Abstract
The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.
Highlights
The hippocampus is a brain region important for learning, memory, and emotional responses [1].In addition to brain development that occurs during the prenatal period, significant brain growthGenes 2020, 11, 162; doi:10.3390/genes11020162 www.mdpi.com/journal/genesGenes 2020, 11, 162 and maturation including synaptogenesis, dendritic growth, and glial cell proliferation occurs during the first few years of life [1,2]
DNA methylation levels play an important role in gene expression and are affected by environmental exposures during development [13]
Due to the known relationship between environmental exposures, DNA methylation, and gene regulation, it is expected that aberrant gene expression resulting from altered DNA methylation levels can help explain phenotypic changes induced by environmental exposures
Summary
Genes 2020, 11, 162 and maturation including synaptogenesis, dendritic growth, and glial cell proliferation occurs during the first few years of life [1,2] Environmental insults during this period can have lasting effects on brain structure and function [3,4,5,6], with the hippocampus displaying high susceptibility to the effects of early life environmental insults [7]. The common univariate approaches for ranking feature relevance fail to capture complex multivariate relationships and apply feature-ranking criteria unrelated to the model accuracy These approaches can be unstable and result in high false discovery rates and unreproducible predictive models [16,17,18]
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