The need for a scientific statement and evidence-based understanding of the epigenomic modulation or programming in early childhood stress or adversity implying early life stress as well as the modification associated MDD and the correlation between ELS and MDD motivated the current systematic review and QES. This study assessed the epigenomic modulation in terms of DNA methylation mechanistic process in early life stress and MDD, as well as the relationship between ELS and MDD in terms of epigenomic aberrations induced by dense DNA methylation. There are a few relevant findings based on this QES. First, DNA methylation of the 1F exon on the NR3C1 gene, a glucocorticoid gene is associated with ELS and directly correlated with MDD in adulthood. Secondly, dense DNA methylation of the 1F exon of the NR3C1 gene is associated with increased risk of ELS. Thirdly, DNA hyper-methylation of the 1F exon of NR3C1 marginally increases the risk of MDD.
We have demonstrated in this systematic review and QES that the DNA methylation of the glucocorticoid receptor gene (NR3C1) results in impaired gene expression and the abnormal protein synthesis, adversely affecting the cellular function of this receptor in response to cortisol and its biologic function in responding to stress and early life adversity, or early life stress. The observed hypermethylation of this receptor gene reflects impaired response resulting in chronic stress and subsequent mental illness given the pathway of cortisol response in MDD. The activation of the hypothalamus–pituitary–adrenal (HPA) axis by social signal transduction results in rapid response to stress and stressful environment and with inhibition of the transcription factor resulting in inactivation of the protein and receptor function. An example of social stressors as ELS has been illustrated in pre and postnatal stress and maternal care insufficiencies associated with behavioral pathologies [24
]. Animal models with rodents demonstrated an inverse correlation between adequate postnatal maternal care and increased stress-reactivity, anxiety, and fear reaction [5
In general, the main neural substrates involved in epigenetic modulation of ELS and maternal care include HPA, amygdala, medial prefrontal cortex, and hippocampal region of the brain. The observed phenotypes in the aberrant epigenomic modulation in ELS are explained by the NR3C1 gene downregulation and decreased expression, a glucocorticoid receptor (GR) gene. The animal model in this context observed the dense methylation of the CpG in the promoter region of NR3C1, increased activity of the HPA axis and elevated serum glucocorticoids level [5
]. Additionally, animal model reveals increased stress reactivity, anxiety, impaired social interaction, and depressive episodes associated with maternal separation. The observed manifestations correlated with genome-wide aberrant DNA methylation and brain neural pathway genes transcripts [28
Prolonged activation of the HPA axis, altered gene transcription, and aberrant DNA methylation were observed in CNS and peripheral T lymphocytes among infants and juveniles deprived of maternal care [31
]. Aberrant epigenomic modulation (mDNA) and hydroxymethyl cytosine at the brain-derived neurotrophic factor (BDNF) locus, a member of the nerve growth factor family of neutrophils, had been observed in adolescence and adulthood distress associated with maternal maltreatment during neonatal nursing of offspring. Other neural changes include hippocampus, amygdala, and medial prefrontal cortex [37
]. Further studies observed increased expression of arginine vasopressin (Avp) and gene loci, a protein-coding gene for antidiuretic hormone (Vasopressin) associated with diabetes insipidus and DNA hypomethylation in paraventricular nucleus of the hippocampus in ELS, due to maternal separation. Similarly, the overexpression of proopiomelanocortin (pomc) gene loci, which is involved in the production of adrenocorticotropic hormone (ACTH) and binds to melanocortin 2 receptor (MC2R), stimulating cortisol release is observed in ELS associated with maternal separation [41
]. The overexpression of NR3C1 inversely correlates with corticotrophin-releasing hormone (CRH) and transcription dysregulation in chronic stress induced by ELS [42
Human models have clearly illustrated how prenatal, perinatal, infant, and adolescence social adversities exposure lead to aberrant epigenomic modulation that are transformational into adulthood. Whereas NR3C1 implicated in ELS in rodents, varieties of NR3CI sequences are observed as regulatory targets with the most consistent and common epigenomic modulation being hypermethylation at exon 1F of human NR3C1 gene in ELS or early life social adversity. The DNA sequence element that encodes methylation-sensitive binding site associated with neural activity-regulated transcription activator (NGFTA) is embedded in exon 1F region of the NR3C1. The hypermethylation of NR3C1 in ELS, implying prolonged stress that results in allostatic load, interrupts the glucocorticoids-mediated to the pituitary and hypothalamus, enhancing HPA axis persistent activation and the consequent psychopathology including chronic inflammation and major depressive disorders (MDD) [43
