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3.3: Epigenetics

  • Page ID
    217170
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    Learning Objectives
    • Explain what the term epigenetics means and the molecular machinery involved.
    • Name and discuss important neural and developmental pathways that are regulated by epigenetic factors, and provide examples of epigenetic effects on personality traits and cognitive behavior.
    • Understand how misregulation of epigenetic mechanisms can lead to disease states, and be able to discuss examples.
    • Recognize how epigenetic machinery can be targets for therapeutic agents, and discuss examples.

    Overview

    Early life experiences exert a profound and long-lasting influence on physical and mental health throughout life. The efforts to identify the primary causes of this have significantly benefited from studies of the epigenome—a dynamic layer of information associated with DNA that differs between individuals and can be altered through various experiences and environments. The epigenome has been heralded as a key “missing piece” of the puzzle for understanding how development of psychological disorders may be influenced by the surrounding environment, in concordance with the genome. Understanding the mechanisms involved in the initiation, maintenance, and heritability of epigenetic states is thus an important aspect of research in current biology, particularly in the study of learning and memory, emotion, and social behavior in humans. Moreover, epigenetics in psychology provides a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behavior, cognition, personality, and mental health. In this section, we survey recent developments revealing epigenetic aspects of mental health and review some of the challenges of epigenetic approaches in psychology to help explain how nurture shapes nature.

    Epigenetics

    A strand of DNA
    Figure \(\PageIndex{1}\): DNA stands for Deoxyribonucleic Acid, and although each person’s DNA is unique to that individual, it is 99.9% similar to every other human on the planet. [Image: CC0 Public Domain, https://goo.gl/m25gce]

    Early childhood is not only a period of physical growth; it is also a time of mental development related to changes in the anatomy, physiology, and chemistry of the nervous system that influence mental health throughout life. Cognitive abilities associated with learning and memory, reasoning, problem solving, and developing relationships continue to emerge during childhood. Brain development is more rapid during this critical or sensitive period than at any other, with more than 700 neural connections created each second. Herein, complex gene–environment interactions serve to increase the number of possible contacts between neurons, as they hone their adult synaptic properties and excitability. Many weak connections form to different neuronal targets; subsequently, they undergo remodeling in which most connections vanish and a few stable connections remain. These structural changes (or plasticity) may be crucial for the development of mature neural networks that support emotional, cognitive, and social behavior.

    The challenge for psychology has been to integrate findings from genetics and environmental (social, biological, chemical) factors into the study of personality and our understanding of the emergence of mental illness. These studies have demonstrated that common DNA sequence variation and rare mutations account for only a small fraction (1%–2%) of the total risk for inheritance of personality traits and mental disorders (Dick, Riley, & Kendler, 2010; Gershon, Alliey-Rodriguez, & Liu, 2011). Additionally, studies that have attempted to examine the mechanisms and conditions under which DNA sequence variation influences brain development and function have been confounded by complex cause-and-effect relationships (Petronis, 2010).

    Epigenetics has the potential to provide answers to these important questions. It refers to the transmission of observable characteristics (phenotype) in terms of gene expression in the absence of changes in DNA sequence (Waddington, 1942; Wolffe & Matzke, 1999). The advent of advanced techniques to study the distributions of regulators of gene expression throughout the genome led to the collective description of the “epigenome.” In contrast to the genome sequence, which is static and the same in almost all cells, the epigenome is highly dynamic, differing among cell types, tissues, and brain regions (Gregg et al., 2010). Recent studies have provided insights into epigenetic regulation of developmental pathways in response to a range of external environmental factors (Dolinoy, Weidman, & Jirtle, 2007). These environmental factors during early childhood and adolescence can cause changes in expression of genes conferring risk of mental health and chronic physical conditions. Thus, the examination of genetic–epigenetic–environment interactions from a developmental perspective may determine the nature of gene misregulation in psychological disorders.

    This module will provide an overview of the main components of the epigenome and review themes in recent epigenetic research that have relevance for psychology, to form the biological basis for the interplay between environmental signals and the genome in the regulation of individual differences in physiology, emotion, cognition, and behavior.

    Molecular control of gene expression: the dynamic epigenome24864920_1fe9b1a663_o.jpg

    Figure \(\PageIndex{2}\): Identical twins are the perfect example of epigenetics. Although they share exactly the same DNA, their unique experiences in life will cause some genes (and not others) to express themselves. This is why, over time, identical twins come to look and behave differently. [Caption: Valentina and Nina are 73 year old twins, both Doctors of Philology. They were dressed exactly the same, down to their shoes and hairdo, and they both voted. Image: M., https://goo.gl/VU5iJv, CC BY-NC-SA 2.0, https://goo.gl/Toc0ZF]

    Almost all the cells in our body are genetically identical, yet our body generates many different cell types, organized into different tissues and organs, and expresses different proteins. Within each type of mammalian cell, about 2 meters of genomic DNA is divided into nuclear chromosomes. Yet the nucleus of a human cell, which contains the chromosomes, is only about 2 μm in diameter. To achieve this 1,000,000-fold compaction, DNA is wrapped around a group of 8 proteins called histones. This combination of DNA and histone proteins forms a special structure called a “nucleosome,” the basic unit of chromatin, which represents a structural solution for maintaining and accessing the tightly compacted genome. These factors alter the likelihood that a gene will be expressed or silenced. Cellular functions such as gene expression, DNA replication, and the generation of specific cell types are therefore influenced by distinct patterns of chromatin structure, involving covalent modification of both histones (Kadonaga, 1998) and DNA (Razin, 1998).

