What is the study of the molecular mechanisms by which environments trigger genetic expression?

Abstract

Epigenetics is the study of heritable changes in genome function that are not associated with DNA sequence alterations. Such changes occur in all kingdoms of life. In bacteria, DNA methylation plays a role in the formation of cell lineages. In eukaryotes, multiple mechanisms of chromatin modification permit mitotic and/or meiotic transmission of epigenetic states. Inheritance of epigenetic marks is crucial for the establishment of cell fates during the development of multicellular organisms. Eukaryotic epigenetic states are reprogrammed during gametogenesis and early embryonic development. Abnormal epigenetic states can predispose to or cause human diseases.

Model Organisms of Epigenetics

Epigenetic processes are widespread and much of our extant knowledge about epigenetics has been derived from model systems, both typical and unique. The ease of manipulation of eukaryotic microbes has facilitated discoveries in the molecular mechanisms of basic epigenetic processes (Chapter 13). In these cases epigenetics may play a key role in genomic protection from invasive DNA elements and in identifying the importance of gene silencing mechanisms in evolution. Drosophila is a mainstay model in biology in general and the epigenetics field is not an exception in this regard. For example, Chapter 14 offers a number of examples of transgenerational inheritance in Drosophila and this model system also shows promise in unraveling the evolutionary aspects of epigenetics. Probably the most useful model system in epigenetics to date is the mouse model (Chapter 15). Randy Jirtle and colleagues review numerous different mouse models that are important in many epigenetic processes such as transgenerational epigenetics and imprinting and these models have potential in illuminating human diseases such as diabetes, neurological disorders and cancer. Plant models (Chapter 16) are of great importance in epigenetics due in part to their plasticity and their ability to silence transposable elements. RNAi silencing in plants has been at the forefront of epigenetics and plant models will likely lead the way in several other epigenetic processes in the future. Thus, model development, like the advances in techniques, have made many of the most exciting discoveries in epigenetics possible for a number of years.

Abstract

Epigenetics refers to any factor that affects gene expression without changing the primary DNA sequence or genotype. Typical epigenetic signatures include alterations in DNA methylation that usually silence genes by blocking transcription factor binding site, histone modifications that change chromatin structure and the availability of genes for transcription, and expression of microRNA antisense transcripts that target and mark mRNA transcripts for destruction. Epigenetic inheritance involves the transmission of patterns of genetic expression to subsequent generations without transmitting any changes to the primary DNA sequence.

Silencing due to epigenetic changes such as DNA methylation is associated with a closed chromatin configuration and loss of accessibility of the DNA to transcription factors. Epigenetics is an area of increasing importance in human and medical genetics because epigenetic silencing of gene expression is a phenomenon that explains such widely diverse phenomena as X inactivation; genomic imprinting in well-known syndromes like Prader–Willi, Angelman, and Beckwith–Wiedemann; and carcinogenesis.

Abstract

Epigenetics is the study of non-genotoxic, reversible, heritable mechanisms that influence gene expression without changing the DNA sequence. Epigenetic mechanisms, such as DNA methylation and histone modifications, play key roles in the development as well as in the maintenance of genomic integrity and imprinted gene expression. Conversely, altered epigenetic marks are commonplace in cancer and developmental disorders, and there is increasing evidence that epigenetic changes acquired in one generation can influence the next generation(s). Thus, an enhanced understanding of how epigenetic mechanisms modulate gene expression and how nutrition can optimize healthy epigenetic patterns can positively influence human health.

Epigenetics is the study of heritable changes in gene expression that do not require, or do not generally involve, changes in genomic DNA sequence. In modern biology, epigenetics initially referred to developmental phenomena, but, more recently, it has come to signify a relation to gene action, while epigenetic inheritance signifies modulation of gene expression without modifying the DNA sequence. Epigenetics began over 60 years ago as a series of isolated observations in three disparate areas of biology. It picked up momentum during the 1970s with the advent of molecular biology and, during the last 10–15 years, has emerged as a stand-alone discipline complementary to genetics. It is instructive to note that from the beginning the strongest evidence favoring a particular epigenetic hypothesis has often come from models outside the animal kingdom such as plants, slime molds, filamentous fungi, microorganisms, and fission yeast. Recently, epigenetics has experienced a period of rapid growth and redefinition, particularly with advances in molecular technology for monitoring the biochemical features of epigenetic change. This chapter was written with the purpose of summarizing the origin, the foundation, and the current state of epigenetics by bringing together concepts, technologies, and experimental evidence that led to its emergence as a field of basic biological inquiry primarily concerned with understanding the handling of genetic information by eukaryotic cells. It concludes with some perspectives on epigenetics in health and disease.

Introduction

Epigenetics refers to variations in traits that are not due to differences in the nucleotide sequence of the underlying gene but rather in the expression of the gene. Classically, epigenetic traits were considered to be those that were heritable between generations, but recently, this definition has often been expanded to include traits in which an altered gene expression state is inherited through cell divisions once the stimulus that has caused it has been removed. Here we will consider epigenetic traits to be those that are heritable through either generations or cell divisions.

