Increased ATP citrate lyase affects maternal diabetes-induced neural tube defects by promoting the H3K27ac modification through the Gadd45g pathway
Research Square (Research Square)(2022)
摘要
Abstract Diabetes mellitus (DM) in early pregnancy increases the risk of neural tube defects (NTDs) in offspring. Enzyme-regulated histone acetylation has been reportedly linked to this pathological process. Few studies have focused on the intermediate acetyl-CoA, a substrate source of histone acetylation modification in maternal DM-induced NTDs. Here, we report that ATP citrate lyase (Acl), a metabolic enzyme of the glucose-related tricarboxylic acid cycle, has increased expression in DM-related NTDs of humans and mice, which induces acetyl-CoA accumulation and subsequently upregulates histone 3 lysine 27 acetylation (H3K27ac). Elevated H3K27ac reduces expression of genes for neural tube closure, Gadd45g and Ddit3. After inhibition of Acl, glucose-induced suppression of Gadd45g is alleviated by downregulation of H3K27ac both in vivo and in vitro, which is a possible mechanism of NTDs. Our results indicate that high glucose regulates NTD-related genes by increasing Acl and upregulating H3K27ac, which provide a novel pathological mechanism of DM-related NTDs.
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关键词
atp citrate lyase,neural tube defects,diabetes-induced
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