    Importantly, epigenetic variation also emerges across the lifespan. For example, although identical twins share a common genotype and are genetically identical and epigenetically similar when they are young, as they age they become more dissimilar in their epigenetic patterns and often display behavioral, personality, or even physical differences, and have different risk levels for serious illness. Thus, understanding the structure of the nucleosome is key to understanding the precise and stable control of gene expression and regulation, providing a molecular interface between genes and environmentally induced changes in cellular activity.

    The primary epigenetic mark: DNA modification

    DNA methylation is the best-understood epigenetic modification influencing gene expression. DNA is composed of four types of naturally occurring nitrogenous bases: adenine (A), thymine (T), guanine (G), and cytosine (C). In mammalian genomes, DNA methylation occurs primarily at cytosine residues in the context of cytosines that are followed by guanines (CpG dinucleotides), to form 5-methylcytosine in a cell-specific pattern (Goll & Bestor, 2005; Law & Jacobsen, 2010; Suzuki & Bird, 2008). The enzymes that perform DNA methylation are called DNA methyltransferases (DNMTs), which catalyze the transfer of a methyl group to the cytosine (Adams, McKay, Craig, & Burdon, 1979). These enzymes are all expressed in the central nervous system and are dynamically regulated during development (Feng, Chang, Li, & Fan, 2005; Goto et al., 1994). The effect of DNA methylation on gene function varies depending on the period of development during which the methylation occurs and location of the methylated cytosine. Methylation of DNA in gene regulatory regions (promoter and enhancer regions) usually results in gene silencing and reduced gene expression (Ooi, O’Donnell, & Bestor, 2009; Suzuki & Bird, 2008; Sutter and Doerfler, 1980; Vardimon et al., 1982). This is a powerful regulatory mechanism that ensures that genes are expressed only when needed. Thus DNA methylation may broadly impact human brain development, and age-related misregulation of DNA methylation is associated with the molecular pathogenesis of neurodevelopmental disorders.

    Histone modification and the histone code

    Model of a histone protein
    Figure \(\PageIndex{3}\): Life experiences, like a stressful event in childhood, can cause the modification of histone proteins (pictured) to help adapt to one’s environment. For example, in response to a stressful event, histone modification of one’s DNA might occur to encourage a more cautions personality—in order to avoid future, stressful encounters. [Image: Zephyris, https://goo.gl/gGrSQd, CC BY-SA 3.0, https://goo.gl/kB1Ogc]

    The modification of histone proteins comprises an important epigenetic mark related to gene expression. One of the most thoroughly studied modifications is histone acetylation, which is associated with gene activation and increased gene expression (Wade, Pruss, & Wolffe, 1997). Acetylation on histone tails is mediated by the opposing enzymatic activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Kuo & Allis, 1998). For example, acetylation of histone in gene regulatory regions by HAT enzymes is generally associated with DNA demethylation, gene activation, and increased gene expression (Hong, Schroth, Matthews, Yau, & Bradbury, 1993; Sealy & Chalkley, 1978). On the other hand, removal of the acetyl group (deacetylation) by HDAC enzymes is generally associated with DNA methylation, gene silencing, and decreased gene expression (Davie & Chadee, 1998). The relationship between patterns of histone modifications and gene activity provides evidence for the existence of a “histone code” for determining cell-specific gene expression programs (Jenuwein & Allis, 2001). Interestingly, recent research using animal models has demonstrated that histone modifications and DNA methylation of certain genes mediates the long-term behavioral effects of the level of care experienced during infancy.

    Parental investment and programming of stress responses in the offspring

    The most comprehensive study to date of variations in parental investment and epigenetic inheritance in mammals is that of the maternally transmitted responses to stress in rats. In rat pups, maternal nurturing (licking and grooming) during the first week of life is associated with long-term programming of individual differences in stress responsiveness, emotionality, cognitive performance, and reproductive behavior (Caldji et al., 1998; Francis, Diorio, Liu, & Meaney, 1999; Liu et al., 1997; Myers, Brunelli, Shair, Squire, & Hofer, 1989; Stern, 1997). In adulthood, the offspring of mothers that exhibit increased levels of pup licking and grooming over the first week of life show increased expression of the glucocorticoid receptor in the hippocampus (a brain structure associated with stress responsivity as well as learning and memory) and a lower hormonal response to stress compared with adult animals reared by low licking and grooming mothers (Francis et al., 1999; Liu et al., 1997). Moreover, rat pups that received low levels of maternal licking and grooming during the first week of life showed decreased histone acetylation and increased DNA methylation of a neuron-specific promoter of the glucocorticoid receptor gene (Weaver et al., 2004). The expression of this gene is then reduced, the number of glucocorticoid receptors in the brain is decreased, and the animals show a higher hormonal response to stress throughout their life.

