Identification of novel nutrient-sensitive gene regulatory networks in amniocytes from fetuses with spina bifida

Abstract

Neural tube defects (NTDs) remain among the most common congenital anomalies. Contributing risk factors include genetics and nutrient deficiencies, however, a comprehensive assessment of nutrient-gene interactions in NTDs is lacking. We applied a nutrient-focused gene expression analysis pipeline to identify nutrient-sensitive gene regulatory networks in amniocyte gene expression data (GSE4182) from fetuses with NTDs (cases; n = 3) and fetuses with no congenital anomalies (controls; n = 5). Differentially expressed genes (DEGs) were screened for having nutrient cofactors. Nutrient-dependent transcriptional regulators (TRs) that regulated DEGs, and nutrient-sensitive miRNAs with a previous link to NTDs, were identified. Of the 880 DEGs in cases, 10% had at least one nutrient cofactor. DEG regulatory network analysis revealed that 39% and 52% of DEGs in cases were regulated by 22 nutrient-sensitive miRNAs and 10 nutrient-dependent TRs, respectively. Zinc- and B vitamin-dependent gene regulatory networks (Zinc: 10 TRs targeting 50.6% of DEGs; B vitamins: 4 TRs targeting 37.7% of DEGs, 9 miRNAs targeting 17.6% of DEGs) were dysregulated in cases. We identified novel, nutrient-sensitive gene regulatory networks not previously linked to NTDs, which may indicate new targets to explore for NTD prevention or to optimise fetal development.