Academic journal article Genetics

Long-Term Memory in Drosophila Is Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

Academic journal article Genetics

Long-Term Memory in Drosophila Is Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

Article excerpt

THE histone deacetylase HDAC4 is widely expressed in neurons throughout the brain (Darcy et al. 2010) and an increasing body of evidence indicates that HDAC4 plays important roles in neurological function (Kumar et al. 2005; Chen and Cepko 2009; Kim et al. 2012; Li et al. 2012; Sando et al. 2012; Sarkar et al. 2014). To that end, we recently demonstrated that in Drosophila, RNA interference (RNAi)mediated knockdown of HDAC4 in the adult brain impairs long-term memory (LTM) in the courtship suppression assay, a model of associative memory (Fitzsimons et al. 2013). Similarly in humans, loss of one copy of HDAC4 correlates with brachydactyly mental retardation syndrome (BDMR), the neurological symptoms of which include intellectual disability and autism (Williams et al. 2010; Morris et al. 2012; Villavicencio-Lorini et al. 2013), and in mice, conditional knockout of HDAC4 in the brain results in impairments in hippocampal-dependent associative LTM (Kim et al. 2012). Despite this growing evidence of a critical role, the mechanism(s) through which HDAC4 positively influences LTM is unknown. This is in part because HDAC4 exists in both nuclear and cytoplasmic pools, and under basal conditions, the majority of HDAC4 is localized to the cytoplasm (Chawla et al. 2003; Darcy et al. 2010). Given the predominant nonnuclear localization, particularly the concentration of HDAC4 at dendritic spines (Darcy et al. 2010), we hypothesize that cytoplasmic HDAC4 is required in memory formation; however, the mechanisms through which HDAC4 acts outside the nucleus are unknown.

The nuclear role of HDAC4 is less of an enigma. When in the nucleus, HDAC4 acts as a transcriptional repressor; although vertebrate HDAC4 is catalytically inactive as a histone deacetylase, rather it facilitates changes in gene expression through direct binding and inhibition of transcription factors such as MEF2 (Miska et al. 1999; Wang et al. 1999; Lu et al. 2000). As described above, HDAC4 must be present for normal LTM; however, increased nuclear HDAC4 also impairs memory (Williams et al. 2010; Sando et al. 2012). An individual with BDMR was identified to carry a point mutation that resulted in a truncated HDAC4 protein (Williams et al. 2010), and further investigation of a similar HDAC4 variant in the mouse revealed a gain of function, with this truncated protein lacking a nuclear export signal and thus being sequestered in the nucleus. The truncated form of HDAC4 also caused cognitive deficits in mice, which were associated with reduced expression of plasticity-related genes (Sando et al. 2012). We also demonstrated that overexpression of HDAC4 in Drosophila resulted in impaired LTM and recruited MEF2 to discrete foci within nuclei (Fitzsimons et al. 2013). Taken together, these data indicate that when in the nucleus, HDAC4 has the capacity to repress expression of plasticity-related genes, which correlates with memory impairment (Sando et al. 2012); however, it also plays a promemory role, as evidenced by the memory impairments that result from reduction of HDAC4 in the adult brain (Kim et al. 2012; Fitzsimons et al. 2013).

Here, we sought to increase understanding of the molecular mechanisms through which HDAC4 regulates memory via a two-pronged approach. First, in order to investigate whether the memory deficits we observed following overexpression of HDAC4 were accompanied by alterations in gene expression, we performed RNA sequencing (RNAseq) on heads of flies that overexpressed HDAC4 in the adult brain; however, very few changes were found, suggesting that wildtype (WT) HDAC4 elicits limited transcriptional effects.

For our second approach, we sought to identify genes that interact with HDAC4 by making use of a rough eye enhancer/ suppressor screen, which would capture both transcriptional and nontranscriptional interactions. Our results indicate that HDAC4 interacts with genes that are important for transcription, the cytoskeleton, and SUMOylation. …

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