Epigenetics of Stress and Stress Disorders

Epigenetics of Stress and Stress Disorders, a new volume in the Translational Epigenetics series, examines the epigenetic mechanisms involved in modifying DNA following prolonged stress or trauma. This is accomplished through the evaluation of both the physiological and molecular effects of stress on the body that can eventually lead to stress disorders. The book begins by providing a psychiatric, biological, and phenomenological foundation for understanding stress disorders, before delving into the genomics of stress disorders. From here, chapter authors discuss a range of recent epigenetic research in the area, highlighting epigenome-wide association studies (EWAS), exciting developments in noncoding RNA studies, possible effects of prolonged stress on telomere shortening, and the long-term physical effects of PTSD on the health of patients. The book also examines the effect of adversity during sensitive periods or development and across the life span. The book concludes by looking at possible transgenerational stress-induced epigenetic alterations on future offspring and important areas of research for public health, along with the potential for epigenetic therapeutics or “epidrugs.

• Examines the epigenetics of stress, trauma, and related stress disorders
• Connects new research to clinical practice and highlights implications for patient care, drug discovery, and public health
• Discusses the epigenetic effect of adversity across the life span, and transgenerational stress-induced epigenetic alterations
• Features chapter contributions from international experts in the field

• Language: English
• Publisher: Academic Press
• Release date: Feb 18, 2022
• ISBN: 9780128230626

Book preview

Chapter 1: The physiology of stress and the human body’s response to stress

Richard S. Lee, PhD    Department of Psychiatry and Behavioral Sciences, Mood Disorders Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract

Stress is an environmental factor that precipitates a potent physiological response involving the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. The modern society has posed unprecedented challenges for the human stress experience, as chronic stress exposure, which has become an integral part of societal living, has led to a maladaptive stress response that is associated with a host of diseases such as cardiovascular disease, diabetes, cancer susceptibility, and obesity, among many others. The brain is especially susceptible to the catabolic effects of stress and its glucocorticoid (GC) hormone cortisol, as prolonged exposure to stress or cortisol leads to the development of psychiatric disorders such as anxiety and depression. Chronic stress exacts its toll on behavior by altering the body’s homeostatic cortisol levels as well as the function of brain-specific genes, in part, by epigenetic mechanisms. This chapter will provide a foundational knowledge on the human stress response and the mediating factors that impair behavior.

Keywords

HPA axis; Sympathetic nervous system; Allostatic load; Epigenetics; Stress response

Acknowledgments

This work supported by the following foundations: Margaret Ann Price Investigator Fund, the James Wah Mood Disorders Scholar Fund via the Charles T. Bauer Foundation, Baker Foundation, and the Project Match Foundation.

Introduction

The term stress was first coined by Hans Selye in 1936 when it was used to define the non-specific response of the body to any demand for change.¹ Stress encompassed what had been known as the fight-or-flight response.² Until our very recent history, the stress response was largely needed and activated for brief bursts of energy for acts of survival of an organism such as evading predators, hunting prey, and securing mates, all of which are requisite survival traits for natural selection. However, the Industrial Revolution in the 18th and 19th centuries changed the human stress experience, the psychosocial remnants of which can still be observed in the very cities in which it started.³ What was finely tuned over eons to enable organisms to exercise competition in nature has become a physiological liability in the modern-day society. The system that had served our ancestors well in evading a lion or engaging in brief skirmishes with other tribes now had to contend with worrying about mortgage or spending hours in traffic; the stress response was not tuned for situations where the stressors became chronic. As a result, humans exposed to chronic stressors began to exhibit a host of ailments driven in part by stress and its associated hormones. Chronic stress exposure contributes to the burden of almost all chronic diseases in the United States, such as heart disease, cancer, stroke, diabetes, and obesity.⁴

This chapter will begin by examining stress as an environmental factor and how it is unique from other environmental factors such as exposures to infections or toxicants. The cascade of neuroendocrine responses to stress, starting from the experience of real or perceived stressors to the activation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis (HPA axis) that culminates in the release of the stress hormone cortisol, will be discussed. The chapter will also distinguish between acute and chronic stress response and the consequences of the latter on different organ systems with special emphasis on the brain, psychiatric disorders, and behavior. A framework for how chronic stress exposure impacts homeostatic cortisol levels will be proposed. Understanding such a framework necessitates a brief introduction to the molecular mechanisms of how cortisol can affect gene expression changes in the cell, where genetic and epigenetic mechanisms become indispensable. However, the molecular mechanisms of how stress exposure impacts gene function will be discussed in greater detail in another chapter. Instead, it is hoped that the readers will gain a foundational knowledge on stress response and some of the basic stress mechanisms to appreciate many of the detailed chapters in this book.

