Epigenetic Determination Of Stress And Stress-Related Diseases

Background

Discuss about the Essay for Epigenetic Determination (Influence) of Stress and Stress Related Diseases.

The ability of environmental factors, such as stress, to promote the epigenetic transgenerational inheritance of disease and phenotypic variation has now been established in a number of organisms ranging from plants to humans, with a variety of environmental exposures. One of the first studies found that environmental toxicants such as fungicides and pesticides promoted epigenetic transgenerational inheritance of reproductive disease. Subsequently a large number of different types of toxicants (plastics, hydrocarbons, dioxin, biocides, dichlorodiphenyltrichloroethane (DDT)) have been shown to promote the transgenerational inheritance of disease from obesity to cancer (Skinner, 2014). Other critical environmental factors found to promote transgenerational disease are nutritional abnormalities such as caloric restriction or high fat diets.

Psychiatric disorders and in particular stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety disorders are multifactorial diseases influenced by both genetic predisposition and environmental factors (Stankiewicz, Swiergiel & Lisowski, 2013) Adverse life events, especially early in life, have consistently been shown to strongly increase the risk for mood and anxiety disorders in large epidemiological studies (Gudsnuk & Champagne, 2012) Although severe forms of early adverse life events such as childhood abuse or neglect have been associated with the highest rates of increased risk (Covington et al., 2011) other forms of early adverse experiences, such as parental loss, bullying, or low socioeconomic status in childhood, were also shown to consistently increase risk for a number of psychiatric disorders . Finally, an increasing body of literature suggests that prenatal adversity, in the form of stress or mood and anxiety disorders of the mother, is also a risk factor for psychiatric disorders. A factor common to these early adversities is that they have all been associated with long-term changes in the regulation of the stress hormone system (Yamawaki et al., 2012), which may be causally related to the development of disease. In addition to the strong effects of the environment, there is a significant genetic contribution to the development of these disorders. However, strong main genetic effects have not been observed for stress-related psychiatric disorders to date, reflected by a lack of genome-wide significant associations in studies with sample sizes that have led to robust genetic association signals for schizophrenia and bipolar disorder (Covington et al., 2011). The genetics of stress-related disorders are therefore confronted with the so-called missing heritability that describes the lack of strong effects in the kind of gene-association studies found in twin and family studies. This is likely accounted for by weak phenotype definitions potentially leading to a dilution of genetic effects. Current diagnostic classification includes a number of pathophysiological subtypes under the broad definitions of anxiety and depressive disorders. In addition, genetic factors may have considerably smaller effect sizes compared to schizophrenia where they explained variance by polygenic factors has consistently increased with growing sample sizes (Yamawaki et al., 2012), In MDD, anxiety disorders, and PTSD, the reliable detection of such polygenic risk factors may need much larger samples.

A deeper understanding of the pathomechanisms leading to stress-related psychiatric disorders is important for the development of more efficient preventive and therapeutic strategies. Epidemiological studies indicate a combined contribution of genetic and environmental factors in the risk for disease. The environment, particularly early life severe stress or trauma, can lead to lifelong molecular changes in the form of epigenetic modifications that can set the organism off on trajectories to health or disease (Bagot et al., 2014). Epigenetic modifications are capable of shaping and storing the molecular response of a cell to its environment as a function of genetic predisposition. This provides a potential mechanism for gene-environment interactions. Thus, in this study aims to explore the recent advances regarding the stress related influence on the epigenetics and the relation of stress with stress disorders.

Animal and human studies have found correlations between poor care during infancy and epigenetic changes that correlate with long-term impairments that result from neglect.

Studies in rats have shown correlations between maternal care in terms of the parental licking of offspring and epigenetic changes. A high level of licking results in a long-term reduction in stress response as measured behaviorally and biochemically in elements of the hypothalamic-pituitary-adrenal axis (HPA). Further, decreased DNA methylation of the glucocorticoid receptor gene was found in offspring that experienced a high level of licking; the glucorticoid receptor plays a key role in regulating the HPA. The opposite is found in offspring that experienced low levels of licking, and when pups are switched, the epigenetic changes are reversed (Bagot et al., 2014). This research provides evidence for an underlying epigenetic mechanism. Further support comes from experiments with the same setup, using drugs that can increase or decrease methylation. Finally, epigenetic variations in parental care can be passed down from one generation to the next, from mother to female offspring. Female offspring who received increased parental care (i.e., high licking) became mothers who engaged in high licking and offspring who received less licking became mothers who engaged in less licking.

