Medical epigenetics is a science of studying various diseases through epigenetics, in which gene expression and gene function change heritably and eventually lead to phenotypic change without the change of DNA sequence. Epigenetic modification mainly includes DNA methylation, histone modification, and noncoding RNA regulation, which play important roles in gene-selective transcription and posttranscriptional regulation. Here, we will focus on introducing prospective advances of DNA methylation, as well as histone modification and noncoding RNA regulation in medical epigenetics, so as to provide a more comprehensive and specific understanding of the pathogenesis of diseases, and also provide scientific basis for clinical diagnosis and development of therapeutic drugs.
The majority of solid tumors harbor disrupted epigenomes that contribute to malignancy. Over the past decade, there has been a substantial increase in our understanding of the epigenetic mechanisms underlying normal and disease states. Profiling of tumors revealed recurrent mutations in key components of the epigenetic machinery and metabolic enzymes that lead to an altered epigenetic state and oncogenic transformation. Unlike genetic events, epigenetic alterations can be targeted pharmacologically and potentially reversed. Drug discovery efforts are focused on developing epigenetic drugs and treatment regimens. Recently, altered DNA methylation has emerged as an important and promising feature for tumor classification. In this chapter, we highlight recent advances in solid tumor epigenetics, specifically focusing on epigenetic therapies and the most promising combination strategies currently under investigation. In addition, we illustrate the utility of epigenetic markers for solid tumor classification and the emerging field of analyzing epigenetic biomarkers in liquid biopsies.
The newly emerged epigenomic technologies promoted a new discipline called pharmacoepigenomics to identify the epigenomic signatures affecting individual response to drugs. There are multiple layers of epigenomic events, including DNA methylation changes, histone modifications, and microRNA-mediated regulation, which are being studied in the field of neurodegenerative disease (NDD) treatment. To date, the Food and Drug Administration-approved drugs mostly provide symptomatic relief or can be able to delay the progression rather than definitively stop the diseases. Due to the multifactorial nature of these disorders, and the documented individualized response to the same treatments, the attention of researchers has been directed toward pharmacoepigenomics. Several clinical trials are ongoing and the search for effective epigenomic-modifying drugs against NDDs is being undertaken worldwide. This exciting research line might lead to novel approaches in drug discovery and in the individualized and personalized application of drug therapy.
Autoimmune diseases (ADs) are a group of immune system disorders with unknown etiology. It is believed that a complex interaction between genetic, epigenetic, and environmental risk factors contributes to the etiology of the most ADs. This chapter will provide an overview of epigenetic mechanisms linked to immune system dysfunction and autoreactivity in idiopathic AD. Because the environment plays such a critical role in the development of ADs, a major theme of this chapter is to highlight an example to provide an insight into the role of one environmental risk factor, trichloroethylene (TCE), in AD etiology. TCE is an industrial solvent and environmental contaminant shown to promote CD4+ T cell dysregulation and autoimmunity. Recent findings demonstrated that the TCE's ability to promote autoimmune disease may be related to epigenetic alterations in CD4+ T cells. Identifying environmental factors that alter immune pathways has important implications for potential therapeutic interventions by normalizing immune responses in TCE-exposed individuals.
Besides the classical view of RNA as an intermediate carrier of genetic information from the DNA, the protein via the template function of messenger RNA (mRNA), a larger and much more heterogeneous group of noncoding RNAs (ncRNAs) contributes to the regulation of gene expression either by providing structural and functional components (ribosomal RNAs and transfer RNAs) and a panoply of other noncoding RNAs that contribute to the regulation of gene expression through an epigenetic mode of action by modulating mRNA stability. While ncRNAs range in size from short polynucleotides to RNA molecules of > 100 kbp, microRNAs (miRNAs), of 21–23 nucleotides in length, are the most studied ncRNAs due to their capacity to modulate gene expression via RNA interference of activation. Here, we summarize the current achievements in the use of ncRNAs as therapeutic approaches. A brief introduction will present the general picture of ncRNAs in the regulation of gene expression and the subjacent molecular mechanisms. Next, the concept of RNA interference and activation mediated by short RNAs will be discussed. Following this introductory part, the behavior of ncRNAs in different pathologies will be discussed, considering their usefulness both as biomarkers as well as promising therapeutic approaches based on the delivery of ncRNAs being able to modulate gene expression. To cover the latest developments in the field, this chapter will terminate with the presentation of some short-interfering RNA- and short-activating RNA-based therapies that have entered clinical trials and even the marketing phase, proving that decades of research on noncoding RNAs have come to clinical fruition.
Healthy living depends on a balanced interaction between lifestyle factors and the epigenome. Converging evidence suggests that lifestyle events such as diet, physical activity, and environment influence the development of a healthy phenotype. These factors may modulate epigenetic marks in such a way that they trigger or mitigate the development of noncommunicable chronic diseases (NCCDs) such as cancer, diabetes, cardiovascular disease, and obesity. Additional knowledge and better understanding of epigenetic signatures and how they directly and indirectly influence disease phenotypes will go a long way toward confronting the growing burden of chronic diseases. Thus, this chapter discusses different lifestyle factors in relation to mechanisms of epigenetics, and how fostering a healthy lifestyle could be harnessed for preventive health care.