Stress as an environmental factor

Sometimes it may take an observer a moment of pause before considering stress as an environmental factor. That is because triggering the stress response may not require that a person be directly exposed to or ingest some physical substance. For instance, it is well established that environmental toxicants such as lead wield a pernicious effect on neurodevelopment when exposed even at low quantities.⁵ Likewise, ionizing radiation, such as those emitted by X-ray machines or a nuclear power plant, causes double stranded breaks in DNA.⁶ However, one can be sitting perfectly still in his car stuck in traffic on the 495 Beltway in DC and yet, his stress hormone level is through the roof. Other than the DC pollution seeping through the car’s ventilation system, no external chemical or physical factor has entered the person to precipitate the stress response. The mere perception or thought of nonimmediate events can trigger a stress response. Stress can also be highly subjective. For instance, the stressful experience of solving mathematical problems in front of a group of people, such as those administered during the Trier Social Stress Test,⁷ may not be challenging to calculus teachers who routinely perform these tasks in front of dozens of students. Even when a person is physically attacked, the stress response is not due to the sustained physical damage, but rather the person’s awareness of the possibility of harm. Yet, the impact of stress can be just as detrimental to the body as many real, physical environmental factors.

Stress is considered an environmental factor because stressors, which can be situational, mental, or physical in nature, are external and can lead to powerful physiological responses in the human body even without any physical contact. In other words, stressors, whether real or perceived, are a consequence of our interactions with the environment even if they only manifest themselves as mere thoughts in the minds of the stressee. In contrast, the response to these external stressors is almost always internal and may require no direct, physical contribution from the environment.

The basics of the stress response

What happens when the stress response is provoked? Once stress has been perceived by the brain, actions of the amygdala, the fear center of the brain, and the hypothalamus activate the sympathetic nervous system that in a matter of seconds lead to the release of cortisol, adrenaline (epinephrine), and noradrenaline (norepinephrine) from the adrenal glands. These actions then activate the HPA axis and involve a cascade of neuroendocrine hormones that culminates in the additional release of the stress hormone cortisol. First, the paraventricular nuclei or PVN, a small subpopulation of neurons in the hypothalamus, release the corticotropin releasing hormone or factor (CRH or CRF), and the release activity is dependent on the anticipation of the outcome.⁸ CRH released from the PVN travels downward to the anterior pituitary via the hypophyseal transport system of capillaries that connect the two structures.⁹ Activation of CRH receptors (CRHR1) on the anterior pituitary promotes the release of adrenocorticotropic hormones (ACTH) that are released into the blood circulation.¹⁰ ACTH reaching the adrenal glands binds and activates the melanocortin receptor type 2 (MC2R)¹¹ that finally leads to the release of cortisol into the bloodstream. Collectively, as mentioned, these three endocrine tissues make up the HPA axis responsible for mounting the stress response and releasing cortisol. While secondary to the sympathetic nervous system in terms of time for activation (minutes vs seconds),¹² the HPA axis plays a more prominent role in chronic diseases due to the prolonged availability of cortisol in the bloodstream, although there is evidence to suggest that both the sympathetic nervous system and the HPA axis are interconnected and contribute to the impact of stress exposure on the body.¹³

