Epigenetics of anxiety and stress-related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), and others. These changes can lead to transgenerational stress inheritance. Epigenetic modifications play a role in the development and heritability of these disorders and related symptoms. For example, regulation of the hypothalamic–pituitary–adrenal axis (HPA) by glucocorticoids plays a major role in the stress response and is known to be epigenetically regulated.
, most work had been done in animal models in laboratories, and little work had been done in humans; the work was not yet applicable to clinical psychiatry. Stress-induced epigenetic changes, particularly to genes that affect the HPA axis, persist into future generations, negatively impacting the capacity of offspring to adapt to stress. Early-life experiences, even when generations removed, can cause permanent epigenetic modifications of DNA packaging, resulting in changes in gene expression, endocrine function, and metabolism. Heritable epigenetic modifications include DNA methylation of the promoter regions of genes that affect sensitivity to stress.
Mechanism Epigenetic modification in response to stress results in molecular and genetic alterations that in turn results in mis-regulated or silenced genes. Heterochromatin is the protein that controls the silencing of these genes epigenetically. For example, epigenetic modifications to the gene BDNF (brain derived neurotrophic factor), as well as Drosophila ATF-2 (dATF-2), as a result of stress can be passed on to offspring. Chronic variable stress induces offspring hypothalamic gene expression modifications, including elevated methylation levels of the BDNF promoter in the hippocampus. This methylation will also occur in the heterochromatin, causing a disrupted heterochromatin to be passed on to the child. Maternal separation and postnatal maternal abuse also increases DNA methylation at regulatory regions of BDNF genes in the prefrontal cortex and hippocampus, leading to potential stress vulnerability in future generations.
Stress can also result in inheritable changes DNA methylation in the promoter regions of the estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). These changes lead to altered expression of these genes in offspring that in turn leads to decreased stress tolerance.
Stress and the HPA axis Gene regulation as it relates to the HPA axis has been implicated in transgenerational stress effects. Environmental prenatal stress exposure, for example, alters glucocorticoid receptor gene expression, gene function, and future stress response in F1 and F2 generations. Maternal care likewise contributes to HPA-related epigenetic modifications. Epigenetic re-programming of gene expression alters stress response in offspring later in life when exposed to decreased maternal care. Inattentive mothering has led to increased levels of gene methyl marks, compared to attentive mothers. Female offspring with low licking-grooming mothers have decreased promoter methylation and increased histone acetylation, leading to increased glucocorticoid receptor expression. Epigenetic modifications as a result of absent maternal care lead to decreased estrogen receptor alpha expression, due to increased methylation at the gene's promoter.
Epigenetic writers, erasers, and readers Epigenetic changes are performed by enzymes known as writers, which can add epigenetic modifications, erasers, which erase epigenetic modifications, and readers, which can recognize epigenetic modifications and cause a downstream effect. Stress-induced modifications of these writers, erasers, and readers result in important epigenetic modifications such as DNA methylation and acetylation.
DNA methylation
DNA methylation is a type of epigenetic modification in which methyl groups are added to cytosines of DNA. It is located on the fifth position of cytosine which has importance in the development of mammals. DNA methylation is an important regulator of gene expression and is usually associated with gene repression. DNA Methylation is a mechanism which can suppress gene expression. It can be inherited through cell divisions in development, and is involved with cell memory. Changes in methylation occur due to mutated or deregulated chromatin regulators. This process is also used in marking cancers for diagnosis.
MeCP2 Laboratory studies have found that early life stress in rodents can cause phosphorylation of methyl CpG binding protein 2 (MeCP2), a protein that preferentially binds CpGs and is most often associated with suppression of gene expression. Stress-dependent phosphorylation of MeCP2 causes MeCP2 to dissociate from the promoter region of a gene called arginine vasopressin (avp), causing avp to become demethylated and upregulated. This may be significant because arginine vasopressin is known to regulate mood and cognitive behavior. Additionally, arginine vasopressin upregulates corticotropin-releasing hormone (CRH), which is a hormone important for stress response. Thus, stress-induced upregulation of avp due to demethylation might alter mood, behavior, and stress responses. Demethylation of this locus can be explained by reduced binding of DNA methyl transferases (DNMT), an enzyme that adds methyl groups to DNA, to this locus.
MeCP2 is known to have interactions with several other enzymes that modify chromatin (for example, HDAC-containing complexes and co-repressors) and in turn regulate activity of genes that modulate stress response either by increasing or decreasing stress tolerance. For example, epigenetic upregulation of genes that increase stress response may cause decreased stress tolerance in an organism. These interactions are dependent on the phosphorylation status of MeCP2, which as previously mentioned, can be altered by stress.
