such deficits and improves memory formation (Korzus et al. 2004; Levenson et cd. 2004), thus highlighting the impor- tance of histone acetylation for memory formation.

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). Sporadic cases of reduced histone acetylation levels are found in the brains of animal models for multiple types of neurodegenerative diseases that in- clude AD. These changes have been shown to cause an epi- genetic blockade of transcription that results in cognitive impairment. (Graff et al. 2012a). Pharmacological treat- ments aimed at increasing histone acetylation levels by inhibiting histone deacetylase action in these models have shown promising effects in reversing cognitive deficits (Kazantsev and Thompson 2008). However, little is known about HATs that modify the neural epigenome by laying down specific epigenetic marks required for proper cognition and thus likely serve as causative agents of memory-impairing histone acetylation changes. A promising candidate is the HAT, Tip60 (Tat interactive protein), which has been impli- cated in AD owing to its role in epigenetically regulating gene expression via complex formation with the amyloid precursor protein (APP) intracellular domain (AICD) (Cao and Sudhof 2001, 2004).

Tip60 is a multifunctional HAT that has been shown by others and us to epigenetically regulate genes essential for neurogenesis (Lorbeck et al. 2011; Pirooznia et al. 2012b). Such an effect is thought to be mediated through recruit- ment of Tip60-containing protein complexes to target gene promoters in the nervous system that are then epigenetically modified via site-specific acetylation and accordingly acti- vated or repressed. We have recently reported that the his- tone acetylase function of Tip60 promotes neuronal and organismal survival in a Drosophila model for AD by activat- ing pro-survival factors while concomitantly repressing acti- vators of cell death (Pirooznia et al. …

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