    A young mother and father are all smiles as they hold their infant.
    Figure \(\PageIndex{4}\): Parental care during one’s childhood has important and consequential effects on the development of an individual, effects that persist even into adulthood. [Image: The White Ribbon Alliance, https://goo.gl/KgY6N5, CC BY-NC-SA 2.0, https://goo.gl/Toc0ZF]

    Several studies have attempted to determine to what extent the findings from model animals are transferable to humans. Examination of post-mortem brain tissue from healthy human subjects found that the human equivalent of the glucocorticoid receptor gene promoter (NR3C1 exon 1F promoter) is also unique to the individual (Turner, Pelascini, Macedo, & Muller, 2008). A similar study examining newborns showed that methylation of the glucocorticoid receptor gene promoter maybe an early epigenetic marker of maternal mood and risk of increased hormonal responses to stress in infants 3 months of age (Oberlander et al., 2008).

    Epigenetic Mechanisms in Psychological Disorders

    Two models of chromatin
    Figure \(\PageIndex{5}\): Pictured above is a chromatin, the spiral-looking macromolecule involved in depression. [Image: Zephyris, https://goo.gl/6DBQ1g, CC BY-SA 3.0, https://goo.gl/eLCn2O]

    Epigenome-wide studies have identified several dozen sites with DNA methylation alterations in genes involved in brain development and neurotransmitter pathways, which had previously been associated with mental illness (Mill et al., 2008). These disorders are complex and typically start at a young age and cause lifelong disability. Often, limited benefits from treatment make these diseases some of the most burdensome disorders for individuals, families, and society. It has become evident that the efforts to identify the primary causes of complex psychiatric disorders may significantly benefit from studies linking environmental effects with changes observed within the individual cells.

    Epigenetic events that alter chromatin structure to regulate programs of gene expression have been associated with depression-related behavior and action of antidepressant medications, with increasing evidence for similar mechanisms occurring in post-mortem brains of depressed individuals. In mice, social avoidance resulted in decreased expression of hippocampal genes important in mediating depressive responses (Tsankova et al., 2006). Similarly, chronic social defeat stress was found to decrease expression of genes implicated in normal emotion processing (Lutter et al., 2008). Consistent with these findings, levels of histone markers of increased gene expression were down regulated in human post-mortem brain samples from individuals with a history of clinical depression (Covington et al., 2009).

    Administration of antidepressants increased histone markers of increased gene expression and reversed the gene repression induced by defeat stress (Lee, Wynder, Schmidt, McCafferty, & Shiekhattar, 2006; Tsankova et al., 2006; Wilkinson et al., 2009). These results provide support for the use of HDAC inhibitors against depression. Accordingly, several HDAC inhibitors have been found to exert antidepressant effects by each modifying distinct cellular targets (Cassel et al., 2006; Schroeder, Lin, Crusio, & Akbarian, 2007).

    Epigenetics and Understanding Gene-Environment Interactions

    An unhappy looking little boy sits with his teddy bear on the floor of a closet.
    Figure \(\PageIndex{6}\): Although there is some evidence that a dysfunctional upbringing can increase one’s likelihood for schizophrenia (an epigenetically inherited disease), some people who have both the predisposition and the stressful environment never develop the mental illness. [Image: Steve White, CC0 Public Domain, https://goo.gl/m25gce]

    While the cellular and molecular mechanisms that influence on physical and mental health have long been a central focus of neuroscience, only in recent years has attention turned to the epigenetic mechanisms behind the dynamic changes in gene expression responsible for normal cognitive function and increased risk for mental illness. Ongoing research will show if this increased attention on epigenetics can be exploited in the development of new therapeutic options that may alter the traces that early environment leaves on the genome.

    However, as discussed in this module, the epigenome is not static and can be molded by developmental signals, environmental perturbations, and disease states, which present an experimental challenge in the search for epigenetic risk factors in psychological disorders (Rakyan, Down, Balding, & Beck, 2011). The combination of genetic association maps studies with epigenome-wide developmental studies may help identify novel molecular mechanisms to explain features of inheritance of personality traits and transform our understanding of the biological basis of psychology. Importantly, these epigenetic studies may lead to identification of novel therapeutic targets and enable the development of improved strategies for early diagnosis, prevention, and better treatment of psychological and behavioral disorders.

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    Attributions

    Adapted from Epigenetics in Psychology by Ian Weaver, in R. Biswas-Diener & E. Diener (Eds), Noba textbook series: Psychology as a Biological Science. Champaign, IL: DEF publishers. Retrieved from http://noba.to/tvz92edh. Licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.


    This page titled 3.3: Epigenetics is shared under a not declared license and was authored, remixed, and/or curated by Naomi Bahm.

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