Epigenetics refers to the collective heritable changes in phenotype that arise independent of genotype. Two broad areas of epigenetics are DNA methylation and histone modifications and numerous techniques have been invented to analyze epigenetic processes not only at the level of specific genes, but also to analyze epigenetic changes that occur in defined regions of the genome as well as genome-wide. Advances have also been made in techniques devised to assess the enzymes that mediate epigenetic processes. These methods that are currently driving the field of epigenetics will greatly facilitate continued expansion of this exponentially growing discipline of genetics.
Epigenetics; DNA methylation; chromatin; methods; histone; technique
Epigenetics is a large and diverse field encompassing a number of different mechanisms essential to development, DNA stability and gene expression. DNA methylation and histone modifications work individually and in conjunction with each other leading to phenotypic changes. An overwhelming amount of evidence exists demonstrating the essential nature of epigenetics to human biology and pathology. This field has spawned a vast array of knowledge, techniques and pharmaceuticals designed to investigate and manipulate epigenetic phenomena. Despite its centricity to molecular biology, little work has been conducted examining how epigenetics affects hearing. In this review, we discuss both the basic tenants of epigenetics and highlight the most recent advances in this field. We discuss its importance to human development, genomic stability, gene expression, epigenetic modifying agents as well as briefly introduce the expansive field of cancer epigenetics. We then examine the evidence of a role for epigenetics in hearing related processes and hearing loss. The article concludes with a discussion of areas of epigenetic research that could be applied to hearing research.
Presbycusis; Hair Cells; Organ of Corti; DNA Methylation; Histone Modifications; Deafness
Increased understanding about the functional complexity of the genome has led to growing recognition about the role of epigenetic variation in the etiology of schizophrenia. Epigenetic processes act to dynamically control gene expression independently of DNA sequence variation and are known to regulate key neurobiological and cognitive processes in the brain. To date, our knowledge about the role of epigenetic processes in schizophrenia is limited and based on analyses of small numbers of samples obtained from a range of different cell and tissue types. Moving forward, it will be important to establish cause and effect in epigenetic studies of schizophrenia and broaden our horizons beyond DNA methylation. Rather than investigating genetic and epigenetic factors independently, an integrative etiological research paradigm based on the combination of genomic, transcriptomic, and epigenomic analyses is required.
schizophrenia; epigenetics; DNA methylation; genetics; epidemiology
Individuals vary in their sociosexual behaviors and reactivity. How the organism interacts with the environment to produce this variation has been a focus in psychology since its inception as a scientific discipline. There is now no question that cumulative experiences throughout life history interact with genetic predispositions to shape the individual’s behavior. Recent evidence suggests that events in past generations may also influence how an individual responds to events in their own life history. Epigenetics is the study of how the environment can affect the genome of the individual during its development as well as the development of its descendants, all without changing the DNA sequence. Several distinctions must be made if this research is to become a staple in behavioral neuroendocrinology. The first distinction concerns perspective, and the need to distinguish and appreciate, the differences between Molecular versus Molar epigenetics. Each has its own lineage of investigation, yet both appear to be unaware of one another. Second, it is important to distinguish the difference between Context-Dependent versus Germline-Dependent epigenetic modifications. In essence the difference is one of the mechanism of heritability or transmission within, as apposed to across, generations. This review illustrates these distinctions while describing several rodent models that have shown particular promise for unraveling the contribution of genetics and the environment on sociosexual behavior. The first focuses on genetically-modified mice and makes the point that the early litter environment alters subsequent brain activity and behavior. This work emphasizes the need to understand behavioral development when doing research with such animals. The second focuses on a new rat model in which the epigenome is permanently imprinted, an effect that crosses generations to impact the descendants without further exposure to the precipitating agent. This work raises the question of how events in generations past can have consequences at both the mechanistic, behavioral, and ultimately evolutionary levels.
Development; Genetically-modified mice; Knockout; Imprinting; Molar epigenetics; Context-Dependent epigenetic modification; Germline-Dependent epigenetic modification; Neural network; Cytochrome oxidase
► Epigenetic control is involved in stress signaling and stress responses. ► Stress can modify epigenetic regulation at many different levels. ► Epigenetic and genetic components of stress responses are connected. ► Epigenetic diversity might be an important factor in stress adaptation and evolution.