The experimental study of the effects of social interactions and stressful life events has relied primarily on laboratory rodent models (typically involving rats and mice), although some primate work is available to provide further support of the profound effects of early-life experiences (Bagot et al., 2014). The effects of prenatal stress, maternal deprivation and/or separation, variation in maternal care, juvenile social enrichment and/or isolation, and adult social stress have been explored in these models and suggest that the quality of social interactions or the experience of stress can induce neuroendocrine effects that influence social behavior, reproductive success, cognitive ability, and stress responses. Although it is clear that during prenatal and early postnatal development there is a period of enhanced sensitivity to these environmentally induced effects, there may also be plasticity beyond infancy that extends into adolescence and adulthood. An intriguing finding within these studies is the long-term effects of early- and later-life experiences on region-specific gene expression in the brain. For example, exposure to stressors during fetal development or in early infancy is associated with an upregulation of genes involved in the hypothalamic-pituitary-adrenal (HPA) response to stress and a downregulation of genes that exert a dampening effect on these pathways (Bagot et al., 2014). These findings have led to further exploration of the molecular mechanisms involved in gene regulation that may mediate this lasting effect.

Epigenetic mechanisms provide a dynamic strategy for changing the expression of genes and are increasingly the focus of studies examining the biological pathways through which early-life experiences exert long-term effects on gene expression (Peña et al., 2014). Across species, it is evident that epigenetic effects can be induced by a variety of experiences, including the quality of social interactions and exposure to stressors. Moreover, in some cases, these developmental effects can be transmitted across generations, leading to neurobiological and behavioral variation in offspring and grand-offspring (Peña et al., 2014). In this review, we highlight research indicating a link between social and stressful experiences occurring over the lifespan and epigenetic variation and the transgenerational implications of these effects. Although motivated by interest in determining contributions to the pathophysiology of human disease, this research is drawn primarily from studies in laboratory rodents and thus can also provide insights into the conditions of life that induce persistent biological changes in laboratory animals. We discuss the implications of findings from the now rapidly advancing study of behavioral epigenetics for laboratory animal treatment and housing conditions. Manipulating the quality of these conditions may have significant long-term consequences for animal welfare and, in particular, the stress physiology and reproductive success of laboratory animals.

In humans, a small clinical research study showed the relationship between prenatal exposure to maternal mood and genetic expression resulting in increased reactivity to stress in offspring. Three groups of infants were examined: those born to mothers medicated for depression with serotonin reuptake inhibitors; those born to depressed mothers not being treated for depression; and those born to non-depressed mothers. Prenatal exposure to depressed/anxious mood was associated with increased DNA methylation at the glucocorticoid receptor gene and to increased HPA axis stress reactivity (Peña et al., 2014). The findings were independent of whether the mothers were being pharmaceutically treated for depression.

Recent research has also shown the relationship of methylation of the maternal glucocorticoid receptor and maternal neural activity in response to mother-infant interactions on video. Longitudinal follow-up of those infants will be important to understand the impact of early care giving in this high-risk population on child epigenetic and behavior (Hunter, R., 2012). Environmental and epigenetic influences seem to work together to increase the risk of addiction. For example, environmental stress has been shown to increase the risk of substance abuse. In an attempt to cope with stress, alcohol and drugs can be used as an escape. Once substance abuse commences, however, epigenetic alterations may further exacerbate the biological and behavioral changes associated with addiction (Sun, Kennedy & Nestler, 2013).

The systematic review methodology has been followed in this research. Systematic review can be classified as the secondary research method, as in this research, previous study findings is being analyzed and conclusion is being made based on these findings. The systematic review method is also dictated as the Meta analysis study. This research method has been selected as it helps to collect authentic secondary data related to the research topic and helps to analyze these data through the emergence of some relevant themes (Klengel & Binder, 2015). This thematic analysis enhances the efficiency of study results. As, the topic “Epigenetic influence of stress and stress related diseases” has been researched well in previous studies, the Meta analysis or systematic review method for the secondary study was suitable.

Relevant literatures have been searched from authenticated search engines including Pubmed, CDU library, Google scholar and Medline. In the process of literature search, initially, the topic has been put in the search area and the results were reviewed based on the abstracts. After going through the abstracts, the inclusion and exclusion criteria for this research study have been aligned with the studies. The studies, which were successfully aligned with the research exclusion and inclusion criteria, have been selected. For secondary data search, key words related to the topic have been used including, “epigenetics, influence of stress, stress and stress related disease, epigenetic modification and epigenetic adaptation of brain”. After getting the search results, these articles were analyzed by their titles initially. After excluding the non-suitable articles, the remaining articles were analyzed based on the abstracts and the appropriate ones were included. Then the final screening was done according to the inclusion and exclusion criteria set for this study. According to that, the studies were selected and information reviewed. The studies were also checked for biasness and limitations. Finally 9 articles were selected for review.

Identify the report as a systematic review, meta-analysis, or both

Not older than 10 years

Includes a clear link between two variables of the study, “stress and epigenetic influence’

Clearly understandable abstract with structured summary for the article including abstract, data source, findings and conclusion

Qualitative research with or without thematic analysis

Identify the report as a systematic review, meta-analysis, or both

Describe method of data extraction from reports

Discuss limitations at study and outcome level

In the following process the literature search has been done.