There are additional factors that are released at the same time as cortisol and constitute a part of the stress response. Additional factors that are integral to the stress response are pro-inflammatory cytokines such as IL-1B and IL-6 that provoke the immune system¹⁴, ¹⁵ and hormones such as prolactin and testosterone.¹⁶, ¹⁷ Release of these types of cytokines may seem counterintuitive given the immune-suppressive nature of cortisol. However, chronic exposure to stress has a prolonged suppressing effect on the immune system, as steroid medications or derivatives of cortisol such as dexamethasone or prednisone are used to treat autoimmune diseases such as rheumatoid arthritis or asthma, or recently the inflammatory cytokine storm associated with COVID-19.¹⁸

Sympathetic and parasympathetic systems

Together, the endocrine factors elicit a specific set of physiological response in the human body. It is entirely geared toward the expenditure of energy in the form of glucose for mounting the fight or flight response. The activation of the stress response mediated by the sympathetic nervous system and the HPA axis involves the immediate increase in heart rate, blood pressure, and glucose release aimed toward providing energy to the muscles. Alertness and vigilance are also increased.¹⁹ In the animal kingdom, the gazelle is able to outmaneuver the charging cheetah, or the male walrus bull is able to overpower another challenger to his harem. A human equivalent may be giving a presentation at a board meeting or running to catch a train. In all of these instances of stress response activation, the stressors are acute for the most part and the body returns to its prestress, homeostatic baseline following the resolution of the conflict.

It is important to note that the stress response that has evolved throughout evolution has been honed mostly as a transient response. Mobilization of energy to tackle what for most of the animals is life-and-death situations is relatively short in duration and comes at a great cost. During this period, activities of several important bodily functions become marginalized in terms of priority. Processes involved in storing away energy, fighting infections, digesting food, and engaging in reproductive transactions come to a halt.²⁰ These are reasonable short-term inconveniences given that a failure to mount an effective fight or flight response to survive predation renders these otherwise essential endeavors moot. However, once the stressor has subsided, the system must return to normal for the animal to continue its life. Therefore the body has also developed a rapid negative feedback system to quickly restore the body to the baseline state. The parasympathetic nervous system is engaged to achieve homeostasis.²¹ Importantly, increased levels of cortisol in the bloodstream, in addition to its primary role of making glucose available, initiate the suppression of CRH and ACTH release from their respective tissues, ultimately causing the attenuation of additional cortisol release. The acute release of stress hormones and the repertoire of coping behavior that they facilitate are ideally suited for the animal kingdom and many instances in the human experience where the stressors are sporadic and brief in nature.

An argument could be made that acute stressors are beneficial for the most part, so long as the organism does not sustain physical harm. For animals avoiding predation and competing for food and mates, stressors provide the means by which their genetic fitness could be tested. Having succeeded through the stressors meant not only the continued opportunities for propagation, but increased fitness and probability to survive the next stressor. The increase in fitness included better physiological response through stronger muscles and cardiovascular system as well as the increases in mental acuity and learned response. In humans, similar adaptive response is also in play, as exposure to acute stressors and transient activation of the sympathetic nervous system is beneficial to physical fitness and mental acuity. One such example is vigorous physical exercise. Exercise can be seen as an acute stressor that causes the release of cortisol and adrenaline for the purpose of predefined energy expenditure.²² Its benefits are many, from prevention of cardiovascular disease, diabetes, obesity, and others that are associated, interestingly, with chronic stress exposure. In particular, regular intermittent exercise can also prevent neurological disorders such as Alzheimer’s disease²³, ²⁴ and the amelioration of psychiatric disorders such as anxiety and depression.²⁵, ²⁶ Unfortunately, as we will see, the development of the modern society and the resulting social infrastructure has created an environment where the stressors are long lasting and recurrent. Such an environment has led to a prolonged activation of the HPA axis with detrimental physiological consequences, especially to the brain.

Allostasis and allostatic load

Prolonged HPA axis activation due to chronic stress exposure is not unique to humans but is an integral part of the human experience in the 21st century. The workweek for some translates to more than 60 h/week to meet deadlines. There is a family to support and mortgage and car payments to make. There are many anxiogenic social events on a daily basis, whether they be from the supervisor, a spouse, or the elected leadership. There is also a pandemic that has greatly diminished the (positive) physical social interactions that are needed for wellbeing. In fact, prolonged social isolation is a potent stressor that also activates the HPA axis and has been used in animals to study various symptoms of depression such as anhedonia, learned helplessness, and cognitive deficits.²⁷–³¹ All of these stressors contribute to the overburdening of the HPA axis and cause deleterious symptoms in multiple organ systems.

