Increased abundance of nuclear HDAC4 impairs neuronal development and long-term memory

Dysregulation of the histone deacetylase HDAC4 results in impairments in neuronal development and formation of long-term memories in the Drosophila brain. In vertebrates, altered expression or subcellular distribution of HDAC4 is associated with both neurodevelopmental and neurodegenerative disorders. In this study we aimed to further investigate the role of HDAC4, specifically to determine a mechanistic link between HDAC4 subcellular distribution, transcriptional changes and neuronal dysfunction. Mutant variants of HDAC4 that were sequestered in the nucleus or cytoplasm were compared to wild-type Drosophila and human HDAC4 to untangle the separate roles of nuclear and cytoplasmic HDAC4 in development and memory. We performed RNA-seq on heads of flies expressing either a nuclear-sequestered variant of hHDAC4 (3SA) or a a cytoplasm-sequestered hHDAC4 (L175A). Surprisingly a nuclear-sequestered variant of hHDAC4 elicits only a small change in transcription in the fly brain compared to controls. Unexpectedly the cytoplasm-sequestered hHDAC4 (L175A) resulted in a larger number of transcriptional changes in fly brains. A direct comparison of 3SA and L175A revealed only 29 genes were significantly differentially expressed by RNA-seq with an FDR < 0.05 and only four of these displayed more than a 2-fold change in expression.