]. A correlation between parental stress, such as domestic violence and intimate partner violence, and NR3C1 CpG hypermethylation had been observed. Likewise, child abuse and neglect had been shown to be associated with dense NR3C1 CpG methylation and the subsequent impaired NR3C1 transcription, leading to NR3C1 downregulation and decreased gene expression [44
]. While NR3C1 hypermethylation results in NR3C1-reduced transcription, it is not clear if other pathways or epigenomic processes influence NR3C1 gene expression. However, noncoding RNA namely IncRNA, GASS, and miRNA have been shown to impair NR3C1 gene expression and protein activities [50
Other epigenomic modulations associated with early life adversities in animal models have implicated similar genes in humans such as BDNF, CRH, PM2D1, and CHRBP [36
]. Additionally, genes involved in early life adversities include MAOA, SLC17A3, MORC1, and FKBP5 [27
]. Overall, child maltreatment implying abuse and neglect and parental care deprivation signal aberrant epigenomic modulation inducing psychopathology and chronic disease such as type II diabetes and hypertension in adolescence and adult life due to allostatic overload and marginalized glucocorticoid-mediated negative feedback to pituitary and hypothalamus.
We have demonstrated that ELS is associated with hypermethylation of glucocorticoid gene (NR3C1) receptor. These findings are supported by previous data including the individual studies in QES that observed hypermethylation of candidate gene expression with ELS. Specifically, the methylation of the promoter region of DNA in this context results in the impairment in RNA polymerase response with respect to transcription and translation and the inhibition of the transcription factor resulting in abnormal gene expression and irregular protein synthesis affecting the receptor functionality. Overall, the observed cellular function is due to this methylation as an effect of social transduction in ELS, such as isolation, sexual abuse, child neglect, violent environment experienced by children at very young age, and maternal isolation and separation. Similarly, ELS has been observed in previous studies to result in psychiatric condition, including though not limited to schizophrenia, anxiety, bipolar, personality disorders, and post-traumatic stress disorder (PTSD) [23
]. To assess the molecular events associated with ELS and psychiatric conditions, those without ELS and MDD were examined. These studies clearly indicated the hypermethylation of glucocorticoid gene among those with depression who suffered ELS relative with those who did not. The finding in this systematic review is supported by previous data [23
] in both animal and human models on epigenomic programming that indicated the epigenomic programming commencing from gametogenesis that are transgenerational and predispose to disease conditions, but reversible. Studies have also indicated that mental activity such as yoga, meditation, and social network improves individual genome as well as “community genome” to response to stress implying lower incidence and prevalence of MDD in such environments [45
The evidence accumulated in this QES may be questionable due to the difficulties in determining the CpG sites with unknown biologic functions that may be incorporated into the methylation or the hypermethylation process while describing the findings in the original papers. Since the methylation state of differentiated tissues is considered to be highly specific, it is not very clear how methylation process in the circulating blood cells or saliva will provide information or data about changes in DNA from the less accessible tissue has the human brain and the autonomic nervous system, as well as the immune system cells.
Despite the strength of these findings in correlating MDD with ELS and providing a scientific statement based on the NR3C1 DNA methylation, there are some limitations. This approach involves the synthesis and quantification of given studies in order to arrive at a CES as evidence in intervention or therapeutics. First, systematic review and QES as an applied meta-analysis is a retrospective design that is prone to information and selection biases. Additionally, some studies incorporated in this QES despite the similarity of the design, implying a comparable measure of effect or point estimate, some studies failed to control for confounding, since no single variable explains everything with respect to causation. In effect, the scientific evidence and statement generated by this QES are subject to biases and unmeasured as well as residual confounding. However, it is highly unlikely that the magnitude of evidence provided on hypermethylation of NR3CI gene in ELS and MD is driven slowly by these limitations.