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. We show that Tip60 shuttles into the nucleus following extracellular stimulation of rat hippocampal neurons with concomitant enhancement of Tip60 binding and activation of specific synaptic plasticity genes. Multicolor three-dimensional (3D) DNA fluorescent in situ hybridization (DNA-FISH) reveals that hippocampal stimulation mobilizes these same synaptic plasticity genes and Tip60 to RNAPII-rich TFs. Our data support a model by which external hippocampal stimulation promotes intracellular Tip60 HAT dynamics with concomitant TF associated genome reorganization to initiate Tip60mediated synaptic gene activation.