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. 2020 Feb 4;11(2):162.
doi: 10.3390/genes11020162.

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

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Free PMC article

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

Kyle M Schachtschneider et al. Genes (Basel). .
Free PMC article

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.

Keywords: DNA methylation; RNA-seq; cognitive development; hippocampus; machine learning; porcine biomedical models.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Alteration of Hippocampal Gene Expression Patterns. Principle component analysis (PCA) based on the expression level of (A) all tested genes and (B) DEGs. (C) Heatmap of the expression levels of the 420 DEGs, represented as z-scores. (D) Identified GO terms enriched for DEGs.
Figure 2
Figure 2
Altered Hippocampal DNA Methylation Patterns. PCA based on the methylation level of (A) all tested regions and (B) DMRs. (C) Heatmap of the methylation levels of the 116 DMRs, represented as z-scores.
Figure 3
Figure 3
Contribution of immune related DEGs to reduced cognition group variation. (A) PCA based on the expression level of 43 immune related DEGs. (B) Breakdown of variables contributing to each principle component. (C) Percent contribution of each gene to principle component 1 (PC1). The red dotted line signifies the expected contribution of each gene, and any genes contributing at a higher rate were considered significant contributors. (D) Sixteen DEGs contributing to PC1 displayed a log2 fold change differences >1 or <−1. Log2 fold changes represent expression levels in the PRRSv infected compared to iron deficient group.
Figure 4
Figure 4
Differential methylation and expression of LRRC32. Hypermethylation of a 60 bp region in the 2nd intron of LRRC32 correlated with increased expression in the reduced cognition group (Pearson’s R = 0.72, p-value = 0.002).
Figure 5
Figure 5
Differential methylation and expression of VWF. Hypomethylation of a 28 bp region in the 11th intron of VWF correlated with increased expression in the reduced cognition group (Pearson’s R = −0.67, p-value = 0.007).
Figure 6
Figure 6
Altered methylation of genes in the cholinergic synapse pathway. Depiction of genes involved in cholinergic signaling. Green represents genes hypermethylated in the reduced cognition group, red represents genes hypomethylated in the reduced cognition group, and grey represents genes without differential methylation. Blue circles represent acetylcholine, orange circles represent potassium, and purple circles represent calcium.
Figure 7
Figure 7
DEGs and genes overlapping DMRs related to calcium transport and binding. Log2 fold changes and percent methylation changes of (A) DEGs and (B) genes overlapping DMRs related to calcium transport and binding.

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