Restoring Histone Acetylation Homeostasis In The Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression And Reinstates Cognition.

Cognitive impairment is a debilitating hallmark during pre-clinical stages of Alzheimer’s disease (AD) yet causes remain unclear. As histone acetylation homeostasis is critical for early developmental epigenetic gene control, we postulated that its misregulation contributes to cognitive deficits preceding AD pathology. Here, we show that disruption of Tip60 HAT/ HDAC2 homeostasis occurs early in the AD Drosophila brain and triggers epigenetic repression of a group of synaptic genes well before Aβ plaques form. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition. Importantly, levels of Tip60, neuroepigenetic acetylation marks and activation of these same synaptic genes are significantly reduced in hippocampus from AD patients. Genomic reorganization of transcription factories (TFs), characterized as specialized nuclear subcompartments enriched in hyperphosphorylated RNAPII and transcriptional regulatory proteins, act as an additional layer of control in coordinating efficient co-regulated gene transcription. Thus, we asked whether Tip60 utilized this mechanism in its epigenetic control of activity- dependent co-regulated synaptic genes in the brain. Our findings reveal that Tip60 shuttles into the nucleus following extracellular stimulation of rat hippocampal neurons with con

Author(s): Felice Elefant

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