Excessive DNA Double-Strand Breaks-Associated 3D Genome Reorganization Contributes to Neural Tube Defects with Folate Deficiency.

Abstract

Neural tube defects (NTDs) are one of the most common congenital malformations. Folic acid deficiency in pregnant women increases the risk of developing NTDs; however, the underlying etiology and mechanisms remain elusive. In this study, the role of DNA double-strand breaks (DSBs) in 3D genome organization in NTDs with folate deficiency is reported. The NTD mouse model is burdened with abundant DSBs associated with the disruption of 3D genome organization. DSBs occurring in active genes lead to the stalling of RNA polymerase II (Pol II) and formation of R-loops in the 3D genome. The DSB ratios of the genomic regions negatively correlated with the distance from the transcription start sites of the gene. The DSB ratios of the proximal and distal enhancers are significantly higher and induce the displacement of loops with busy anchors. Furthermore, DSB-associated dysregulation of chromatin loops occurs in neural tube closure-associated genes that are abnormally expressed in human NTDs. Taken together, excessive DSB-associated 3D genome organization disruption within NTDs with folate deficiency contributes to the dysregulation of neural tube closure-associated genes.