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

Abstract

Background: 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 hypothesised that multiple nutrient-gene interactions would be evident in NTD-associated gene signatures. Methods: We applied a novel, 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 identified and screened for having nutrient cofactors. Transcription factors (TFs) with nutrient cofactors that regulated DEGs, and nutrient-sensitive miRNAs that had a previous link to NTDs, were identified and used to construct DEG regulatory networks. Results: Of the 880 DEGs in cases (vs. controls), 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 TFs, respectively. Zinc- and B vitamin- dependent genes and gene regulatory networks (Zinc: 10 TFs targeting 50.6% of DEGs; B vitamins: 4 TFs [targeting 37.7% of DEGs], 9 miRNAs [targeting 17.6% of DEGs]) were dysregulated in cases. Two nutrient-dependent TFs predicted to target DEGs in cases (Tumor Protein 63 and Churchill Domain Containing 1) have not been previously linked to NTDs. Conclusions: We identified multiple novel nutrient-sensitive gene regulatory networks associated with NTDs, which may relate to NTD pathogenesis, and indicate new targets to explore for NTD prevention or to optimise fetal development.

Identification of MicroRNA Profiles in Fetal Spina Bifida: The Role in Pathomechanism and Diagnostic Significance

“…The study performed by Wang et al showed that SOX11 is essential for both embryonic and adult neurogenesis, by transient proliferation deficits in neural progenitor cell proliferation [ 46 , 47 ]. Moreover, QSOX1 has been associated with neural tube defect development via its interaction with valproic acid and folic acid [ 12 ]. The potentially disturbed function of genes indicated by DE miRNAs suggests involvement in the processes of neurogenesis, responses to oxidative stress, lipid metabolism, and the transport and distribution of folic acid, which confirms the complex pathogenesis of developmental defects in SB.…”

“…Moreover, introducing miRNA expression patterns to the diagnostic protocol may improve SB detection and also aid personalized clinical management [ 10 ]. Since the pathogenesis of SB is still unknown, the comprehensive knowledge of SB development may introduce new treatment targets, improve surgical techniques, and enhance the prognosis for neonates [ 11 , 12 , 13 ]. Thus, the main objective of the current study was to evaluate the significance of miRNAs in the pathogenesis of SB.…”

Early life programming of neurodevelopment and growth: understanding nutritional, inflammatory, and placental contributions in complex pregnancies

“…To determine whether patterns of differential gene expression in cases differed according to placental location, DEGs with known cell-specific expression at the maternal-fetal interface were also identified (expression threshold ≥ 1; PlacentaCellEnrich) and characterized according to known expression patterns in the placenta 227,228 . Lastly, to determine the extent to which DEGs in cases are sensitive to, or interact with, nutrients, DEGs that coded for micronutrient-dependent proteins (i.e., proteins with ≥1 micronutrient cofactor) were identified and used to construct DEG-nutrient interaction networks 229,230 .…”