DNMT1 DNA methyltransferase 1 (DNMT1) belongs to a family of proteins known as DNA methyltransferases, which are enzymes that add methyl groups to DNA. DNMT1 is specifically involved in maintaining DNA methylation; hence it is also known as the maintenance methylase DNMT1. DNMT1 aids in regulation of gene expression by methylating promoter regions of genes, causing transcriptional repression of these genes.
DNMT1 is transcriptionally repressed under stress-mimicking exposure both in vitro and in vivo using a mouse model. Accordingly, transcriptional repression of DNMT1 in response to long-term stress-mimicking exposure causes decreased DNA methylation, which is a marker of gene activation. In particular, there is decreased methylation of a gene called fkbp5, which plays a role in stress response as a glucocorticoid-responsive gene. Thus, chronic stress may cause demethylation and hyperactivation of a stress-related gene, causing increased stress response.
Additionally, DNMT1 gene locus has increased methylation in individuals who were exposed to trauma and developed post-traumatic stress disorder (PTSD). Increased methylation of DNMT1 did not occur in trauma-exposed individuals who did not develop PTSD. This may indicate an epigenetic phenotype that can differentiate PTSD-susceptible and PTSD-resilient individuals after exposure to trauma.
Transcription factors Transcription factors are proteins that bind DNA and modulate the transcription of genes into RNA such as mRNA, tRNA, rRNA, and more; thus they are essential components of gene activation. Stress and trauma can affect expression of transcription factors, which in turn alter DNA methylation patterns.
For example, transcription factor nerve growth-induced protein A (NGFI-A, also called NAB1) is up-regulated in response to high maternal care in rodents, and down-regulated in response to low maternal care (a form of early life stress). Decreased NGFI-A due to low maternal care increases methylation of a glucocorticoid receptor promoter in rats. Glucocorticoid is known to play a role in downregulating stress response; therefore, downregulation of glucocorticoid receptor by methylation causes increased sensitivity to stress.
Histone acetylation
Histone acetylation and deacetylation is a type of epigenetic modification in which acetyl groups are added to lysine on histone tails. Histone acetylation, performed by enzymes known as histone acetyltransferases (HATs), removes the positive charge from lysine and results in gene activation by weakening the histone's interaction with negatively-charged DNA. In contrast, histone deacetylation performed by histone deacetylases (HDACs) results in gene deactivation.
HDAC Transcriptional activity and expression of HDACs is altered in response to early life stress. For animals exposed to early life stress, HDAC expression tends to be lower when they are young and higher when they are older. This suggests an age-dependent effect of early life stress on HDAC expression. These HDACs may result in deacetylation and thus activation of genes that upregulate stress response and decrease stress tolerance.
Transgenerational epigenetic influences Genome-wide association studies have shown that psychiatric disorders are partly heritable; however, heritability cannot be fully explained by classical Mendelian genetics, but rather epigenetics. There are many components in understanding the heritability of psychiatric disorders. Understanding epigenetic modifications and its ability to impact epigenomes over generations is vital in analyzing potential behavioral disorders. But we must acknowledge the concept of transgenerational epigenetics (epigenetic inheritance) which is the occurrence in which parents are able to transfer traits not present in their DNA sequencing to their offspring; it is the passing of environmentally manipulated traits for two or more generations without direct DNA alteration. For example, one study found transmission of DNA methylation patterns from fathers to offspring during spermatogenesis. Similarly, several studies have shown that traits of psychiatric illnesses (such as traits of PTSD and other anxiety disorders) can be transmitted epigenetically Parental exposure to various stimuli, both positive and negative, can cause transgenerational epigenetic and behavioral effects.
Parental exposure to trauma and stress Trauma and stress experienced by a parent can cause epigenetic changes to its offspring. This has been observed both in population and experimental studies.
Biological vulnerability and HPA axis alterations may be observed after maternal epigenetic programing during pregnancy, leading to similar modifications in future generations. Child abuse exposure, for example, is associated with lower baseline infant cortisol levels as well as modified HPA axis function. Human studies investigating posttraumatic stress disorder (PTSD) and its effects on offspring have illustrated similar molecular and HPA axis modification and function. PTSD patients who experienced trauma from genocides or terrorist attacks frequently exhibited aggressive or neglectful behavior toward offspring during critical developmental periods, possibly contributing to permanent glucocorticoid deregulation in offspring. PTSD mothers and children illustrate lower basal cortisol levels and glucocorticoid receptors and increased mineralocorticoid receptors when exposed to stress. Therefore, developmental experiences, such as stress exposure, may have critical effects on neuromodulatory mechanisms transgenerationally.