Here, we introduce the term allostasis and allostatic load to describe the body’s maladaptive response to chronic stress. Allostasis refers to the ability and desire of the body to return to homeostasis following stress exposure.³² As mentioned before, the actions of the sympathetic nervous system, the HPA axis, and their hormones cortisol and adrenaline to mount a stress response and the negative feedback system involving cortisol and the parasympathetic nervous system altogether constitute an adaptive response designed to reestablish homeostasis once the stressor has passed. Unfortunately, many man-made events and circumstances have created environments where allostasis cannot be rapidly achieved. Repeated and/or prolonged stressful events impact the HPA axis by flooding the bloodstream with cortisol and adrenaline. The negative feedback system and the parasympathetic nervous system become impaired, and hypercortisolemia continues to wreak havoc on different organ systems. The term allostatic load was first coined by McEwen and Stellar in 1993 and refers to the degree to which the amount of wear and tear or disease burden that chronic stress has exacted on the body.³³ In instances of acute stress, allostatic load is minimal. However, with allostasis being overburdened by chronic or repetitive stress, the allostatic load becomes substantial and the overall stress response becomes maladaptive.

Allostatic load and disease burden

The sequelae of increased allostatic load are many and serve as a testament to the pernicious effects of chronic stress. Many of the symptoms logically follow the long-term effects of the adaptive response in terms of energy utilization and marginalization of processes that are secondary to immediate survival. For instance, increased risk to cardiovascular disease, hypertension, and diabetes makes intuitive sense, since acute stressors cause increased heart rate, blood pressure, and hyperglycemia, respectively.³⁴, ³⁵ Also, impaired fertility, disruptions in GI function, and susceptibility to infections are likely to be long-term manifestations of noncritical processes that have become marginalized during the fight or flight response.³⁶–³⁸ In contrast, there are some that may be counterintuitive such as obesity, since acute stressors favor energy utilization rather than storage.³⁹ Regardless, it is important to note that stress exposure plays such a significant role in the development of diseases that occupy such prominent positions in terms of disease burden and prevalence in the United States.⁴ It would be of critical importance to be able to empirically assess the extent to which chronic stress exposure contributes to these diseases.

Great effort has been made to operationalize the concept of allostatic load in terms of physiological parameters that can be measured. The MacArthur Successful Aging Study concluded that the major determinants of allostatic load include systolic and diastolic blood pressure, waist hip ratio, LDL cholesterol, HbA1C, DHEA-S, norepinephrine, epinephrine, and the glucocorticoid cortisol.⁴⁰ Although many of these measurements also have nonstress-related causes, they are nonetheless important assessments for estimating the cumulative wear and tear on the body and can be recapitulated in a myriad of animal models of stress that have excluded other contributing factors such as high-fat diet.⁴¹–⁴⁴ The contribution of chronic stress to any particular disease cannot be accurately assessed in humans due to the difficulty of controlling for genetic diversity, food intake, environmental exposures, and behavior as one can when using animal models. Instead, human studies must involve large swaths of the population, and these confounding factors have to be controlled for by statistics.

The potential role for allostatic load in the human population can be best exemplified by the two Whitehall studies of British civil servants. The first study examined 17,530 male civil servants and observed that the grade of employment was a stronger predictor for coronary heart disease (CHD) mortality than any other major coronary risk factors.⁴⁵ The second Whitehall study was longitudinal and prospective in design and examined 10,314 participants that included both male and female civil servants.⁴⁶ In addition to replicating the inverse correlation between grade level and CHD mortality of the first study, the second study also focused on psychosocial factors such as stressful work environment, lack of social support, and financial difficulties, all of which were also inversely correlated with the employment grade. While there is no universally accepted causal factor(s) for these relationships, it is widely believed that chronic psychosocial stress (or job strain) likely played a prominent role given its contribution to CHD and other metabolic diseases.⁴⁷, ⁴⁸

