TY - JOUR T1 - A Neuronal activity-Dependent Dual Function chromatin-Modifying Complex Regulates <em>Arc</em> Expression JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0020-14.2015 SP - ENEURO.0020-14.2015 AU - Nicodemus E. Oey AU - How Wing Leung AU - Rajaram Ezhilarasan AU - Lei Zhou AU - Roger W. Beuerman AU - Hendrika M.A. VanDongen AU - Antonius M.J. VanDongen Y1 - 2015/01/27 UR - http://www.eneuro.org/content/early/2015/01/27/ENEURO.0020-14.2015.abstract N2 - Chromatin modification is an important epigenetic mechanism underlying neuroplasticity. Histone methylation and acetylation have both been shown to modulate gene expression, but the machinery responsible for mediating these changes in neurons has remained elusive. Here we identify a chromatin-modifying complex containing the histone demethylase PHF8 and the acetyltransferase TIP60 as a key regulator of the activity-induced expression of Arc, an important mediator of synaptic plasticity. Clinically, mutations in PHF8 cause X-linked mental retardation while TIP60 has been implicated in the pathogenesis of Alzheimer’s disease. Within minutes of increased synaptic activity, this dual function complex is rapidly recruited to the Arc promoter where it specifically counteracts the transcriptionally repressive histone mark H3K9me2 to facilitate the formation of the transcriptionally permissive H3K9acS10P, thereby favoring transcriptional activation. Consequently, gain-of-function of the PHF8-TIP60 complex in primary rat hippocampal neurons has a positive effect on early activity-induced Arc gene expression, whereas interfering with the function of this complex abrogates it. A global proteomics screen revealed that the majority of common interactors of PHF8 and TIP60 were involved in mRNA processing, including PSF, an important molecule involved in neuronal gene regulation. Finally, we proceeded to show using super-resolution microscopy that PHF8 and TIP60 interact at the single molecule level with PSF, thereby situating this chromatin modifying complex at the crossroads of transcriptional activation. These findings point toward a mechanism by which an epigenetic pathway can regulate neuronal activity-dependent gene transcription, which has implications in the development of novel therapeutics for disorders of learning and memory. Significance Statement: The regulation of neuronal gene expression requires dynamic changes in chromatin structure as evidenced by the fact that dysregulation of the enzymes responsible for chromatin modification often leads to intellectual disability. In this article we characterize a chromatin-modifying complex containing the X-linked mental retardation-associated protein PHF8 and the Alzheimer’s disease-associated protein TIP60 which regulates the expression of an important neuronal activity-dependent gene, Arc. By interfering with the enzymatic function of this complex, we show that it is possible to alter the ability of neurons to induce transcription in response to synaptic activity. This work supports an enzymatic mechanism for the epigenetic control of neuronal transcriptional programs with implications in the possible development of novel therapeutics for disorders of learning and memory. ER -