Author	Year	Name of the article
Michael K Skinner	2014	Environmental stress and epigenetic transgenerational inheritance
Adrian M. Stankiewicz ,  Artur H. Swiergiel,  Pawel Lisowski	2013	Epigenetics of stress adaptations in the brain
Kathryn Gudsnuk and Frances A. Champagne	2012	Epigenetic Influence of Stress and the Social Environment
Rosemary C. Bagot, Benoit Labonte, Catherine J. Peña, Eric J. Nestler	2014	Epigenetic signaling in psychiatric disorders: stress and depression
Richard G. Hunter	2012	Epigenetic effects of stress and corticosteroids in the brain
Torsten Klengel, Elisabeth B. Binder	2015	Epigenetics of Stress-Related Psychiatric Disorders and Gene × Environment Interactions
Sun H1, Kennedy PJ, Nestler EJ.	2013	Epigenetics of the depressed brain: role of histone acetylation and methylation.
Kathleen Saavedra , Ana María Molina-Márquez , Nicolás Saavedra , Tomás Zambrano and Luis A. Salazar	2016	Epigenetic Modifications of Major Depressive Disorder
Trump, S., Bieg, M., Gu, Z., Thürmann, L., Bauer, T., Bauer, M., … & Lawerenz, C	2016	Prenatal maternal stress and wheeze in children: novel insights into epigenetic regulation

Overview of epigenetic regulatory mechanisms

Epigenetic modes of gene regulation can be grouped into three general domains: (i) histone post-translational modifications (PTMs) and histone variant exchange; (ii) chromatin remodeling; and (iii) DNA methylation. While individually important, these mechanisms work together to orchestrate precise phenotypic outputs in mammalian cells. Also important for epigenetic control is the regulation of noncoding RNAs, which is not discussed here due to space limitations (Trump et al., 2016).

Histone modifications

The best-characterized mode of epigenetic regulation in brain is the post-translational, covalent modifications of histones. Histones are proteins that stably interact with DNA to form nucleosomes, which package DNA into chromatin. The nucleosome consists of DNA wrapped around an octamer of core histone proteins, two copies each of H3, H4, H2A, and H2B. For each of the core histones in mammals, with the exception of H4, variants exist that can exhibit significantly distinct structures, temporal regulation, and cell-type specificity from their canonical counterparts (Trump et al., 2016). Histone variants may also provide an alternative mechanism of encoding and transmitting epigenetic information.

Figure: Chromatin structure and histone modifications at N-terminal histone tails. (A) The eukaryotic genome is organized by wrapping DNA around histone octamers to form the basic units of chromatin and nucleosomes, which are then further, organized and compacted into higher ordered structures. (B) The histone octamer consists of two copies each of H2A, H2B, H3, and H4.

(Source: Sun, Kennedy & Nestler, 2013)

Interactions between DNA and core histone proteins can be altered by covalent modifications to histone N-terminal and C- terminal tails. Histone acetylation and phosphorylation decrease the affinity of histone octamers for DNA to loosen chromatin structure. This relaxed chromatin state, referred to as euchromatin, allows the transcriptional machinery, DNA binding proteins, and chromatin remodeling complexes access to genes and is often associated with active gene transcription. Methylation of lysine or arginine residues in histone tails is generally thought to be more stable than other histone PTMs, and plays roles in both transcriptional activation and repression depending on the residue being methylated (Sun, Kennedy & Nestler, 2013).

The enzymes that mediate histone modifications and their reversal can be understood as “writers” and “erasers,” respectively. For example, histone acetyltransferases (HATs) catalyze acetylation and histone deacetylases (HDACs) catalyze removal (deacetylation) of this mark. Similarly, histone methyltransferases (HMTs) catalyze methylation and histone demethylases (HDMs) catalyze removal of methylation marks. Proteins that bind to specific modified residues, termed “readers,” mediate the functional consequences of histone PTMs through effecting transcriptional change (Sun, Kennedy & Nestler, 2013). Distinct roles for histone PTMs, along with their writers, readers, and erasers, led scientists to develop what is commonly referred to as the “histone code hypothesis,” which proposes that specific histone modifications work sequentially or in combination to form a code that can be read by other proteins to effect downstream changes in gene expression (Archer, 2015). While it is true that certain histone PTMs is read in this way, it is becoming increasingly clear that a histone code per se does not work in isolation to direct the complex mechanisms of epigenetic regulation. Rather, this code cooperates with many other mechanisms, such as DNA methylation and chromatin remodeling, to produce a given phenotype.

Chromatin remodeling

With or without histone PTMs, nucleosomes themselves function as physical barriers to transcription. The precise positions of nucleosomes along DNA are controlled by chromatin remodeling complexes, which act to insert, slide, and eject histone octamers from the chromatin template. These multi-subunit complexes regulate the expression of many transcription factors. Chromatin remodelers also regulate alternative splicing, events that occur cotranscriptionally (Archer, 2015). It is likely that interactions between remodelers and associated transcription factors, other DNA binding proteins, histone PTMs, and DNA methylation, work together to direct remodeling activity in a manner that alters nucleosome positioning to affect gene transcription. 

