Epigenome Interactions In Complex Neurogenetic Disorders

Folic acid (FA) supplementation has been shown to decrease the occurrence of neural tube defects (NTDs) in humans. Two allelic mutations in the WNT signaling pathway gene, low density lipoprotein receptor 6 (Lrp6), provide mouse models of neural tube defects (NTDs) with opposing responses to folic acid (FA) supplementation; a high FA diet decreases incidence of NTDs in Crooked Tail (Lrp6Cd/Cd) mice, while increasing NTD occurrence in Lrp6?/? knockout mice. We gathered gene expression (RNA-seq) and DNA methylation (Enhanced-reduced representation bisulfite sequence, or ERRBS) data from two different stages in development of these two strains to investigate the mechanisms of FA rescue, and compared results to WGS and RRBS data from a human cohort of spina bifida patients. Analysis of RNA-seq from embryonic day 9.5 (E9.5) mice found more than 400 genes that were affected by dietary FA levels consistently over all conditions in both strains. Expression of the majority of those genes was suppressed by FA, with an enrichment among genes affecting nuclear processes such as histone and chromatin modification, as well as DNA methylation. Human orthologs of those genes, taken as a set, were significantly enriched for rare (minor allele frequency<0.05) SNPs and indels in the human cohort of 248 patients compared to 380 controls (q-value 3.49E-39, logistic regression). Sixteen (16) of those genes affected by dietary FA levels in mice were also enriched for genetic variants in humans (q-value