Underlying the epigenetically altered expression state of a gene are chemical modifications to either the deoxyribonucleic acid (DNA) or the chromatin into which the DNA is packaged. The major modification to DNA is the addition of 5-methylcytosine, whereas chromatin is modified by the addition of various side chains to the histone protein component of the chromatin (e.g., methylation, acetylation, and ubiquitination Figure 1). Often these modifications are referred to as ‘epigenetic marks’ or ‘epigenetic modifications’; however, this is not strictly true as these modifications are widespread through the genome and do not necessarily confer an epigenetic trait as defined above. For example, the histone modification H3K4me3 (histone H3 lysine 4 trimethylation), is present in many transcribed genes as it is added during the process of transcription, but it does not necessarily confer a heritable active state on that gene.

While most of our understanding of epigenetics in plants is based on research in the model plant Arabidopsis thaliana (Arabidopsis), there are increasing numbers of examples of epigenetic traits in crop and horticulture plants. This article will give some examples of plant traits that appear to be regulated by epigenetic mechanisms, and also how epigenetic effects impinge on the application of biotechnology in plants through the silencing of transgenes.

Epigenetics refers to cellular processes that regulate chromatin structure and subsequent gene expression in the absence of changes in deoxyribonucleic acid (DNA) sequence. The primary molecular epigenetic mechanisms responsible for regulation of chromatin structure and gene expression are DNA methylation, histone modifications, and ncRNAs. Disruption of these processes is associated with a number of disease states including cancer, cardiovascular disease, obesity, diabetes, and reduced fertility. The environment has a tremendous impact on the epigenome, giving rise to disease through exposure to adverse environmental stimuli that can significantly alter the landscape of the epigenome. Examples include exposure to heavy metals and endocrine disruptors, which are associated with changes in chromatin structure and increased susceptibility to disease. In this chapter, we will introduce readers to the burgeoning field of epigenetics through review of the basic mechanisms of epigenetic gene regulation. We will then explore mechanisms by which toxicants can disrupt the epigenome using both well-characterized examples and newly identified pathways. The final section in this chapter is aimed at highlighting some of the tools used to investigate the epigenome.

5.1 The Epigenome as the Molecular Hub of Information Encoding in Addiction

Epigenetics

The term epigenetics was coined by Conrad Waddington to describe a conceptual solution to a fundamental consideration—and conundrum—in developmental biology. All the different types of cells that make up our body, bar exceptions in our reproductive and immune systems, have exactly the same genome. Yet, how can the identical DNA template produce vastly different gene products and yield distinct cell types like myocytes or neurons? Waddington reasoned there must be a mechanism above the level of DNA that controls the readout of genes encoded in its nucleotide sequence—coining the term epigenetics. These epigenetic mechanisms specify certain sets of genes that are turned into functional products in neurons, for instance, yet not in myocytes. Diverse epigenetic marks are set up during early cell fate decisions, in due course forming a memory system that perpetuates cellular phenotypes over the lifespan of our bodies. In view of that, classic epigenetics is the study of a change in gene expression or cellular phenotype that is stably inherited by a cell and that is not associated with changes in DNA sequence. Today, many epigenetic modifications are known to be highly dynamic with critical functions in neuronal plasticity that are implicated in neurodegenerative and psychiatric disorders.

Although many cellular phenomena may be considered epigenetic, the primary focus of the field has been to illuminate environment–genome interactions at the level of chromatin. Chromatin describes the DNA–protein packaging complex that determines the accessibility of DNA in eukaryotic cells, making it the focal point of transcriptional gene regulation. The basic repeating unit of the chromatin structure is the nucleosome: ~ 146 base pairs of genomic DNA wrapped around a protein octamer, assembled from two molecules each of histone H2A, H2B, H3, and H4. In essence, the nucleosome constitutes a platform for complex chemical modifications—i.e., epigenetic marks—that dynamically regulate chromatin architecture and gene transcription (Rivera and Ren, 2013). The entirety of these epigenetic features has been denoted the epigenome—it defines neuronal identity and expresses the regulatory channels that operate at the interface of genome and environment (Day and Sweatt, 2011).

Posttranslational modifications of histones elicit structural and functional changes within chromatin and regulate various epigenetic processes. To date, numerous histone modifications have been identified and include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, and ADP-ribosylation (Berger, 2007; Kouzarides, 2007). Acetylation, for instance, along with methylation, is the most extensively studied histone modification, and has broad effects on chromatin function and nuclear signaling pathways (Berndsen and Denu, 2008; Shahbazian and Grunstein, 2007). Histone acetylation is regulated by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate-specific lysine residues of histone proteins, which neutralizes their positive charge, and can thus help to decondense chromatin leading to active gene transcription (Berndsen and Denu, 2008). Additionally, histone acetylation marks can be bound by small protein modules called bromodomains, often referred to as “readers.” These domains are conserved within many chromatin-associated proteins—including HATs themselves—that regulate transcription-mediated biological processes, and whose aberrant activities are correlated with several human diseases (Bannister and Kouzarides, 2011; Burdge and Lillycrop, 2010; Filippakopoulos and Knapp, 2014).