DNA Methylation

Historically, the most studied epigenetic modification is the direct methylation of DNA, involving the addition of a methyl group to cytosine (Branchi et al., 2011). DNA methylation is classically regarded as a highly stable epigenetic mark and can be maintained throughout the lifetime of an organism. DNA methyltransferase (DNMT) catalyzes DNA methylation and occurs most commonly at CpG dinucleotides (Curley et al., 2011). DNA methylation generally exerts a repressive effect on gene transcription, as exemplified by the X chromosome inactivation in females and genomic imprinting, where hypermethylation of one parental allele for a given gene results in monoallelic expression. methylated DNA is recognized by methyl-CpG-binding domain (MBD) proteins, such as MECP2 (protein-coding) and MBD1, whose binding can further recruit histone modifying enzymes and chromatin-remodeling complexes to compact nucleosomes and inhibit gene expression (Radtke et al., 2011). The process is also associated with splicing mechanism.

Recently, additional DNA modifications have been discovered, including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine (Roth et al., 2011). These chemical modifications are thought to be derived from 5-methylcytosine through oxidation steps catalyzed by members of the ten-eleven translocation (TET) enzyme family, potentially representing a process of active DNA demethylation. DNA methylation in the brain may be more dynamic than in other tissues. Support for this idea comes from the discovery that: (i) the de novo DNA methyltransferase, DNMT3a, is the main DNMT expressed in neuron (Mahgoub & Monteggia, 2013) (ii) the highest levels of oxidized forms of methylcytosine are found in the brain; and (iii) active DNA repair results in demethylated DNA in nondividing neurons (Hasan et al., 2013). There is also evidence that the primary effect of 5-hmC is to promote gene expression through mechanisms that remain poorly understood.

Emerging themes from the literatures

Epigenetic Impact of Prenatal Stress

Chronic variable stress experienced by gestational females has been demonstrated to induce a long-term impact on HPA pathways, including altered gene expression within the hypothalamus. In mice, stress during the 1^st week of pregnancy has been found to induce significant impairments in male offspring (Skinner, 2014). Among male pups born to a stressed dam, CRF gene expression is increased and GR gene expression is decreased in adulthood. Analysis of DNA methylation within the promoter region of the Crfgene in hypothalamic tissue of stressed offspring versus control offspring indicates stress-induced reduction in DNA methylation. In contrast, within the promoter region of the Nr3c1 gene (encoding GR), prenatal stress is associated with increased DNA methylation. The direction of these epigenetic effects coincides well with the notion that increased DNA methylation leads to reduced gene expression.

Although prenatal stress effects have been attributed to the direct exposure of the developing fetus to maternal glucocorticoids (Skinner, 2014). it is important to consider the placenta—the interface between maternal and fetal physiological systems—as a mediating mechanism of prenatal effects. The expression of DNMTs in the placenta of prenatally stressed mice has been examined, and elevations in DNMT1 were observed (Skinner, 2014). Unlike the behavioral effects of this stress paradigm, stress-induced elevations in placental DNMT1 levels were observed in female offspring (with only a trend for an increase in males), which raises questions about the mechanisms of the sex specificity of prenatal stress. Prenatal stress exposure also has an impact on stress reactivity in adulthood. Chronic exposures produce exaggerated corticosterone responses to stress and a number of deficits in hippocampal structure and function.

Variation in Early Postnatal Experiences: Effects on DNA Methylation and Histone Modifications

Animal models of neglect, abuse, and variation in maternal care are increasingly incorporating analyses of epigenetic mechanisms to account for the persistent effects of these experiences. In mice, maternal separation (3 hours/day on postnatal days 1–10) has been found to increase Avp gene expression in the PVN, and analysis of the promoter of this gene indicates decreased DNA methylation at several cytosine nucleotides within this region (Stankiewicz, Swiergiel & Lisowski, 2013). These epigenetic effects are apparent at 6 weeks, 3 months, and 1 year after the experience of maternal separation. Hypomethylation of the Avp gene associated with maternal separation was also associated with reduced levels of binding of MeCP2 (a protein that binds to methylated DNA). Notably, MeCP2 is also associated with the primary pathology of Rett syndrome (Gudsnuk & Champagne, 2012), and to play a role in the regulation of the expression of stress responsive genes such as BDNF. By means of a similar maternal separation paradigm, male offspring exposed to postnatal separation were found to have elevated levels of DNA methylation within the Mecp2 gene and decreased methylation within the Crf receptor (Crfr2) gene (Gudsnuk & Champagne, 2012). Abusive behavior toward pups has been found to induce significant changes in the epigenetic regulation of BDNF. Studies of Long-Evans rats indicate that daily exposure to 30 minutes of aggressive caregiving on postnatal days 1 through 7 is associated with increased DNA methylation of the Bdnf promoter at postnatal days 8, 30, and 90 (Gudsnuk & Champagne, 2012). Although a limited range of targets has been explored, these initial studies suggest that epigenetic modifications, particularly DNA methylation, are associated with early-life manipulation of the quality and frequency of contact between dams and pups. Another early life stress model, using stressed and abusive dams, showed that the pups reared under these conditions showed reduced levels of BDNF expression in the prefrontal cortex, which correlated with DNA hypermethylation at the activity dependent exon IV promoter. The investigators were able to reverse this effect by infusing the DNA methylation inhibitor zebularine (Gudsnuk & Champagne, 2012).