Stressful conditions for plants can originate from numerous physical, chemical and biological factors, and plants have developed a plethora of survival strategies including developmental and morphological adaptations, specific signaling and defense pathways as well as innate and acquired immunity. While it has become clear in recent years that many stress responses involve epigenetic components, we are far from understanding the mechanisms and molecular interactions. Extending our knowledge is fundamental, not least for plant breeding and conservation biology. This review will highlight recent insights into epigenetic stress responses at the level of signaling, chromatin modification, and potentially heritable consequences.
The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy.
epigenetics; cancer; acetylation; methylation; histone; transcription; tumor
Epigenetics is focused on understanding the control of gene expression beyond what is encoded in the sequence of DNA. Central to growing interest in the field is the hope that more can be learned about the epigenetic regulatory mechanisms underlying processes of human development and disease. Researchers have begun to examine epigenetic alterations – such as changes in promoter DNA methylation, genomic imprinting, and expression of miRNA – to learn more about epigenetic regulation in the placenta, an organ whose proper development and function are crucial to the health growth and survival of the developing fetus. A number of studies are now making important links between alterations to appropriate epigenetic regulation in the placenta and diseases of gestation and early life. In addition, these studies are adding important insight into our understanding of trophoblast biology and differentiation as well as placental immunology. Examining epigenetic alterations in the placenta will prove especially important in the search for biomarkers of exposure, pathology, and disease risk and can provide critical insights into the biology of development and pathogenesis of disease. Thus, epigenetic alterations may aid in disease diagnosis and prognosis as well as in targeting new treatment and prevention strategies.
DNA methylation; environmental exposure; miRNA; imprinting
Personalised medicine provides patients with treatments that are specific to their genetic profiles. It requires efficient data sharing of disparate data types across a variety of scientific disciplines, such as molecular biology, pathology, radiology and clinical practice. Personalised medicine aims to offer the safest and most effective therapeutic strategy based on the gene variations of each subject. In particular, this is valid in oncology, where knowledge about genetic mutations has already led to new therapies. Current molecular biology techniques (microarrays, proteomics, epigenetic technology and improved DNA sequencing technology) enable better characterisation of cancer tumours. The vast amounts of data, however, coupled with the use of different terms - or semantic heterogeneity - in each discipline makes the retrieval and integration of information difficult.
Existing software infrastructures for data-sharing in the cancer domain, such as caGrid, support access to distributed information. caGrid follows a service-oriented model-driven architecture. Each data source in caGrid is associated with metadata at increasing levels of abstraction, including syntactic, structural, reference and domain metadata. The domain metadata consists of ontology-based annotations associated with the structural information of each data source. However, caGrid's current querying functionality is given at the structural metadata level, without capitalising on the ontology-based annotations. This paper presents the design of and theoretical foundations for distributed ontology-based queries over cancer research data. Concept-based queries are reformulated to the target query language, where join conditions between multiple data sources are found by exploiting the semantic annotations. The system has been implemented, as a proof of concept, over the caGrid infrastructure. The approach is applicable to other model-driven architectures. A graphical user interface has been developed, supporting ontology-based queries over caGrid data sources. An extensive evaluation of the query reformulation technique is included.
To support personalised medicine in oncology, it is crucial to retrieve and integrate molecular, pathology, radiology and clinical data in an efficient manner. The semantic heterogeneity of the data makes this a challenging task. Ontologies provide a formal framework to support querying and integration. This paper provides an ontology-based solution for querying distributed databases over service-oriented, model-driven infrastructures.
As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When “imprinted” early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulation, epigenetic modifications participate in the malignant transformation of cells. Their reversible nature has led to the emergence of the promising field of epigenetic therapy. The efforts made to inhibit in particular the epigenetic enzyme family called histone deacetylases (HDACs) are described. HDAC inhibitors (HDACi) have been proposed as a viable clinical therapeutic approach for the treatment of leukemia and solid tumors, but also to a lesser degree for noncancerous diseases. Three epigenetic drugs are already arriving at the patient’s bedside, and more than 100 clinical assays for HDACi are registered on the National Cancer Institute website. They explore the eventual additive benefits of combined therapies. In the context of the pleiotropic effects of HDAC isoforms, more specific HDACi and more informative screening tests are being developed for the benefit of the patients.
