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Downregulation of SIRT2 by Chronic Stress Reduces Expression of Synaptic Plasticity-related Genes through the Upregulation of Ehmt2

Experimental Neurobiology 2019년 28권 4호 p.537 ~ 546
 ( Wang Sung-Eun ) - Hanyang University Graduate School of Biomedical Science and Engineering Hanyang Biomedical Research Institute

 ( Ko Seung-Yeon ) - Hanyang University Graduate School of Biomedical Science and Engineering Hanyang Biomedical Research Institute
 ( Jo Sung-Sin ) - Hanyang University Hanyang University Hospital for Rheumatic Disease
 ( Jo Hye-Ryeong ) - Hanyang University Graduate School of Biomedical Science and Engineering Hanyang Biomedical Research Institute
 ( Han Jin-Il ) - Gencurix Inc.
 ( Kim Yong-Seok ) - Hanyang University College of Medicine Department of Biochemistry and Molecular Biology
 ( Son Hye-On ) - Hanyang University College of Medicine Department of Biochemistry and Molecular Biology

Abstract


Silent information regulator 2 (Sirtuin2 / SIRT2) is a NAD+-dependent deacetylase that regulates the cellular oxidative stress response. It modulates transcriptional silencing and protein stability through deacetylation of target proteins including histones. Previous studies have shown that SIRT2 plays a role in mood disorders and hippocampus-dependent cognitive function, but the underlying neurobiological mechanism is poorly understood. Here, we report that chronic stress suppresses SIRT2 expression in the hippocampus. Molecular and biochemical analyses indicate that the stress-induced decrease in the SIRT2 expression downregulates synaptic plasticity-related genes in the hippocampus through the increase of euchromatic histone-lysine N-methyltransferase 2 (Ehmt2) (also known as G9a). shRNA-mediated knockdown of SIRT2 in the dentate gyrus alters the expression of synaptic plasticity-related genes in a way similar to those induced by chronic stress, and produces depression-like behaviors. Our results indicate that SIRT2 plays an important role in the response to stress, thereby modulating depression-like behaviors.

키워드

SIRT2; depression; Ehmt2; Synaptic plasticity; Hippocampus
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