Effects of peripheral viral infection on hippocampal DNA methylation and gene expression patterns in a pig model of cognitive development

K. Schachtschneider, L. Rund, O. Madsen, R. Johnson, M. Groenen, L. Schook
Swine in Biomedical Research Meeting, July 6-8, 2014, Raleigh, NC


DNA methylation is an epigenetic mark that occurs at cytosines throughout the genome, is associated with aberrant gene transcription, and is believed to play important roles in a variety of human diseases. Neonatal environmental insults can affect hippocampal development and function, and infectious disease is the most common cause of illness in children. However, little is known about the long term effects of neonatal peripheral infection on brain development and function. Elmore et al. (2014) assessed the effects of porcine reproductive and respiratory syndrome virus infection on spatial learning and memory in a neonatal pig model of human infants, finding increased microglia activation in the hippocampus, neuroinflammation, and cognitive impairments in infected piglets at 4 weeks of age. Hippocampus samples (4 infected, 5 control) from this study were assessed for DNA methylation and gene expression via reduced representation bisulfite sequencing (RRBS) and RNAseq, respectively. Transcriptional analysis revealed 455 known and 130 novel differentially expressed genes between the infected and control hippocampus samples. Several of these genes are of particular interest for their association with hippocampal-based learning and memory, including PRSS12, RGS14, and MEF2C. Increased expression of MEF2C and decreased expression of PRSS12 and RGS14, which is associated with reduced spatial learning and memory, was observed in the infected group. In addition, TMEM173, TLR3, IFIH1, and DHX58, which are involved in recognition and initiation of immune responses to viral infections, showed increased expression in the infected group's hippocampus samples. RRBS analysis resulted in 709,512 CpG sites (25% 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, peripheral viral infection has significant effects on hippocampal gene expression and DNA methylation patterns that could account for the cognitive impairment phenotype in infected neonatal piglets.

Funding: NIH grant: HD069899; Jeju National University of Rural Development Administration of the Republic of Korea (538 JNU Korea 2012-06052)

Reference: Elmore M.R. et al. (2014). Respiratory viral infection in neonatal piglets causes marked microglia activation in the hippocampus and deficits in spatial learning. J. Neurosci. 34(6), 2120-2129.