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Table 2 Early stress-induced epigenetic changes in stress-regulatory genes in animal studies

From: Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders

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
[20, 43]
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]
  1. ↑ increased, ↓ decreased, ↔ no change, Avp arginine vasopressin, CBP CREB binding protein, Crfr2 corticotrophin-releasing hormone receptor 2, Crh corticotrophin-releasing hormone, exp expression, F female, GR glucocorticoid receptor, h hour, hnRNA heterogeneous nuclear ribonucleic acid, LG-ABN licking grooming arched-back nursing, M male, mRNA messenger ribonucleic acid, MS maternal separation, NGF nerve growth factor, NGFI-A nerve growth factor inducible protein A, NT3 neurotophin 3, PND postnatal day, PVN paraventricular nucleus, RDac regional differences in acetylation, RDme regional differences in methylation, Pcdh: Protocadherin, CA-1 Cornu Ammonis area 1, MeCP2 Methyl CpG binding protein 2
  2. aF2: MS M and control F were bred to produce F2 offspring