Exp Neurobiol.  2019 Aug;28(4):537-546. 10.5607/en.2019.28.4.537.

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

Affiliations
  • 1Hanyang Biomedical Research Institute, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea. hyeonson@hanyang.ac.kr
  • 2Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea.
  • 3Gencurix, Inc, Hanhwan Bizmetro 1, Seoul 08394, Korea.
  • 4Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea.

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.

Keyword

SIRT2; depression; Ehmt2; Synaptic plasticity; Hippocampus
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