Non-coding RNA and epigenetic effects of stress

The effects of stress on non-coding RNA activity and the regulation of the stress axis by ncRNA in the brain, have received less attention than DNA methylation and histone modification, but the few studies thus far completed demonstrate that the epigenetic actions of RNA are also likely to be a significant part of the effects of stress upon the brain. The GR is the target of a number of miRNAs (Hunter, 2012). The effects of stress on non-coding RNA activity and the regulation of the stress axis by ncRNA in the brain, have received less attention than DNA methylation and histone modification, but the few studies thus far completed demonstrate that the epigenetic actions of RNA are also likely to be a significant part of the effects of stress upon the brain. The GR is the target of a number of miRNAs (Hunter, 2012).

Activation of Transcription Factors that Lead to Local Changes in the Epigenetic Profile

An additional molecular mechanism leading to long-term epigenetic changes in response to stress is the activation of specific transcription factors that in turn lead to local changes in epigenetic profiles. Early reports on the transcription factor Sp-1 showed that binding of Sp-1 leads to a local inhibition of de novo DNA methylation (Sun, Kennedy & Nestler, 2013). Furthermore, glucocorticoid receptor (GR) activation can lead to a local demethylation of GR response elements (GREs) (Sun, Kennedy & Nestler, 2013). The mechanism of GR-induced local demethylation has not been fully understood, but the DNA repair machinery was implicated in this process, allowing the replacement of methylated by unmethylated cytosines. This demethylation of GREs subsequently facilitates the transcriptional effects of the GR on the target gene (Sun, Kennedy & Nestler, 2013). Another example is the activation of the Nuclear Factor 1 A-type (NF1A) transcription factor by maternal care in rodents. Weaver et al. showed that high levels of maternal care in early life are linked to serotonin signaling in the rat hippocampus with an increase in expression of the transcription factor nerve growth factorinduced protein A (NGFI-A). This is the transcription factor that binds to the I7 promoter of the rat GR gene, increasing its expression. Binding of NGFI-A leads to a decrease in methylation of the promoter with subsequent higher transcription factor binding and increased GR expression (Sun, Kennedy & Nestler, 2013). Recently, collaborative effects of increased expression and GR promoter binding of the methyl-CpG-binding domain protein 2 (MBD2) and NGF1-A activation by maternal care have been implicated in this demethylation (Sun, Kennedy & Nestler, 2013).

From a Short-Term Stress-Induced Imbalance to Long-Lasting Dysregulation and Disease

An altered mRNA transcription following exposure to environmental impact can be seen as a short-term compensatory reaction of the organism to maintain homeostasis and to overcome the environmental impact (Klengel & Binder, 2015). These immediate responses at the transcriptional level do not inevitably lead to long-lasting epigenetic changes. The longterm epigenetic changes in response to a qualifying environmental stressor require a sequence of short-term immediate molecular responses leading to long-lasting epigenetic adjustments. An example for such concerted changes is the modification of the rodent arginine vasopressin (avp) promoter in response to maternal separation (Trump et al., 2016). Directly after a 10-day maternal separation period at postnatal day 10, the transcriptional activation of AVP is detectable with changes in phosphorylation of MeCP2 and protein occupancy but without changes in the DNA methylation. At this time point, the epigenetic memory has not been formed, and it is an intriguing question to ask if an early intervention e.g., by compensatory high maternal care, could prevent the transition from short-term MeCP2 phosphorylation to DNA methylation changes (Trump et al., 2016). The long-lasting epigenetic changes are established in a subsequent step, engraving the short-term transcriptional change by creating a long-lasting epigenetic memory by a reduced DNA methylation at the avp enhancer site for MeCP2 in the paraventricular nucleus of the hypothalamus (PVN) of early-life-stress-exposed mice. These data suggest that the immediate response via phosphorylation of MeCP2 is subsequently replaced by DNA methylation changes that persist over time (Trump et al., 2016). This example highlights that an understanding of factors leading to long-lasting modifications might help in improving our abilities to prevent and treat stress-related disorders.

Epigenetics and depression: development vulnerability

It is well established that adults who experienced childhood stress or maltreatment are at a significantly greater lifetime risk for a range of mood or other disorders. It is well established that adults who experienced childhood stress or maltreatment are at a significantly greater lifetime risk for a range of mood or other disorders (Skinner, 2014).

