Overactivation of ATP citrate lyase–H3K27 acetylation axis leads to maternal diabetes induced neural tube defect [RNA-seq]
Diabetes mellitus in early pregnancy is a non–genetic maternal risk factor for neural tube defects, which are associated with dysregulated gene expression and disruption of cellular behaviors. However, the key molecules linking high glucose metabolism to gene dysregulation remain unclear. Here, we report elevation of ATP citrate lyase (ACL), a metabolic enzyme of the glucose–related tricarboxylic acid cycle in brains of DM–induced mouse embryos with neural tube defects. Consistent with high glucose exposure, manipulation of ACL expression controlled the levels of acetyl-CoA and subsequent lysine 27 acetylation of histone H3 (H3K27ac). Inhibition of ACL activity significantly ameliorated diabetes mellitus–induced exencephaly in mouse embryos. Combinational analysis of H3K27ac ChIP-seq and RNA-seq data revealed a genome–wide synergistic dysregulation of 566 genes, among which the most highly upregulated gene was Txnip, which encodes a thioredoxin–interacting protein. Manipulation of ACL expression disrupted the levels of TXNIP protein, subsequent phosphorylation of apoptosis signal–regulating kinase 1 (ASK1) and neuroepithelial apoptosis. Such pathogenic pathway involving high glucose–induced ACL–H3K27ac, increased–TXNIP upregulation and excessive apoptosis was validated in human embryonic brain tissue affected by neural tube defects. Our study uncovers an intermediary role of ACL in linking high glucose metabolism to epigenetic alterations and neural tube defect formation. Overall design: To obtain the genetic expression profile in fetuses with neural tube defects caused by maternal diabetes, we collected three sets of brain tissue samples each from E9.5 normal group and NTD-afflicted fetus groups.