Altered hippocampal DNA methylation, gene transcription, and RNA editing in response to early life environmental insults in 2 independent studies of cognitive development

• Published in: Journal of animal science 2016-09, Vol.94, p.39-39
• Main Authors: Schachtschneider, K M, Rund, L A, Madsen, O, Johnson, R W, Groenen, M A, Schook, L B
• Format: Article
• Language: English
• Subjects: Adenosine; Animal models; Biomedical research; Bisulfite; Brain; Cognitive ability; Cognitive development; CpG islands; Deoxyribonucleic acid; DNA; DNA methylation; Editing; Gene expression; Gene sequencing; Genes; Genomes; Hippocampus; Infections; Iron; Iron deficiency; Neurodevelopment; Nutrient deficiency; Proteins; Ribonucleic acid; RNA; RNA editing; Spatial discrimination learning; Spatial memory
• ISSN: 0021-8812; 1525-3163

DNA methylation is an epigenetic mark that occurs at cytosiiies throughout the genome, is involved in regulating gene expression, and can be altered in response to environmental signals. This study investigated DNA methylation and gene expression patterns in hippocampus samples from 2 studies observing reduced hippocampal-based spatial learning and memory in response to early life environmental insults (iron deficiency and PRRSv infection) in porcine biomedical models of cognitive development (Rytych et al.9 2012; Elmore et aL 2014). Reduced representation bisulfite sequencing and RNA-seq were performed on 16 hippocampus samples (iron deficiency, with 3 deficient and 4 control; PRRSv infection, with 4 infected and 5 control). In total. 192 and 455 differentially expressed genes (DEG) were detected in the iron-deficient and PRRSv-infected groups, respectively Of these. 53 were differentially expressed in both studies, including genes involved in neurodevelopment and function. such as CARTPT. NTNG1. PRSS12. GABRE. and HTR2C. Differential DNA methylation was assessed at more than 600.000 CpG and 2.4 million non-CpG sites in both studies, identifying 853 differentially methylated (DM) CpG and 99 DM non-CpG sites in the iron-deficient group, including 12 sites associated with 9 DEGs. In total. 1.857 DM CpG and 153 DM non-CpG sites were identified in the PRRSv-infected group, including 26 sites associated with 19 DEGs. Increased expression of VWF (log2 fold change >1.S) and HTR2C (log2 fold change >1.0) was associated with hypomethylation of the same genomic regions iii the iron-deficient and PRRSv-infected groups. In addition, as HTR2C undergoes adenosine-to-inosine (A-to-I) RNA editing at 5 sites affecting human HTR2C receptor activity and brain function, HTR2C editing frequencies were determined. Increased editing was detected at the first site (site A) in both groups, although the difference was only significant for the iron-deficient group (P = 0.019). In addition. 1 RNA isoform (IAAAI) and 1 protein isoform (V-S-I) were expressed exclusively in both the iron-deficient and PRRSv-infected groups. Together, these results provide evidence for altered liippocampal DNA methy-lation. gene expression, and HTR2C RNA editing in response to early life environmental insults in 2 independent studies of cognitive development.