The study of the role of epigenetics in regulating disease and degeneration is a constantly expanding field encompassing a broad range of marks from DNA methylation, histone modification, and small RNA regulation that can make rapid changes in gene expression activity in response to extrinsic factors. These modifications are becoming increasingly important in our understanding of degeneration and our pursuit of regenerative therapies. Here, we discuss recent advances in epigenetic regulation in aging and disease and have identified new epigenetic changes that both broaden our understanding of epigenetic misregulation as a driver of degeneration, and we present novel epigenetic editing tools with promising therapeutic and research potential.
The epigenetic mechanisms controlling muscle physiology in health and disease are under intense research as their dynamic properties and their relation to environmental exposures offer attractive preventive and therapeutic opportunities. This chapter summarizes current evidence on DNA methylation patterns, histone posttranslational modification landscape, miRNomes, and the potential involvement of long noncoding RNAs associating with genetic determinants of muscle disorders, as potential mechanisms to be targeted in the clinic. Since chromatin status of terminally differentiated muscle cells might influence the epigenetic layers affected by disease, a focus on atrial fibrillation, fibromyalgia, and gastrointestinal tract disorders is used to explore potential representative epigenetic mechanisms involving cardiac, skeletal muscle, and smooth muscle diseases, respectively. Interestingly, some genes, a few muscle-associated miRNAs, and other miRNA related to inflammatory conditions and fibrosis seem to be involved in muscle disease with independence of their histologic type, perhaps reflecting the influence of other intimately connected cell types. Reconciliation of the genetic and epigenetic factors modulating muscle performance are contemplated as remaining future challenges of research. So are the addition of new epigenetic marks such as cytosine hydroxymethylation (5-hmC), N6-methyladenosine (m6A), histone crotonylation, butyrylation, hydroxybutyrylation, propionylation or citrullination, or others which are starting to emerge, to the already complex regulatory network of muscle disorders.
Numerous genetic and environmental risk factors have been implicated in the pathogenesis of various eye diseases. However, the development of eye disorders often could not be fully explicated by these risk factors until the contribution of the epigenetic modifications was discovered. Epigenetically mediated alterations in gene expression link environmental exposures, signal pathways, and genetic control in both normal ocular development and disease pathogenesis. DNA methylation, histone alteration, chromatin remodeling, and noncoding RNA change are involved in many key elements during ocular disease development, including oxidative stress, inflammation, intracellular signaling, cell proliferation, apoptosis, epithelial-mesenchymal transition, and angiogenesis. Some components of epigenome have been suggested as novel biomarkers for diagnostic, prognostic, or therapeutic targets in ocular medicine. In this chapter, recent findings of epigenetic alterations in common eye diseases and their effects in regulatory pathways as well as clinical implications are summarized and discussed in detail.
Epigenetic modifications are involved in relevant cellular mechanisms, and their dysregulation can be responsible for the development of numerous diseases. They have become very interesting biomarkers for the early detection of disease, prognosis, and drug response assessment. The reversible nature of these modifications offers a promising direct target for therapeutic interventions, which can be monitored with the same biomarkers. In this context, a deeper understanding of both the genetic and epigenetic heterogeneity would contribute to the design of targeted therapies based on specific molecular information extracted from individual tumors. Currently, the detection and analysis of epigenetic changes have seen extraordinary advances, not only from the technological point of view. We are witnessing a great development in the understanding of the complex interaction between the transcriptomic machinery and genetic variation, as well as their association with phenotype in healthy and pathological conditions. However, further optimization of affordable tests and increased knowledge on the regulation of these mechanisms would be needed to fully explore their potential as clinical biomarkers. In this chapter, we review the relevance and usefulness of epigenetic modifications as biomarkers of disease, a research field that is in continuous expansion and still gaining global interest for its projection into the clinics in combination with other more established biomarkers. The regulation of epigenetic alterations plays a major role in carcinogenesis, with different stages presenting specific epigenetic profiles. Due to the promising potential held by epigenetic biomarkers to become more conclusive diagnostic and prognostic cancer biomarkers, we will be focusing on the applications to cancer detection and disease progression. Moreover, we will elaborate on the most recent technologies that are used to identify the disease-associated epigenetic profiles.
Deacetylases are a class of enzymes which remove the ɛ-N-acetyl groups from lysine amino acids in histone and nonhistone targets. There are four classes of HDACs, with a distinct subgroup called sirtuins (HDAC class III) that rely on nicotinamide adenine dinucleotide (NAD+) for their catalytic activity. The fact that most of the sirtuins require NAD+ for their deacetylase activity indicates that they are major energy-sensing proteins in cells and tissues with the potency to affect a plethora of biochemical, physiological, and pathological processes. These effects exerted by various sirtuins are discussed in this chapter, as well as the processes regulating NAD+ levels by de novo and salvage pathways. Finally, we elaborate on various agents that modulate salvage pathway enzymes and sirtuin activity, and their preclinical and clinical implications in health and disease.
