TY - JOUR T1 - Nuclear Arc Interacts with the Histone Acetyltransferase Tip60 to Modify H4K12 Acetylation JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0019-14.2014 SP - ENEURO.0019-14.2014 AU - Caroline L. Wee AU - Shaun Teo AU - Nicodemus E. Oey AU - Graham D. Wright AU - Hendrika M.A. VanDongen AU - Antonius M.J. VanDongen Y1 - 2014/11/12 UR - http://www.eneuro.org/content/early/2014/11/18/ENEURO.0019-14.2014.abstract N2 - Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein localizes to neuronal synapses, it also localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the β-spectrin isoform βSpIVΣ5 and associates with PML bodies, sites of epigenetic regulation of gene expression. We report here a novel interaction between Arc and Tip60, a histone-acetyltransferase and subunit of a chromatin-remodelling complex, using biochemistry and super-resolution microscopy in primary rat hippocampal neurons. Arc and βSpIVΣ5 are recruited to nuclear Tip60 speckles, and the three proteins form a tight complex that localizes to nuclear perichromatin regions, sites of transcriptional activity. Neuronal activity-induced expression of Arc i) increases endogenous nuclear Tip60 puncta, ii) recruits Tip60 to PML bodies, and iii) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification. These mechanisms point to an epigenetic role for Arc in regulating memory consolidation. Significance Statement: This manuscript reports a novel epigenetic role for the neuronal immediate early gene Arc, a master regulator of synaptic plasticity and critical effector of memory consolidation. Arc protein is localized both to synapses, where its role is well studied, and to the nucleus, where its function is still obscure. We now report that Arc interacts with the histone acetyltransferase Tip60, a subunit of the NuA4 chromatin modifying complex that functions in transcriptional regulation, implicated in Alzheimer's disease. We present data showing that Arc associates with and enhances Tip60's acetylation of its substrate H4K12, an important learning-induced histone mark. This discovery of an epigenetic function of Arc may shed light in the elucidation of mechanisms of learning and memory. ER -