Allostatic load and the brain

One of the organs associated with chronic stress exposure not mentioned before (but of primary focus in this book) is the brain. As mentioned previously, acute stress, for the most part, can be beneficial to multiple organ systems, and the brain is no exception. Exposure to acute stress is associated with enhanced short-term memory and memory consolidation.⁴⁹, ⁵⁰ These benefits are further supported by increased neurogenesis and neuroprotection following exposure to acute stress.⁵¹–⁵³ Interestingly, a recent work using animal models of stress reported that acute stress inoculation can even increase resilience against future stressors.⁵⁴ In contrast, chronic stress exposure generally has the opposite effect and is associated with poor cognitive performance and memory.⁵⁵, ⁵⁶ In fact, one of the primary physiological response of the brain to chronic stress has been a reduction in the volume of the hippocampus that is associated with memory loss.⁵⁷–⁵⁹ Reduction of hippocampal volume is supported by animal models of stress, in which prolonged exposure to chronic stress is associated with suppression of neuronal proliferation, differentiation, and survival.⁶⁰–⁶² In addition, chronic stress exposure is associated with affective disorders such as depression and anxiety.⁶³, ⁶⁴ Another psychiatric disorder that arguably can be included is posttraumatic stress disorder (PTSD). Although the term trauma often implies a stressor of high magnitude and short duration, PTSD can be borne from stressful experiences that span years, such as combat duty or child abuse.⁶⁵, ⁶⁶

Cortisol as the primary driver of the chronic stress response

Of the several endocrine factors and cytokines that mediate the chronic stress response, the primary factor is cortisol. This is because adrenaline and noradrenaline are rapidly metabolized by the liver after several minutes.⁶⁷ On the other hand, cortisol has a longer half-life on the order of 1–2 h and as will be discussed shortly, can have a long-lasting effect on gene function.⁶⁸ Unlike adrenaline and noradrenaline that are derived from the amino acid tyrosine, cortisol is derived from cholesterol.⁶⁹ As such, it is a hydrophobic compound that readily crosses the plasma membrane. While water-soluble ligands bind to their corresponding receptors residing on the cell surface, receptors for cortisol reside in the cytoplasm. Two main receptors are the mineralocorticoid (MR) and glucocorticoid receptors (GR). Cortisol is preferentially bound to the MR at low concentrations but shifts its preference for the GR at higher concentrations.⁷⁰ For the remainder half of the chapter, there will be much more focus on cortisol as the primary hormone and the GR, as this receptor species mediates the intracellular signaling at elevated cortisol concentrations.

Cortisol is also one of many steroid hormones (corticosteroids) classified under the umbrella term glucocorticoids (GCs). Other glucocorticoids differ from cortisol from their route of administration, bioavailability, and potency among many attributes. For instance, hydrocortisone is available as an ointment for reducing swelling and inflammation on the skin, whereas prednisone is often prescribed as an inhalant for asthma. Dexamethasone is a synthetic derivative of cortisol generally used for its antiinflammatory and immunosuppressant properties that are up to 30 times more potent than the actions of cortisol.⁷¹

Glucocorticoids and the brain

The effect of GCs on the brain as part of its physiological response to chronic stress can be best appreciated by several important studies that highlight cortisol’s impact on psychiatric symptoms. The Whitehall Studies mentioned before reported significant association between depression and lower employment grade (i.e., psychosocial stress).⁷² Clinical studies of Cushing’s disease in which ACTH-secreting pituitary tumors cause the copious release of cortisol (hypercortisolemia) delineate a causal role of cortisol on psychiatric disorders. Cushing’s patients have a high incidence of depression and anxiety in 50%–80% of cases, both of which become alleviated following the resolution of hypercortisolemia with a surgical or biochemical cure.⁷³–⁷⁶ An even more powerful demonstration of the actions of GCs can be seen in a large epidemiological study involving hundreds of thousands of participants, in which significantly higher incidences (hazard ratios) of mania, depression, suicidal ideation, and panic disorder were observed in patients administered corticosteroids over nonsteroidal antiinflammatory drugs for nonpsychiatric, autoimmune-related diseases such as rheumatoid arthritis, lupus, and asthma.⁷⁷ These studies in humans are supported by hundreds of studies that have employed various chronic stress regimen or GC exposure in rodents to provoke a stress response. These rodent studies have not only examined stress-induced behavior under controlled conditions but have also investigated molecular changes in the brain that can potentially account for behavior.⁷⁸

