DNA methylation is an epigenetic mark that occurs at cytosines throughout the genome. DNA methylation plays a crucial role in gene expression and altered methylation patterns are associated with aberrant gene transcription. Furthermore, DNA methylation represents a link between genetics and environmental signals that is believed to play an important role in human pathologies including cancer and neurological disorders, revealing the importance of accessing DNA methylation patterns in understanding disease development. Iron deficiency is a common worldwide childhood nutrient deficiency, and has been linked to cognitive impairments. Rytych et al. (2012) assessed the effects of iron deficiency on spatial learning and memory in a neonatal pig model of human infants, finding cognitive impairments in iron deficient piglets at 4 weeks of age. Hippocampus samples from this study (3 deficient, 4 control) were assessed for DNA methylation and gene expression via reduced representation bisulfite sequencing (RRBS) and RNAseq, respectively. Transcriptional analysis revealed 192 known and 69 novel differentially expressed genes between the iron deficient and control hippocampus samples. Several of these genes are of particular interest for their association with spatial learning and memory, including PRSS12 and NETO1. PRSS12 plays an essential role in cognitive functions and causes mental retardation when truncated in humans, while NETO1 knockout mice show signs of reduced spatial learning and memory. Reduced expression of both genes was seen in the iron deficient samples, providing a genetic link to the reduced spatial learning and cognitive development phenotype. RRBS analysis resulted in 602,446 CpG sites (21% of targeted CpG sites) covered in all samples, and correlations with gene expression were assessed by investigating differentially methylated regions located near differentially expressed genes. In conclusion, iron deficiency has significant effects on gene expression and DNA methylation patterns that could account for the cognitive impairment phenotype in iron deficient neonatal piglets.
Funding: NIH grant: HD069899; Jeju National University of Rural Development Administration of the Republic of Korea (538 JNU Korea 2012-06052)
Reference: Rytych J.L. et al. (2012). Early life iron deficiency impairs spatial cognition in neonatal piglets. J. Nutr. 142,11, 2050-2056.