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High glucose‐induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects


Aberrant epigenetic modifications are implicated in maternal diabetes‐induced neural tube defects (NTDs). Because cellular stress plays a causal role in diabetic embryopathy, we investigated the possible role of the stress‐resistant sirtuin (SIRT) family histone deacetylases. Among the seven sirtuins (SIRT1‐7), pre‐gestational maternal diabetes in vivo or high glucose in vitro significantly reduced the expression of SIRT 2 and SIRT6 in the embryo or neural stem cells, respectively. The down‐regulation of SIRT2 and SIRT6 was reversed by superoxide dismutase 1 (SOD1) overexpression in the in vivo mouse model of diabetic embryopathy and the SOD mimetic, tempol and cell permeable SOD, PEGSOD in neural stem cell cultures. DMNQ, a superoxide generating agent, mimicked high glucose‐suppressed SIRT2 and SIRT6 expression. The acetylation of histone 3 at lysine residues 56 (H3K56), H3K14, H3K9 and H3K27, putative substrates of SIRT2 and SIRT6, was increased by maternal diabetes in vivo or high glucose in vitro, and these increases were blocked by SOD1 overexpression or tempol treatment. SIRT2 or SIRT6 overexpression abrogated high glucose‐suppressed SIRT2 or SIRT6 expression, and prevented the increase in acetylation of their histone substrates. The potent sirtuin activator (SRT1720) blocked high glucose‐increased histone acetylation and NTD formation, whereas the combination of a pharmacological SIRT2 inhibitor and a pan SIRT inhibitor mimicked the effect of high glucose on increased histone acetylation and NTD induction. Thus, diabetes in vivo or high glucose in vitro suppresses SIRT2 and SIRT6 expression through oxidative stress, and sirtuin down‐regulation‐induced histone acetylation may be involved in diabetes‐induced NTDs.

This article is protected by copyright. All rights reserved.

Authors:   Jingwen Yu, Yanqing Wu, Peixin Yang
Journal:   Journal of Neurochemistry
Year:   2016
Pages:   n/a
DOI:   10.1111/jnc.13587
Publication date:   20-Feb-2016
Facts, background information, dossiers
  • Acetylation
  • diabetes
  • oxidative stress
  • inhibitors
  • Expression
  • superoxide dismutase
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