Molecular mechanism of cortisol action

Up to this point, response to stress has been described in the context of neuroendocrine hormones and their outcomes on physiology. A stress response at the cellular level of GC/cortisol signaling necessarily follows a physiological response involving a systemic disruption of GC homeostasis. To better understand how the maladaptive stress response unfolds in the tissues, especially the brain, a molecular understanding of cortisol action on cells is needed. Since the granular detail of cortisol action will be discussed elsewhere, only a summary will be provided to help the readers gain a glimpse of the overall framework. In the chronically stressed state, cortisol has the capacity to reprogram cellular function by genomic and nongenomic mechanisms in the cell.

The basic GC signaling involves the binding of cortisol to the GR and its dissociation from a complex of chaperone proteins that aids in the proper folding of proteins under challenging conditions such as elevated heat and oxidative stress.⁷⁹, ⁸⁰ Some of these proteins include heat shock proteins 70 and 90,⁸¹ as well as a protein called FKBP5 (or FK506-binding protein 5) that plays a crucial role in regulating GC signaling.⁸² Once dissociated from this complex, cortisol-bound GR homodimerizes with other GR proteins and interacts with structural and motor proteins that facilitate its entry into the nucleus.⁸³, ⁸⁴ Once in the nucleus, the GR dimer acts as either a transcription factor or repressor where its DNA binding domain binds DNA sequences called GC response elements (GREs) and facilitates either transcription or suppression by recruiting appropriate cofactors to the gene promoter.⁸⁵, ⁸⁶ Interestingly, the dual function of the GR as both receptor and transcription factor is a unique feature of nuclear receptor hormone signaling that also extends to other sex steroid hormones such as estrogen, androgen, and progesterone.⁸⁷ Genomic effects of GC signaling in the cell affects a common set of GC target genes across all cell types as well as those specific to each tissue for exacting a well-defined physiological response that likely contributes to the different organ diseases associated with chronic stress exposure.⁸⁸ It is also worthwhile to note that the activated glucocorticoid receptor has additional functions in the cell that involves nongenomic effects such as protein modifications and protein interactions.⁸⁹ However, it is unclear how different stress conditions, i.e., chronic vs acute, affect protein interactions and lead to chronic disease conditions. The differential response between chronic vs. acute stress exposure has been better understood in the context of genomic effects of GC signaling that has an impact on systemic cortisol dynamics and cell-specific function through epigenetic mechanisms.

Intracellular negative feedback and glucocorticoid resistance

In addition to the negative feedback system that exists at the HPA axis tissue level, there is also an additional feedback control at the intracellular level. While the tissues of the HPA axis seek to attenuate further cortisol release from the adrenal glands, proteins seek to limit intracellular signaling mediated by chronically elevated cortisol. One of the target genes that are immediately transcribed by GC signaling is the FKBP5 gene (gene: FKBP5 and protein: FKBP5).⁹⁰ Other than its potential involvement in the suppression of the immune system by cortisol,⁹¹ the FKBP5 protein functions to suppress intracellular GC signaling by binding closely to the GR and preventing its activation by cortisol.⁸⁴, ⁹² Consequently, the inability of the GR to utilize the available cortisol leads to a buildup of cortisol outside of cells (hypercortisolemia) and a condition called glucocorticoid resistance, where the cells become less sensitive to high levels of cortisol. In fact, cross-species molecular analysis of FKBP5 showed hypercortisolemia and glucocorticoid resistance observed in New World monkeys is due to the overexpression of FKBP5 and the increased affinity of the monkey FKBP5 protein for the GR complex compared to that of the human protein.⁹³, ⁹⁴