Indeed, drug addiction is one of these syndromes. Epigenetic remodeling has emerged as a potent regulator of drug-induced plasticity and has been implicated in addiction to stimulants, opiates, ethanol, and nicotine (Walker et al., 2015). For example, hypermethylation of the dopamine transporter gene has been observed in human alcoholics and was shown to be predictive of addiction severity (Ponomarev, 2013). In human heroin addicts, impairments in both glutamatergic neurotransmission and chromatin remodeling were observed, including increased enrichment of lysine-27 acetylated histone H3 (H3K27) that affected GluR2, the subunit of the AMPA receptor that confers calcium permeability (Egervari et al., 2017). Similar changes were seen in rodents that underwent heroin self-administration and these changes were directly linked to self-administration behavior. Other work with cocaine has shown reduced levels of H3K9 dimethylation in the nucleus NAc, which was found to be mediated through the repression of G9a, a methyltransferase (Maze et al., 2010). These reductions led to increases in immediate early gene expression, and thus, could act to prime these genes to respond quickly and to a greater extent upon cellular activation. Together, changes in the ability of transcription to dynamically respond to the changing cellular microenvironment is important as it dysregulates not only the protein composition of cells, but their ability to quickly respond in a temporally specific fashion to information.

4.1.3 What is the Mechanism for the “Trainable” Brain?

The recent popularity of books and articles on how the brain is “trainable” further pushes the search for mechanisms of this flexibility in brain growth.79 To understand the mechanism, we turn again to genes. When genes are activated (i.e., are turned on), they produce proteins that are used in building the body and in its functions. They are not continually active, but rather produce the proteins needed when they are called upon. The activation of genes is controlled by a complex chemical sequence involving hormones, whose production and dispersal into the blood stream is highly influenced by experience, both psychological and physical. This process by which genes are turned on and off is called epigenetics, and it forms the basis for our real understanding of how nature and nurture intertwine in development (see Box 4.5). Thus, genes map onto the processes that influence brain function, but the brain's experience also influences the genetic activation. This interplay between genetics and environment is currently the most challenging area for developmental neuroscience (see Figure 4.3). Although we cannot go into detail here, we can see that this is the mechanism for gene-by-environment interactions and for understanding how environment influences brain growth (especially with respect to stressful environments). There are far too many factors for there to be a simple effect of either genes or environment to account for all the variation in outcomes. Having a specific gene provides only probabilities concerning outcomes, just as having a specific experience only increases the likelihood of success or failure at a task.

Box 4.5

Epigenetics

“… behavioral development is thought to result from the interplay among genetic inheritance, congenital characteristics, cultural contexts, and parental practices as they directly impact the individual… [A]nother contributor, epigenetic inheritance, [is] the transmission to offspring of parental phenotypic responses to environmental challenges—even when the young do not experience the challenges themselves. Genetic inheritance is not altered, gene expression is… Maternal stress during the latter half of a daughter's gestation may affect not only the daughter's but also grand-offspring's physical growth… temperamental variation may be influenced in the same way.”128, p 340

One of the recent findings in epigenetics is that patterns of gene regulation can be passed down across generations, adding a further complication to the story. It turns out the influence of inheritance from the mother and father is not simply the gene types received, but also their influence on gene expression (this is called imprinting).

Abstract

This introductory article for the Epigenetic section of the Encyclopedia of Human Biology places the discipline of epigenetics into its wider context of genetics to which it genuinely belongs. The mechanisms operative in epigenetics have far reaching implications for many fields of biology but are all dependent on DNA and its interactions with proteins and RNA. The term epigenetics is misleading since it might be misunderstood to relate to events outside or above (ɛ' πι-) genetics, which is definitely not the case. Nevertheless, the name epigenetics has been widely applied in the biomedical literature with the implicit, though not always explicitly mentioned, caveat that “epigenetics is just a different way of looking at genetics.” The contributions in the Epigenetics Section of the Encyclopedia address a wide range of topics in biomedical research. This introductory article relates to the early history of the field, mainly on DNA methylation. In addition, this article also considers the growing importance of nucleotide sequences in between genes which have recently been highlighted in the ENCODE project. In these analyses, numerous DNA motifs and sites for protein interactions have been identified. This project has mainly relied on biostatistical methods. It is still unproven, whether the actual functional meaning of DNA motifs in intact genomes can be reliably deduced from the results of reconstruction experiments. Undoubtedly, studies on the multifactorial regulation of gene expression – transcriptional or posttranscriptional – in different cells of an organism or in different organisms will continue to occupy biomedical research for many years, regardless of the name one applied to this field of research.