Histone modifications

Very little is known about the prenatal effects of stress on histone modifications. Treatment with the nonspecific HDAC inhibitor valproic acid, which has many additional pharmacological actions, after prenatal stress was shown to ameliorate several behavioral measures (), although more work is needed to elucidate the mechanisms responsible for these effects. More is known concerning the consequences of postnatal adversity in the form of maternal separation. In stress-susceptible BALB/C mice, MS reduces levels ofHdac1, -3, -7, -8, and -10 in the forebrain in adulthoods, and increases acetylation of histone H4 (Skinner, 2014). Adult male rats that underwent maternal separation had reduced levels of Hdac1mRNA, consistent with the elevated H3 and H4 acetylation levels reported in the HPC of juvenile mice after maternal separation (Yamawaki et al., 2012). Adolescent fluoxetine treatment potentiated effects of maternal separation, but coadministration of fluoxetine with an HDAC inhibitor ameliorated the effects of maternal separation (Covington et al., 2011). These findings suggest that adolescence may be a relevant period for pharmacological intervention and that it may be possible to erase at least some of the damaging epigenetic signature of early-life stress. Similarly, low maternal LG is associated with decreased HPC H3K9 acetylation at the glucocorticoid receptor (Gr) exon 1₇promoter. These modifications are associated with the expression of depressive-like symptoms, reduced gene expression, and changes in DNA methylation spanning large regions of the genome (Skinner, 2014). Treatment with the nonselective HDAC inhibitor trichostatin A, infused either intracerebroventricularly (ICV) or intra HPC, reversed both the molecular and behavioral effects of low maternal care.

DNA methylation

Under normal conditions, the developing fetus is largely protected from maternal glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which converts active glucocorticoids to their inactive form. However, 10% to 20% of maternal Cortisol is estimated to pass through the placenta to the fetus (Covington et al., 2011). Evidence suggests that maternal stress during pregnancy induces a hypermethylation of Hsd11b2 in the placenta and hypomethylation in the fetal hypothalamus that may consequently interfere with 11β-HSD2 enzymatic activity (Yamawaki et al., 2012) and induce heightened stress responses among offspring. Mice exposed to prenatal stress had elevated levels of Dnmt3aand Dnmt1 mRNA in the PFC and HPC at birth, changes that persisted at postnatal day 7, 14, and 60 (Skinner, 2014). Furthermore, prenatal stress increased binding of DNMTl and MECP2, along with increased 5-methylcytosine and 5-hydroxymethylcytosine, within theReelin and Gad67 promoters. Thus, existing evidence points to a role of prenatal stress in altering adult vulnerability to depression, in part via changes in DNA methylation. These alterations occur in specific genes and in specific brain regions, highlighting the difficulty in using peripheral tissues to predict functionally relevant changes within the brain.

Postnatal experience, particularly variations in the level and quality of maternal care, alters DNA methylation levels in genes thought to be critically involved in behavioral stress responses. For instance, the offspring of low-LG mothers, compared with those reared by high-LG mothers, exhibit robust DNA methylation changes that colocalized with chromatin modifications (Covington et al., 2011). This coincides with lower HPC expression of several variants of Gr,including the HPC specific variant 17 (Yamawaki et al., 2012). These alterations preferentially affect promoters, as evidenced in the cluster of protocadherin genes, and follow a nonrandom, discontinuous pattern across large genomic regions. Similar alterations have been reported in the HPC of suicide completers with a history of child abuse. Individuals with a history of abuse who committed suicide exhibit lower expression levels of the 1_B, 1_C, and 1_F variants of Gr compared with nonabused suicides and controls (Covington et al., 2011). These changes coincide with altered DNA methylation within respective promoters that may interfere with transcription factor binding. Furthermore, similar alterations within Gr positively correlate with different features of child abuse in individuals with major depressive disorders. Stress also alters epigenetic marks beyond the early neonatal period. Three weeks of adolescent isolation induced depressive-like behaviors accompanied by a sustained (12 weeks) hypermethylation of the tyrosine hydroxylase (Th) gene promoter in the VTA of aDisc1 mutant mouse. Promoter hypermethylation was associated with both Disc1 mutations and adolescent isolation, and these effects were additive, although only in specific cell populations (Hollis et al., 2011).

The impact of abuse becomes obvious when assessing the gene functions enriched with differential methylation: differential methylation in the abused suicide group is enriched in genes related to cellular plasticity, while learning and memory genes were particularly affected in suicide. This suggests that among depressed suicide completers, intense early-life adversity might induce distinct longlasting epigenetic alterations. 