Another protein that can limit excess cortisol signaling is GR itself.⁹⁵ In fact, studies have shown that GC signaling via GR can suppress the NR3C1 gene (Nuclear Receptor Subfamily 3 Group C Member 1 that encodes the GR) by binding negative GREs within an intron of NR3C1 and promoting its suppression.⁹⁶ This second negative feedback is a more obvious mechanism that directly limits the level of the GR protein involved in binding cortisol and mediating its effects on transcription. The transcriptional regulation of FKBP5 and NR3C1 occurs in both instances of acute and chronic stress exposure. However, the development of GC resistance is specific to chronic stress exposure where dynamic changes in gene function occur from prolonged cortisol action or in individuals with genetic variations in NR3C1 that impair GC signaling.⁹⁷–⁹⁹ To gain an insight into how chronic stress exposure leads to long-term changes in gene function, a basic understanding of epigenetic mechanisms is needed.

Epigenetics

A mechanistic insight of how GCs affect gene function through epigenetic modifications is integral to our understanding of our body’s physiological response to stress. As the name suggests, epigenetics refers to modifications on DNA, modifications on histones, or cylindrical proteins around which genomic DNA is wrapped, and noncoding RNA species that affect transcription or translation of target genes. These epigenetic factors can influence gene function without involving any changes in the underlying DNA sequence. Modifications on DNA and histones work by either structurally restricting or facilitating the access of transcription factors to DNA. Noncoding RNAs can be small RNA species such as microRNAs, which are ~  22 nucleotides (nts) or bases long and impair translation of mRNAs by sequence-specifically binding to their 3′-untranslated regions.¹⁰⁰, ¹⁰¹ There are also long noncoding RNAs defined as >  200 nts and can be as long as 17 kilobases in the case of the X-inactive specific transcript (Xist) for silencing one of the two X chromosomes in females.¹⁰² Recent studies have identified yet a fourth candidate epigenetic mechanism in the form of covalent modifications on RNA that influence its stability in an emerging field called epitranscriptomics.¹⁰³, ¹⁰⁴ Importantly, there is functional crosstalk among the different epigenetic mechanisms to influence gene function. For example, methylated DNA promotes the binding of transcriptional repressors such as MeCP2 that alters DNA accessibility by recruiting histone-modifying enzymes.¹⁰⁵, ¹⁰⁶

There are many biological processes that depend on epigenetic mechanisms, such as cell differentiation, X-inactivation, and genomic imprinting among many others.¹⁰⁷–¹⁰⁹ Epigenetic mechanisms become especially relevant for understanding the physiological impact of environmental factors. Here, exposure to an environmental stressor, i.e., chronic exposure to psychosocial stress or GCs, leads to elevated levels of cortisol (or GCs) inside the body that begins to alter the functions of genes, tissues, and organs through, in part, epigenetic mechanisms (Fig. 1.1). In fact, epigenetic mechanisms have been shown to play a role in modulating GC-induced changes in gene expression.¹¹⁰ They are important in GC signaling, because they, along with altered GC homeostasis (see later), genetic risk, and nongenomic protein modifications (e.g., protein kinase and phosphatase activity), provide the means to transduce environmental exposure or stimuli into persistent changes in gene function. It is important to note that acute stress or GC exposure generally does not cause persistent epigenetic changes on a given genomic locus, since the degree of epigenetic change is dependent on dose (duration and/or magnitude) of exposure.¹¹¹, ¹¹²

Fig. 1.1

Fig. 1.1 Physiological response to chronic stress and glucocorticoid (GC) exposure. Top: Sources of cortisol or GC exposure can be environmental or iatrogenic, such as through steroidal medications for the treatment of asthma, rheumatoid arthritis, or lupus. Middle: Chronically elevated GC levels lead to several endocrine and molecular consequences. One of these consequences is impaired negative feedback of the HPA axis and altered systemic GC homeostasis. At the cellular level, excess GC signaling alters gene function through interactions with genetic variations (genetic risk) and by epigenetic mechanisms. Nongenomic mechanisms such as protein modifications may also be involved. Alterations in gene function can further influence homeostatic GC levels and tissue-specific processes. Bottom: Disruption of normal tissue-specific processes by GCs contributes to diseases and symptoms across multiple organ systems.