Coined in 1942, by Conrad Waddington, epigenetics was defined as "the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being." Since then, many have alternated the definition to fit different roots, including geneticists, developmental biologists, etc.; however, each definition was obsolescent. A modern definition was created to encompass the many different components of epigenetic events: "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states." Focusing on chromosomes and genes, this definition is also inclusive of chromosomal marks and heritability of a phenotype across several cell generations. The definition also suggests that epigenetic marks act in response to an already-imposed event rather than initiating an event.
Disease therapeutics is an expanding field where novel ways of treating disease are being explored. "Epigenetics" is an old branch of sciences that is now attracting attention with respect to human disease conditions. External signals such as environment, lifestyle, nutrition, and psychological factors impact the epigenetic machinery. These factors can generate "Stress Signals" which can trigger the disease conditions. The initial part of the chapter discusses the association of stress with human physiological and psychological mechanisms through the epigenetic route. The next section of the chapter discusses human chromosomal disorder in the context of epigenetic deregulations. This section describes different clinical morbidities associated with human chromosomal aneuploidy and their connection with epigenetic mechanisms. Finally, the chapter elaborates on the future implications of epigenetic processes in the management of human disorders and therapeutic.
Genetic factors, including hereditary and somatic mutations in regulatory sequences, can regulate gene expression. Epigenetic mechanisms also regulate gene expression through modifications in chromatin structure that do not involve changes in the DNA sequence. Multiple lines of evidence in animal, in vitro model, as well as in humans, have linked epigenetic modifications with human health with a particular impact being noted in the systems (male and female) of reproduction. Epigenetic reprogramming does not occur only in intrauterine life but also in germ cell development and early embryogenesis, affecting developmental cues for gene expression during the lifetime. The transmission of epigenetic marks that might play a role in reproduction occurs through DNA methylation, histone modification, microRNAs (miRNAs), and chromatin remodeling. The regulation of gene expression through these mechanisms is a key mechanism for transcriptome dysregulation in human reproductive disorders. This chapter provides a comprehensive summary of the role of epigenetics in reproductive diseases.
Machine learning of DNA methylation patterns and other epigenetic phenomena possesses great potential in the prediction of disease. Machine learning has emerged as a powerful tool that enables the discovery of unknown features in the epigenome to predict phenotypes of interest and to suggest diagnoses and clinical courses. It has been successfully applied to select DNA methylation features to identify biomarkers for complex diseases and to predict treatment outcomes. Epigenetic classifiers can be used in combination with current tools to complement and assist in diagnosis, and several epigenetic biomarkers are currently used clinically. Applications of machine learning in clinical epigenetics hold forth the possibility of molecular diagnostics for specific diseases, complex conditions, or physiologic abnormalities.
Medical processes ranging from epidemiological aspects of medicine to medical therapy can be significantly affected by the primary mechanisms of epigenetics consisting of DNA methylation, histone modifications, and noncoding RNA. It is now apparent that many medical disorders have a component of epigenetics that contributes to their pathology and epigenetic mechanisms can influence numerous aspects of medical management such as diagnosis, disease progression, and prognosis of medical disorders. The immune, gastrointestinal, cardiovascular, and reproductive systems as well as many others can be affected by epigenetic aberrations that lead to disease manifestations. In addition, multisystem disorders such as those relevant to infections, pediatrics, and metastasis as well as numerous others are also very important to the expression and manifestation of epigenetic diseases. The advent of epigenetic approaches to medical therapy has advanced significantly and this very small field has now grown to include new DNA methylation, histone deacetylase, and histone acetylase inhibitors as well as the development of epigenetic-based RNA molecules for therapy. These approaches are being developed for applications for the management of pain and precision medicine and may have future roles in stem cells as well as regenerative medicines. The many applications of clinical epigenetics have significantly expanded and are most likely secondary to the importance that this discipline has in the vast field of health care.
In the last two decades, strong evidence has emerged about the link between diet and the epigenetic mechanisms of human pathologies. Dietary bioactive molecules from vegetables, fruits, and some beverages have been shown to exhibit antiinflammatory, antioxidative, and anticancer activities through multiple mechanisms, including epigenetic changes associated with DNA methylation, histone modifications, and modulation of microRNAs. The interconnected epigenetic molecular mechanisms that contribute to the chemopreventive nature of dietary polyphenols have been widely studied in different diseases including diabetes, neurological and metabolic disorders, and cancer. In addition, the immunosensitizing and chemosensitizing properties of dietary agents make them viable candidates for combinatorial strategies with synergistic beneficial effects. In this chapter, we summarize current data on the most studied nutrients and plant-based food components (phytonutrients) and their effects on epigenetic machinery. We also provide a review of accessible epigenetic clinical trials of the effects of dietary compounds on human disease susceptibility. The accumulated knowledge provides information about the epigenetic mechanisms of the action of dietary minerals, vitamins, and phytochemicals, which may offer novel and promising pharmacological targets and define the potential of dietary bioactive molecules as epigenetic chemopreventive agents and components of the epigenetic drugs of the future.