Epigenetic Effects of Stress during Adulthood

The hippocampus shows high expression levels for a large number of epigenetic enzymes, so it is unsurprising that both stress and memory formation have been shown to utilize epigenetic mechanisms at the level of the hippocampus. Fear conditioning is associated with a variety of short and long-term epigenetic changes. (Yamawaki et al., 2012) showed that fear conditioning causes increased expression of the DNA methyltransferases DNMT3A and DNMT3B and that the inhibition of these enzymes impaired the consolidation of fear memories (Hollis et al., 2011). Further, they found that fear conditioning altered DNA methylation on the reelin and PP1 genes, both of which have an influence on memory in other models (Razzoli et al., 2011), as well as methylation of the BDNF gene (Hollis et al., 2011). PP1 is notable in that one of its activities seems to be removing phosphorylations from histone H3 at serine 10, and that this seems to be the basis for its role in long-term memory (Hollis et al., 2011). A subsequent study established that HDAC2 was the major neuronal class I HDAC and the HDAC responsible for modulating memory and synaptic plasticity, via a surprisingly select number of genes, including glutamate receptor subunits and BDNF. These findings provide the outlines of a complex set of interactions between memory, stress, or fear, a number of different epigenetic actors and long-term plasticity of the brain and behavior.

With regard to explicit examinations of the effects of stress upon epigenetic modifications in the brain one of the earliest findings found that forced swim stress produced a significant increase in phospho-acetylation of Histone H3, at serine 10 and lysine 14 (H3S10p-K14ac) respectively, in the dentate gyrus of the hippocampal formation (Hollis et al., 2011). This combination of histone marks is associated with a transcriptionally active chromatin state. His initial finding established that a similar induction was produced by novelty stress and the phenomenon was N-Methyl-D-aspartate (NMDA) receptor dependent and associated with c-Fos induction in the same cells, which showed the H3S10p-K14ac signal. Voluntary exercise, which is typically protective against the negative sequelae of stress, actually increases the levels of H3S10p-K14ac after both novelty and swim stress, suggesting that this may be part of an adaptive stress response rather than a pathological one.

Social defeat stress, which represents one of the stronger models of human depression in terms of ethological and face validity (Razzoli et al., 2011), has a clear epigenetic component. Razzoli et al., ( 2011) found that chronic social defeat profoundly increased the levels of the repressive histone mark H3 lysine 27 dimethyl at promoter regions of the BDNF gene, while treatment with antidepressants produced and increase in activating marks such as histone H3 acetylation and histone H3 lysine four dimethylation (Tsankova et al., 2004, 2006). Subsequent studies found associations between chronic cocaine and social stress and HDAC5 (Renthal et al., 2007), as well as an antidepressant effect of HDAC2 in the social defeat model.

In the study of Razzoli et al., (2011), it has been shown that Psychological stress during pregnancy increases the risk of childhood wheeze and asthma. Since epigenetic alterations have emerged as a link between perturbations in the prenatal environment and an increased disease risk we used whole genome bisulfite sequencing (WGBS) to analyze changes in DNA methylation in mothers and their children related to prenatal psychosocial stress and assessed its role in the development of wheeze in the child. The authors evaluated genomic regions altered in their methylation level due to maternal stress based of WGBS data of 10 mother-child-pairs. These data were complemented by longitudinal targeted methylation and transcriptional analyses in children from our prospective mother-child cohort LINA for whom maternal stress and wheezing information was available (n = 443). High maternal stress was associated with an increased risk for persistent wheezing in the child until the age of 5. Both mothers and children showed genome-wide alterations in DNA-methylation specifically in enhancer elements. Deregulated neuroendocrine and neurotransmitter receptor interactions were observed in stressed mothers and their children. In children but not in mothers, calcium- and Wnt-signaling required for lung maturation in the prenatal period were epigenetically deregulated and could be linked with wheezing later in children’s life.

The study aimed to review the recent advances in the field of epigenetics and its relation with stress and stress related diseases. Here, the study revealed similar findings from the articles selected for reviewing. All the studies showed relationship of the epigenetic modification with environmental stressors. Studies found the role of non-coding RNAs and histone proteins based on the epigenetic signaling and it has been found that stress and depressive signs can stimulate the histone and DNA methylation or acetylation. Hollis et al., (2011) found that the gene transcription modification in prenatal stage can have significant effect in adulthood.  One study showed the role of corticosteroid signaling in epigenetic modifications. On the other hand, 7 articles discussed about the role of histone modification as the significant effect of stress events. Several themes emerged from the previous studies, which have been reviewed further. The effect of pre and perinatal stress on epigenetic modificantions has also been evaluated (Chen, Ernst & Turecki, 2011).  3 studies showed the effect of exposure to Prenatal Stress and its implications for brain development and behavior in animal model. One study findings included therapeutic implications of epigenetic modifications inhibitors can successfully combat with stress related symptoms.

Chapter 5: Discussion and Conclusion

These studies suggest that the experience of stress, whether during early-life or adulthood, has profound, genome-wide epigenetic consequences in the brain and peripheral tissues. Modifications of DNA methylation signatures in different regions of the brain are a plausible mechanism to explain how stress can induce enduring behavioral alterations. Peripheral tissues may provide biomarkers of stress exposure and vulnerability, although this remains to be determined. 

