Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain.

Disruption of histone acetylation-mediated gene control is a critical step in Alzheimer's Disease (AD), yet chromatin analysis of antagonistic histone acetyltransferases (HATs) and histone deacetylases (HDACs) causing these alterations remains uncharacterized. We report the first Tip60 HAT versus HDAC2 chromatin (ChIP-seq) and transcriptional (RNA-seq) profiling study in brains that model early human AD. We find Tip60 and HDAC2 predominantly recruited to identical neuronal genes.

Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer's Disease.

Amyloid-β (Aβ) peptides can form protease-resistant aggregates within and outside of neurons. Accumulation of these aggregates is a hallmark of Alzheimer's disease (AD) neuropathology and contributes to devastating cognitive deficits associated with this disorder. The primary etiological factor for Aβ aggregation is either an increase in Aβ production or a decrease in its clearance.

Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown.

Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases.

Epigenetic dysregulation is a common mechanism shared by molecularly and clinically heterogenous neurodegenerative diseases (NDs). Histone acetylation homeostasis, maintained by the antagonistic activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), is necessary for appropriate gene expression and neuronal function. Disruption of neural acetylation homeostasis has been implicated in multiple types of NDs including Alzheimer's disease (AD), yet mechanisms underlying alterations remain unclear.

Hippocampal stimulation promotes intracellular Tip60 dynamics with concomitant genome reorganization and synaptic gene activation.

Genomic reorganizations mediating the engagement of target genes to transcription factories (TFs), characterized as specialized nuclear subcompartments enriched in hyperphosphorylated RNA polymerase II (RNAPII) and transcriptional regulators, act as an important layer of control in coordinating efficient gene transcription. However, their presence in hippocampal neurons and potential role in activity-dependent coregulation of genes within the brain remains unclear. Here, we investigate whether the well-characterized role for the histone acetyltransferase (HAT) Tip60 in mediating epigenetic control of inducible neuroplasticity genes involves TF associated chromatin reorganization in the hippocampus.