Abstract
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.
Footnotes
↵1 The authors report no financial conflicts of interest.
↵3 This work was supported by Grant MOE2012-T2-1-039 from the Singapore Ministry of Education to A.M.J.V.D. and an award from the Singapore Ministry of Health and A*STAR, the Agency for Science, Technology and Research. The SIM experiments were performed at the IMB Microscopy Unit, Institute of Medical Biology, A*STAR. The STED and STORM experiments were performed at the SingHealth Advanced Bio-imaging Core facility.
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