Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review

Abstract

Early life stress (ELS) is a known risk factor for suffering psychopathology in adulthood. The hypothalamic-pituitary-adrenal (HPA) axis has been described to be deregulated in both individuals who experienced early psychosocial stress and in patients with a wide range of psychiatric disorders. The NR3C1 gene codes for the glucocorticoid receptor, a key element involved in several steps of HPA axis modulation. In this review, we gather existing evidence linking NR3C1 methylation pattern with either ELS or psychopathology. We summarize that several types of ELS have been frequently associated with NR3C1 hypermethylation whereas hypomethylation has been continuously found to be associated with post-traumatic stress disorder. In light of the reported findings, the main concerns of ongoing research in this field are the lack of methodological consensus and selection of CpG sites. Further studies should target individual CpG site methylation assessment focusing in biologically relevant areas such as transcription factor binding regions whereas widening the examined sequence in order to include all non-coding first exons of the NR3C1 gene in the analysis.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis

“…These results provide further evidence of the previously suggested biological relevance of CpG site-specific methylation when compared with average methylation of a region spanning several CpG sites. 22 Interest in the methylation signature of NR3C1 exon 1 F followed the publication of the seminal work developed in rats by Weaver and collaborators. 24 They described a maternally mediated change in DNA methylation in the rat homolog of human CpG site 37, which is located at a transcription factor (NGFI-A)-binding region, thus suggesting the functional relevance of this modification.…”

“…Fifth, all the methylation analyses were performed in peripheral tissues such as cord blood or saliva (see Table 1 for further details), which calls into question the comparability with brain measures; nevertheless, similar NR3C1 methylation findings have been found in both peripheral and brain tissues in relation with early adversity thus suggesting the tissue unspecificity of the signatures elicited by psychosocial stress in this gene. 22 Furthermore, NR3C1 peripheral methylation and its correlated GR differential expression may be informative on their own as a substantial component of cortisol's actions occurs at a peripheral level. Finally, the overall methylation differences reported by all the reviewed papers, when specified, are modest (below 5 percent) and significance should be interpreted with caution.…”

“…The NR3C1 gene, which codes for the GR, has extensively been studied regarding its role in several psychiatric disorders characterized by HPA axis dysfunction and in subjects exposed to several forms of early stress by means of both genetic and epigenetic approaches. 22,23 In this regard, several authors have analyzed DNA methylation at a CpG island located at the promoter region of this gene in different paradigms of early stress exposure. First, the discovery of a CpG-specific hypermethylation as found in exon 1 7 of postnatally neglected rat pups when compared to pups reared by mothers exhibiting high licking, grooming, and arched-back nursing (LG-ABN) behavior, prompted a new research field that has extended to human populations in the last decade.…”

“…First, the discovery of a CpG-specific hypermethylation as found in exon 1 7 of postnatally neglected rat pups when compared to pups reared by mothers exhibiting high licking, grooming, and arched-back nursing (LG-ABN) behavior, prompted a new research field that has extended to human populations in the last decade. 22,24 Special attention has been paid to exon 1 F due to its homology with rat exon 1 7 . Nevertheless, there is still no consensus about the effects of early stress on NR3C1 methylation due to the heterogeneity of assessed stress variables, regions analyzed, and subjects included in human studies.…”

“…Nevertheless, there is still no consensus about the effects of early stress on NR3C1 methylation due to the heterogeneity of assessed stress variables, regions analyzed, and subjects included in human studies. 22 Although animal studies have largely focused in the study of postnatal stress as a modulator of epigenetic patterns, prenatal stages arise as a key ontogenic window of development where stress sensitization can also occur and become embedded in the epigenome; in fact, there is one study developed in mice that reported an increase in methylation in males exposed to early prenatal stress, which was restricted to an NGF1A binding region within GR promoter exon 1 7 , thus paralleling prior results obtained in postnatal paradigms. 25 By reviewing and meta-analyzing all previously published empirical reports in human populations, the current work aims to determine whether there is enough evidence to support a link between maternal chronic psychosocial stress (as experienced during pregnancy) and site-specific NR3C1 promoter methylation (as assessed in their offspring).…”