Table 2 Early stress-induced epigenetic changes in stress-regulatory genes in animal studies
Candidate gene | Objective | Model/tissue type | Early stress/assessment age | Epigenetic and expression changes | Interpretation | References |
|---|---|---|---|---|---|---|
GR promoter | Determine the effect of maternal care on exon 17 GR promoter methylation and histone H3K9 acetylation | Long-Evans rats | Maternal care variations: high vs low LG-ABN Assessed: PND6, 21 and 90 | ↓ methylation 5′ CpG of NGFI-A response element in high vs low LG-ABN offspring (↔3′ CpG) ↑ histone H3K9 acetylation in high vs low LG-ABN offspring ↑ NGFI-A binding to exon 17 GR promoter in high vs low LG-ABN offspring ↑ GR mRNA in high vs low LG-ABN offspring ↑ CBP associated with exon 17 GR promoter in high vs low LG-ABN offspring | High maternal care was associated with ↑ exp of GR mRNA and protein and ↑ binding of NGFI-A in the hippocampus. This correlated with ↓ exon 17 GR promoter methylation and ↑Histone H3K9 acetylation Changes were persistent from early life to adulthood | |
Determine strain-specific epigenetic alterations of MS in mice | C57BL/6 J and DBA/2 J mice Hippocampus | MS: PND9, 24 h separation Assessed: 11–12 weeks | ↔ Nr3c1 methylation in C57BL/6J mice ↑Nr3c1 CpG 13, 14 and 17 methylation in MS-treated DBA/2J mice | MS in DBA/2J mice ↑ methylation of CpG 13, 14 and 17 in Nr3c1 at 3 months of age | [45] | |
Determine the effect of MS on exon 17 GR promoter methylation | Sprague Dawley rats Hippocampus | MS: PND2–14, 3 h/day Assessed: PND21 | ↔ methylation of exon 17 GR promoter or NGFI-A binding site ↑ NGF mRNA exp ↔NT-3 | No effect of MS on methylation status of exon 17 of the GR promoter or the NGFI-A binding site in hippocampus | [44] | |
GR gene locus (7 million base pairs) | Determine the effect maternal care on DNA methylation and H3K9 acetylation of a region of Chr 18 containing the Nr3c1 gene | Long-Evans Rats Hippocampus | High vs low LG- ABN Assessed: PND90 | 723 RDme and 471 RDac in GR gene were identified across the entire locus in high vs low LG-ABN Clustering patterns revealed changes in exp of Pcdh family genes. 20 out of 33 had ↑ exp in high compared to low LG-ABN offspring | Identified that variations in maternal care affect a broad genomic region and epigenetic and exp changes act on a family of genes localised in that broad genomic region Finding of the association of the Pcdh cluster of genes involved in synaptic plasticity | [46] |
Crh promoter | Determine the effect of MS on Crh promoter methylation | Sprague Dawley rats Hypothalamus | MS: PND2–13, 4 h/day Assessed: PND61 | ↓ methylation of Crh promoter in hypothalamus (Met-C2) ↓ methylation of Met-C2 ↑ phosphoCREB binding to CRH CRE ↑ Crh hnRNA exp in hypothalamus (↔ amygdala) ↔ Crh mRNA exp in hypothalamus and amygdala | MS ↓ methylation of Met-C2 and ↑ transcriptional activity of Crh in the PVN on PND61 | [47] |
Determine the effect of MS on Crh promoter methylation | Sprague Dawley rats Hippocampus CA1 | MS: PND1–10, 3 h/day Assessed: 10 weeks of age | ↑ H3 acetylation of the Crh promoter in MS vs no MS pups ↓methylation and ↓ binding of MeCP2 in the Crh promoter ↑Crh mRNA in MS vs no MS pups Enriched environment reversed the epigenetic up-regulation of Crh | MS ↑ acetylation of the Crh promoter region thereby allowing for increased transcriptional activity of Crh which was reversed when mice were treated to enriched environment | [48] | |
Crfr2 | Determine the effect of MS on Crfr2 methylation | C57Bl/6 mice Genomic DNA from sperm in F1 and F2 males Cortex in F2 females | Unpredictable MS: PND1–14, 3 h/day in F1 Assessed: 3–8 months of age | F1 ↓ methylation of 5′ CpG of Crfr2 in M F2a ↓ methylation of 5′ CpG of Crfr2 in F Changes in gene exp were accompanied by ↓ mRNA exp | Early stress ↓ methylation of Crfr2 and mRNA exp in adult C57/BL6 mice and that is transmitted across generations | [21] |
Avp enhancer | Determine the effect of MS on Avp enhancer methylation and mRNA exp | C57Bl/6 mice PVN of hypothalamus | MS: PND1–10, 3 h/days Assessed: PND10, 6 weeks, 3 months and 1 year | ↓ Avp enhancer methylation at 6 weeks, 3 months and 1 year ↓ methylation of CpGs largely mapped to CG13 of Avp enhancer from 6 weeks (↔ at PND10) ↓ binding of CG13 Avp enhancer at PND10 and 6 weeks ↓ methylation of CpGs w age (11 CpGs at 6 weeks, 7 at 3 months, 3 at 1 year) ↑ AVP mRNA exp from 6 weeks | MS causes ↓ methylation of the Avp enhancer from 6 weeks of age in C57/BL6 mice which is accompanied by persistent up-regulation of Avp exp in parvocellular neurons in the PVN | [23] |
Determine strain-specific epigenetic alterations of MS in mice | C57BL/6J and DBA/2J mice Hippocampus | MS: PND9, 24-h separation Assessed: 11–12 weeks | ↑ methylation of CpG1 of Avp in MS treated M of C57BL/6J and DBA/2J strain | MS ↑ methylation of CpG 1 unit in the Avp enhancer DNA sequence | [45] |