Nuclear Arc Interacts with the Histone Acetyltransferase Tip60 to Modify H4K12 Acetylation(1,2,3).


Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein is found at 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 (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) 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.





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Publication Info

Wee, Caroline L, Shaun Teo, Nicodemus E Oey, Graham D Wright, Hendrika MA VanDongen and Antonius MJ VanDongen (2014). Nuclear Arc Interacts with the Histone Acetyltransferase Tip60 to Modify H4K12 Acetylation(1,2,3). eNeuro, 1(1). 10.1523/ENEURO.0019-14.2014 Retrieved from

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Antonius M. J. VanDongen

Associate Professor of Pharmacology & Cancer Biology

We have discovered a new connection between the memory gene Arc (Activity Regulated, Cytoskeletal-associated protein) and Alzheimer's disease. Arc is a master regulator of of synaptic plasticity and epigenetically controls the transcription of 1900 genes associated with with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Approximately 100 genes whose activity-dependent expression level depends on Arc are associated with the pathophysiology of Alzheimer’s disease, suggesting a critical role for Arc in the development of neurodegenerative disorders.

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