Increased ACL impacts maternal diabetes induced neural tube defects by promoting modification of H3K27ac through Gadd45g pathway

Abstract Diabetes mellitus (DM) in early pregnancy increases the risk of offspring neural tube defects (NTDs). Enzymes regulated histone acetylation has been reported lin ked to this pathogenic process. While few studies focus on the intermediate acetyl-CoA, a substrate source of histone acetylation modification to maternal DM induced NTDs. Here, by using HPLC-MS/MS, western blot (WB) et al., technologies, we report that ATP citrate lyase (Acl), metabolic enzyme of glucose related tricarboxylic acid cycle, increased expressed in human and mice DM related NTDs, which further induced acetyl-CoA accumulation, and subsequently upregulated histone 3 lysine 27 acetylation (H3K27ac). Elevated H3K27ac reduce to target the neural tube closure genes: Gadd45g, Ddit3. Once inhibition of Acl, the glucose- induced suppression of Gadd45g can be alleviated by downregulation of the level of H3K27ac both in vivo and in vitro, which is a possible mechanism leading to NTDs. Our results indicated that high glucose regulates NTDs related genes by increasing Acl and up-regulating the level of H3K27ac, provide a new pathogenic mechanism for DM related NTDs.