627 - Perinatal Low Sodium Intake affects Sex-specific Epigenetic Regulation of Key Neurogenic Genes in Adult Mouse Hippocampus

Publication Number: 627.6285

Xingrao Ke, Children's Mercy Hospital, Kansas City, KS, United States; Connie Grobe, Medical College of Wisconsin, Milwaukee, WI, United States; Kaela M. Varberg, Children's Mercy, Kansas City, MO, United States; Justin Grobe, Medical College of Wisconsin, Milwaukee, WI, United States; Jeffrey Segar, Medical College of Wisconsin, Milwaukee, WI, United States; Robert Lane, The Physician Career Solutin Institute, Parkville, MO, United States

Background: Development and operation of the nervous system requires sodium (Na). Na depletion occurs when total body Na stores are lower than normal. Prematurity predisposes critically ill infants to Na depletion, often due to low Na intake (LSI) and urine Na losses. The long-term consequences of perinatal sodium depletion are unclear although data from our group and others highlight a role of Na homeostasis in spatial memory in adult mice of both sexes. Spatial memory resides in the hippocampus, the function of which is dependent upon neurogenesis. The transcription factor sex determining region Y-box (Sox2) maintains pluripotency of stem cells and regulates neurogenesis. Downregulation of Sox2 impairs neurogenesis. We have previously demonstrated that perinatal LSI decreases hippocampal neurogenesis and Sox2 expression in adult mice. The impact of perinatal LSI on epigenetic regulation of Sox2 signaling in adult hippocampus remains unknown.

Objective: We hypothesized that perinatal LSI impairs hippocampal neurogenesis through epigenetic regulation of Sox2 and its downstream targets Ngn2 and NeuroD1 in adult mice.

Design/Methods: Pregnant C57BL/6J mice consumed diets containing 0.04% or 0.3% Na from gestational day 14 until postnatal day 21 (P21). Post-weaning, pups were fed a 0.15% Na diet and sacrificed at P70. Hippocampi were harvested and DNA methylation and histone code in the regulatory regions of Sox2, Ngn2 and neuroD1 were analyzed using sodium bisulfite pyrosequencing and chromatin immunoprecipitation assays.

Results: Perinatal LSI increased DNA methylation in male hippocampi at select CpG sites in the Sox2 promoter and Sox2 regulatory region. In female hippocampi, perinatal LSI decreased active histone mark H3 lysine (K) 4 trimethylation (H3K4me3) but increased repressive histone mark H3K27me3 densities in the Sox2 promoter and regulatory region. Also, specifically in females, perinatal LSI decreased SOX2 binding and active mark H3K27 acetylation densities at Ngn2 and NeuroD1 promoters.

Conclusion(s): Perinatal LSI affects epigenetic regulation of Sox2 signaling in a sex-specific manner in adult mice. We speculate that perinatal LSI-induced epigenetic modifications of Sox2 and its targets represses Sox2 signaling to impair hippocampal neurogenesis in adult mice. Future studies will investigate mechanisms underlying the sexual dimorphic responses to perinatal LSI.