title: High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects.
abstract: 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) over-expression in the in vivo mouse model of diabetic embryopathy and the SOD mimetic, tempol and cell permeable SOD, PEGSOD in neural stem cell cultures. 2,3-dimethoxy-1,4-naphthoquinone (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 over-expression or tempol treatment. SIRT2 or SIRT6 over-expression 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. The mechanism underlying pre-gestational diabetes-induced neural tube defects (NTDs) is still elusive. Our study unravels a new epigenetic mechanism in which maternal diabetes-induced oxidative stress represses sirtuin deacetylase 2 (SIRT2) and 6 (SIRT6) expression leading to histone acetylation and gene expression. SIRT down-regulation mediates the teratogenicity of diabetes leading to (NTD) formation. The study provides a mechanistic basis for the development of natural antioxidants and SIRT activators as therapeutics for diabetic embryopathy.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D000818:Animals; D016640:Diabetes, Gestational / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D005947:Glucose / Q000633:toxicity*; D056545:Group III Histone Deacetylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology; D058953:Neural Stem Cells / Q000378:metabolism; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D006657:Histones; D009285:Naphthoquinones; C525422:SRT1720; C063002:2,3-dimethoxy-1,4-naphthoquinone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C501860:Sirt6 protein, mouse; D056545:Group III Histone Deacetylases; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2; D037761:Sirtuins; D005947:Glucose
keywords: epigenetic mechanism; histone acetylation; maternal diabetes; neural tube defects; oxidative stress; sirtuin deacetylase