A Neuronal Activity-Dependent Dual Function Chromatin-Modifying Complex Regulates Arc Expression(1,2,3).
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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.
immediate early gene
Published Version (Please cite this version)10.1523/ENEURO.0020-14.2015
Publication InfoBeuerman, R; Ezhilarasan, R; Leung, H; Oey, N; VanDongen, Antonius MJ; VanDongen, H; & Zhou, L (2015). A Neuronal Activity-Dependent Dual Function Chromatin-Modifying Complex Regulates Arc Expression(1,2,3). eNeuro, 2(1). 10.1523/ENEURO.0020-14.2015. Retrieved from http://hdl.handle.net/10161/15435.
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Associate Professor of Pharmacology & Cancer Biology
Ion channels are complex integral membrane proteins that serve many physiological roles. Our primary objective is to understand how ion channels function, at both the molecular and cellular level. For this aim we employ two model systems: drk1 (Kv2.1), a voltage-gated K channel expressed in the central nervous system and the heart, and the NMDA receptor, a member of the ionotropic glutamte receptor family critically involved in learning and memory. The relationship