Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental period can affect epigenetic patterns and have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation (reduced representation bisulfite sequencing) and gene transcription (RNA-seq) from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and PRRSv infection) using porcine biomedical models. The Boruta machine learning approach was utilized to identify DNA methylation and gene expression features attributed to the reduced cognition phenotype. In total, 1,743 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, with samples clustering by group when comparing expression of the identified DEGs (ANOSIM R = 0.6842, p-value = 0.001). GO term enrichment analysis resulted in the identification of 219 GO terms enriched for DEGs, including terms associated with immune responses, angiogenesis, cellular signaling, development, differentiation, and proliferation. In addition, 943 differentially methylated CpG regions (DMRs) were identified between the reduced cognition and control groups. While samples did not cluster by group when comparing methylation levels of the 30,696 tested regions (ANOSIM R = -0.06899, p-value = 0.731), samples clustered by group when comparing expression levels of the 943 DMRs (ANOSIM R = 0.9216, p-value = 0.001). These 943 DMRs overlapped with 891 gene regions. Overlapping genes were enriched for 171 GO terms, including terms associated with neurodevelopment, cellular signaling, development, differentiation, and proliferation. Finally, the identified DMRs overlapped with 67 DEGs, including 18 genes involved in neurodevelopment, function, and maintenance of the blood brain barrier. Together, these results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across two independent studies.