Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors

Abstract

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

Childhood Abuse, Promoter Methylation of Leukocyte NR3C1 and the Potential Modifying Effect of Emotional Support

“…Specifically, the site is 2803 bp downstream from the first CpG site analyzed by Oberlander et al [2] in the 1F promoter, the region of NR3C1 that has been most frequently studied in methylation analyses [5,10,[38][39][40][41][42][43][44][45][46][47]. We …”

Methylation at the CpG island shore region upregulatesNr3c1promoter activity after early-life stress

“…5 The structure of NR3C1 is highly conserved between human, rat, 6 and mouse 7 ; strong homologies are also found in multiple 5'untranslated exons in the proximal promoter regions, which produce various mRNA isoforms encoding the same protein. 8 Pioneer studies in the rat showed that persistent changes in exon 1 7 DNA methylation occur as a function of quality of maternal care 9 ; subsequently, childhood trauma, suicide, 15,16 BPD, [17][18][19] and PTSD [20][21][22] were shown to produce similar epigenetic modifications. While most of the latter studies focused on exon 1F, the human homolog of 1 7 , some authors reported upregulation of multiple transcripts after early-life stress (ELS).…”

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

“…Many studies in both humans and animals have suggested that the epigenetic regulation of distinct genes play roles in the pathogenesis of PTSD (Labonté et al, 2014;Byun et al, 2015). Vukojevic et al (2014) reported that an epigenetic alteration in the glucocorticoid receptor (GR) gene promoter is linked to individual and gender-specific differences in memory function and risk of PTSD. Additionally, evidence of this epigenetic regulation has been found in an animal model of fear conditioning (Kwapis and Wood, 2014).…”