Affiliations: 1) Drexel University, Philadelphia, PA; 2) University of Pennsylvania, Philadelphia, PA
Keywords: a. chromatin structure; a. neural degeneration
Reduced histone acetylation causes chromatin packaging alterations in neurons with concomitant transcriptional dysregulation that is a key initial step in Alzheimer’s disease (AD) etiology. In this regard, we have previously established a central role for Tip60 histone acetyltransferase (HAT) mediated chromatin dynamics in neuronal function, cognition, and AD. However, it remains to be elucidated if Tip60 has alternative cellular functions other than histone acetylation that could contribute towards AD pathogenesis. Altered RNA splicing has recently been highlighted as a widespread hallmark in AD transcriptome that is implicated in the disease. Strikingly, we discovered a novel RNA binding function for Tip60 in the Drosophila brain that is conserved in the human hippocampus and impaired in brains from both, AD fly models and AD patients. Our transcriptomic analysis of the RNA molecules specifically bound to Tip60 by Tip60-RNA immunoprecipitation (RIP) revealed an RNA binding function for Tip60 that was highly specific, selective, and reproducible, with Tip60 RNA targets enriched for critical neuronal processes that are implicated in AD. Remarkably, 79% of Tip60’s RNA targets overlap with its chromatin gene targets, supporting a model by which Tip60 orchestrates bi-level transcriptional regulation at both the chromatin and RNA level, a function unprecedented for any HAT to date. Since RNA splicing typically occurs co-transcriptionally and defects are a recent hallmark of AD, we hypothesized that Tip60 regulates splicing of its RNA targets and that this process is disrupted in AD. Transcriptome analysis from Drosophila brains that model AD showed reduced Tip60 levels and intriguingly, revealed that the residual Tip60 targets a different set of RNA when compared to wild-type flies. Additionally, we observed significant Tip60-associated RNA splicing defects in the Drosophila AD brain, some of which were prevented by increasing Tip60 levels in the brain. Thus, we are the first to uncover distinct histone and RNA binding capabilities for Tip60 that mediate its function in neural gene control and RNA splicing, respectively, and may underly the chromatin packaging and splicing defects that are now characterized as hallmarks of AD.