A Neuronal Activity-Dependent Dual Function Chromatin-Modifying Complex Regulates Arc Expression(1,2,3).

Abstract

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.

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Published Version (Please cite this version)

10.1523/ENEURO.0020-14.2015

Publication Info

Oey, Nicodemus E, How Wing Leung, Rajaram Ezhilarasan, Lei Zhou, Roger W Beuerman, Hendrika MA VanDongen and Antonius MJ VanDongen (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 https://hdl.handle.net/10161/15435.

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VanDongen

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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