Skinner (2014) found that a sleep deprivation stress caused significant changes in the expression of 10 miRNAs in the mouse brain, as seven of these did not change in adrenalectomized mice, it is probable they are regulated by corticosteroids (Gudsnuk and Champagne, 2012). While the relations of whole classes of ncRNA’s to stress and the stress axis remain to be explored, it can be said that ncRNA has a clear relation to the epigenetic tuning of the stress response and will likely provide a novel avenue to understanding stress and its associated pathologies.

Given that, the prenatal period is susceptible to external stimuli that can shape the epigenetic landscape and thereby determine disease susceptibility later in life. Gudsnuk and Champagne (2012) found that both mothers and children experienced genome-wide perturbations in DNA-methylation affecting genomic regulatory elements in particular enhancer elements. Although this preferential deregulation in DNA methylation has already been described in disease states especially in cancer, the results show that also changes in the prenatal environment can lead to perturbed enhancer methylation already at a time at which no disease phenotype has yet developed. Epigenetic perturbations in DNA methylation by stress are not random but rather preferentially occur in enhancer elements regulating more than one gene in the genome, which might contribute to the broad ramifications for children’s health attributed to maternal prenatal stress. Stressful life events have been widely related to changes in the cortisol mediated stress response. DNA methylation of NR3C1 (“glucocorticoid receptor”) as the key mediator of this response has been associated with different types of stressful life events. The study showed that the epigenetic modifications of Wnt-signaling affected the alveolar differentiation and alters the lung development (Gudsnuk and Champagne, 2012).

Alterations in epigenetics mechanism, such as DNA methylation, histone modification and microRNA expression could favor MDD advance in response to stressful experiences and environmental factors.

The animal models in this review demonstrated that long-term epigenetic impact of agonistic social experiences, whereas communal care and juvenile social enrichment improved the benefits of social contact. As is the case for maternal behavior, modulation of the impact of social experiences will likely depend on contextual factors, particularly factors that increase or decrease HPA responses. Thus, housing conditions within the laboratory and manipulations of those conditions during experimental protocols may induce molecular changes followed by a long-term impact on social and anxiety-like behaviors.

Studies presented in this review showed that stress-induced epigenetic changes can be reversed in adulthood using agents such as HDAC inhibitors or methyl group donors (Bagot et al., 2014). Functional effects of such treatment have been confirmed in studies on rodents and epigenetic drugs are already being developed (Hunter, 2012). Additionally, at least some of the epigenetic mechanisms active during stress are shared between rodents and humans, providing rationales for translatory potential. For example, perinatal epigenetic programming of GR expression seems to follow this logic, as the same changes were found in hippocampi of both postnatally stressed adult mice and human suicidal victims with history of child abuse (Gudsnuk & Champagne, 2012). Unfortunately, potential unspecific and undesirable effects of such systemic treatment seem troubling. Only through more comprehensive research of epigenetic mechanism we may be able to develop safe and effective epigenetic-based therapies.

The study of Klengel and Binder (2015) supports a role of ancestral stress in the epigenetic transgenerational inheritance of disease. Although direct stress exposure of adults can influence pathologies in the individual and offspring, the multigenerational versus transgenerational inheritance characteristics of the pathology need to be considered. A direct exposure generally affects somatic tissues that will be critical for the individual’s disease, but a transgenerational effect requires a transmission of epigenetic information by the germline. Often, as shown in the current study (Sun, Kennedy & Nestler, 2013), the transgenerational disease and pathology is distinct and/or has greater frequency than the direct exposure pathology

In conclusion, it can be said that the complex epigenetic regulatory orchestra is just beginning to be understood. The role of many of its components such as non-coding RNA, 5hmC, histone variants and the editing of nucleic acids is still largely unknown. Without recognition of the impact of temporal dynamics, cellular diversity and systemic approach, both intra- and inter-cellular or structural, the final picture of the pathway from experience to changes in gene expression and behavior may continue to be vague and elusive. The study findings has been explored the research aim and established the influence of stress and stress related diseases on epigenetic changes.

A variety of environmental factors promote the epigenetic transgenerational inheritance of disease. The observation that environmental stress can also promote transgenerational pathologies suggests ancestral stress conditions may be a significant factor in our own disease and what we pass down to our grandchildren. Several studies have considered the multigenerational impacts of stress on future generations, including World War 2 holocaust survivors’ offspring and traumatic stress generational effects in several African countries. The concept that ancestral stress, particularly during gestation, may influence disease etiology for generations to come is an important aspect to consider in regards to our environment and society. . Several studies now support the role of environmental stress in promoting the epigenetic transgenerational inheritance of disease. Observations suggest ancestral environmental stress may be a component of disease etiology in the current population. This is a novel concept that will need to be seriously considered in future health management and therapy.

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