One of the more widely studied epigenetic mechanisms in GC signaling is DNA methylation. Studies have shown changes in DNA methylation in intronic regions of the FKBP5 and NR3C1 (both of which are two primary drivers of GC signaling and resistance) that coincide with GREs.¹¹³, ¹¹⁴ In other words, binding of GR to its response element (GRE) facilitates methylation changes to nearby DNA. Several studies of these genes in humans, cell lines, and animal models have also demonstrated that these epigenetic changes in response to stress or GC exposure are persistent, especially in the brain and through periods of no additional exposure to stress or GCs.¹¹³, ¹¹⁵–¹¹⁷, How these epigenetic changes affect gene function is a priming of target genes for a more robust activation or suppression of expression by GR when the cells are exposed again.¹¹⁸, ¹¹⁹ In the case of FKBP5 and NR3C1, a secondary exposure to stress or GCs would expedite the onset of GC resistance by attenuating GC signaling and the accessibility of the GR homodimers to the GREs. The epigenetic damage by the initial exposure is consistent with the long-lasting effect of stressful events such as the impact of child abuse on adult psychopathologies.¹²⁰

Effect of chronic stress on systemic cortisol dynamics

In addition to the stress- or GC-induced epigenetic dysregulation of FKBP5 and NR3C1, other important genes include CRH (or CRF) and ACTH (also known as POMC).¹²¹, ¹²² There are likely to be additional genes that undergo epigenetic modifications following stress exposure, such as those that encode receptors for these hormones.¹²³ Collectively, epigenetic changes at these genes that are essential for HPA axis function, GC signaling, and homeostatic cortisol levels likely contribute to hypercortisolemia and glucocorticoid resistance.¹²⁴ However, it is important to note that it is not clearly known as to how each of these genes and their epigenetic regulation affect homeostatic cortisol levels.

Effect of chronic stress on neurotransmitter function and behavior

Similar to epigenetic changes that occur in genes that regulate GC signaling, there are many genes in the brain that are important for neurodevelopment and neurotransmission and are regulated by GC signaling. The brain is highly susceptible to the effects of stress, and many regions and circuits are impacted.¹²⁵ Brain-specific genes such as that encoding the brain-derived neurotrophic factor (BDNF) have been studied extensively in behavior and neurodevelopment.¹²⁶, ¹²⁷ The BDNF gene is regulated by the binding of GR to its intronic negative GRE or nGRE.¹²⁸ Other genes include tyrosine hydroxylase (TH) that is involved in the synthesis of dopamine,¹²⁹ tryptophan hydroxylase that is involved in the synthesis of serotonin,¹³⁰ and monoamine oxidase A (MAOA) that is involved in the metabolism of serotonin, dopamine, and adrenaline.¹³¹ Additional genes that are regulated by GCs include genes whose proteins are involved in the transport and binding of serotonin such as 5-HTT (or SLC6A4)¹³² and 5-HT2C,¹³³ respectively. GC-induced epigenetic regulation of these genes is likely to affect psychiatric symptoms given that MAOA and 5-HTT are often targeted by antidepressants such as MAO inhibitors (MAOIs) or selective serotonin reuptake inhibitors (SSRIs). Dysregulation of these genes may occur due to prolonged GC exposure alone or in conjunction with the disruption of GC signaling following altered cortisol dynamics.

Conclusion

In this chapter, we sought to explain the physiological response to stress starting from the perception of stress to the activation of the sympathetic nervous system and the HPA axis, all of which culminate in the release of the glucocorticoid cortisol. The physiological response to chronic stress or GC exposure that can manifest itself as diseases of metabolism, cardiovascular system, and the brain are mediated, in part, by epigenetic and transcriptional changes in gene function exacted by GC action via the GR. These target genes of GC signaling include those that undergo epigenetic modifications to alter systemic cortisol dynamics as well as those that are tissue-specific and affect vital processes in different tissues and organs. There is a great deal of effort to understand the gap in knowledge between our response to stress and how stress precipitates psychiatric behaviors, and it is a fertile ground of investigation that will bring together the fields of genetics, epigenetics, psychiatry, and neuroscience.

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