histone deacetylase inhibitors; epigenetic; clinical trials interpretation
The perspective presented here is that modern genetics is at a similar stage of development as were early formulations of quantum mechanics theory in the 1920s and that in 2010 we are at the dawn of a new revolution in genetics that promises to enrich and deepen our understanding of the gene and the genome. The interrelationships and interdependence of two views of the gene – the molecular biological view and the epigenetic view – are explored, and it is argued that the classical molecular biological view is incomplete without incorporation of the epigenetic perspective and that in a sense the molecular biological view has been evolving to include the epigenetic view. Intriguingly, this evolution of the molecular view toward the broader and more inclusive epigenetic view of the gene has an intriguing, if not precise, parallel in the evolution of concepts of atomic physics from Newtonian mechanics to quantum mechanics that are interesting to consider.
aperiodic crystal; paragenetics; parachromatin; transgenerational inheritance; histone code
Schizophrenia is a severe psychiatric disease affecting about 1% of the world's population, with significant effects on patients and society. Genetic studies have identified several candidate risk genes or genomic regions for schizophrenia, and epidemiological studies have revealed several environmental risk factors. However, the etiology of schizophrenia still remains largely unknown. Epigenetic mechanisms such as DNA methylation and histone modifications can explain the interaction between genetic and environmental factors at the molecular level, and accumulating evidence suggests that such epigenetic alterations are involved in the pathophysiology of schizophrenia. However, replication studies to validate previous findings and investigations of the causality of epigenetic alterations in schizophrenia are needed. Here, we review epigenetic studies of schizophrenia patients using postmortem brains or peripheral tissues, focusing mainly on DNA methylation. We also highlight the recent progress and challenges in characterizing the potentially complex and dynamic patterns of epigenomic variations. Such studies are expected to contribute to our understanding of schizophrenia etiology and should provide novel opportunities for the development of therapeutic drugs.
DNA methylation, gene-environment interaction (G × E); hydroxymethylcytosine; psychiatric disease; mental disorder
In the early years of the molecular biology revolution, cancer research was mainly focused on genetic changes (ie, those that altered DNA sequences). Although this has been extremely useful as our understanding of the pathogenesis and biology of cancer has grown and matured, there is another realm in tumor development that does not involve changing the sequence of cellular DNA. This field is called “epigenetics” and broadly encompasses changes in the methylation of cytosines in DNA, changes in histone and chromatin structure, and alterations in the expression of microRNAs, which control the stability of many messenger RNAs and serve as “master regulators” of gene expression. This review focuses on the epigenetics of colorectal cancer and illustrates the impact epigenetics has had on this field.
microRNA; DNA Methylation; Histone Modifications; Genomic Instability
The study of epigenetics has experienced exponential growth in the past 15 years and continues to be a major focus of study across biological disciplines. A new reference text Epigenetics: A Reference Manual, published by Caister Academic Press and edited by Jeffrey M. Craig and Nicholas C. Wong (Developmental Epigenetics Group, Murdoch Children's Research Institute, Victoria, Australia), presents a current and comprehensive look into the many facets of epigenetics research. The information targets a wide scientific audience and accommodates the expectations of both the novice and expert alike. Scientists with an inquisitive interest in epigenetics will appreciate the thorough description of epigenetic mechanisms with little a priori knowledge required. Scientists working in the field will find the current techniques, description of the technologies and resource tools valuable. With an ever evolving and expanding research field, the established epigenetic investigator will appreciate a centralized tome containing reviews across epigenetic mechanism and model system.
epigenetic inheritance; epigenetic memory; DNA methylation; histone modification; RNA modification; telomeres; epigenetic bioinformatics
There are many published studies about the epigenetic effects of the prenatal and infant periods on health outcomes. However, there is very little knowledge regarding the effects of the intrapartum period (labor and birth) on health and epigenetic remodeling. Although the intrapartum period is relatively short compared to the complete perinatal period, there is emerging evidence that this time frame may be a critical formative phase for the human genome. Given the debates from the National Institutes of Health and World Health Organization regarding routine childbirth procedures, it is essential to establish the state of the science concerning normal intrapartum epigenetic physiology. EPIIC (Epigenetic Impact of Childbirth) is an international, interdisciplinary research collaboration with expertise in the fields of genetics, physiology, developmental biology, epidemiology, medicine, midwifery, and nursing. We hypothesize that events during the intrapartum period – specifically the use of synthetic oxytocin, antibiotics, and cesarean section – affect the epigenetic remodeling processes and subsequent health of the mother and offspring. The rationale for this hypothesis is based on recent evidence and current best practice.
Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
Post-translational modifications of histones are critical not only for local regulation of gene expression, but also for higher-order structure of the chromosome and genome organization in general. These modifications enable a preset state to be maintained over subsequent generations and thus provide an epigenetic level of regulation. Heterochromatic regions of the genome are epigenetically regulated to maintain a “silent state” and protein coding genes inserted into these regions are subject to the same epigenetic silencing. The fission yeast Schizosaccharomyces pombe has well characterized regions of heterochromatin and has proven to be a powerful model for elucidation of epigenetic silencing mechanisms. Research in S. pombe led to the breakthrough discovery that epigenetic silencing is not solely a chromatin-driven transcriptional repression and that RNA interference of nascent transcripts can guide epigenetic silencing and associated histone modifications. Over the last 10 years, an eloquent integration of genetic and biochemical studies have greatly propelled our understanding of major players and effector complexes for regulation of RNAi-mediated epigenetic silencing in S. pombe. Here, we review recent research related to regulation of the epigenetic state in S. pombe heterochromatin, focusing specifically on the mechanisms by which transcription and RNA processing interact with the chromatin modification machinery to maintain the epigenetically silent state.
epigenetic silencing; fission yeast; heterochromatin; histone methyltransferase; RNA interference
As a biological discipline, zoology has one of the longest histories. Today it occasionally appears as though, due to the rapid expansion of life sciences, zoology has been replaced by more or less independent sub-disciplines amongst which exchange is often sparse. However, the recent advance of molecular methodology into "classical" fields of biology, and the development of theories that can explain phenomena on different levels of organisation, has led to a re-integration of zoological disciplines promoting a broader than usual approach to zoological questions. Zoology has re-emerged as an integrative discipline encompassing the most diverse aspects of animal life, from the level of the gene to the level of the ecosystem.
The new journal Frontiers in Zoology is the first Open Access journal focussing on zoology as a whole. It aims to represent and re-unite the various disciplines that look at animal life from different perspectives and at providing the basis for a comprehensive understanding of zoological phenomena on all levels of analysis. Frontiers in Zoology provides a unique opportunity to publish high quality research and reviews on zoological issues that will be internationally accessible to any reader at no cost.
Recent advances in genomic technologies now enable a reunion of molecular and evolutionary biology. Researchers investigating naturally living animal populations are thus increasingly able to capitalize upon genomic technologies to connect molecular findings with multiple levels of biological organization. Using this vertical approach in the laboratory, epigenetic gene regulation has emerged as an important mechanism integrating genotype and phenotype. To connect phenotype to population fitness, however, this same vertical approach must now be applied to naturally living populations. A major obstacle to studying epigenetics in noninvasive samples is tissue specificity of epigenetic marks. Here, using the mouse as a proof-of-principle model, we present the first known attempt to validate an epigenetic assay for use in noninvasive samples. Specifically, we compare DNA methylation of the NGFI-A (nerve growth factor-inducible protein A) binding site in the promoter of the glucocorticoid receptor (Nr3c1) gene between central (hippocampal) and peripheral noninvasive (fecal) tissues in juvenile Balb/c mice that had received varying levels of postnatal maternal care. Our results indicate that while hippocampal DNA methylation profiles correspond to maternal behavior, fecal DNA methylation levels do not. Moreover, concordance in methylation levels between these tissues within individuals only emerges after accounting for the effects of postnatal maternal care. Thus, although these findings may be specific to the Nr3c1 gene, we urge caution when interpreting DNA methylation patterns from noninvasive tissues, and offer suggestions for further research in this field.
DNA methylation; fecal samples; glucocorticoid receptor; maternal behavior; mouse
Immunological thought is exerting a growing effect in cancer research, correcting a divorce that occurred in the mainstream of the field decades ago just as cancer genetics began to emerge as a dominant movement. Today, with a general consensus on the significance of epigenetics, the inflammatory cancer microenvironment and the immune response in determining cancer pathophysiology, a new synthesis of thought is being spurred by a remarriage with cancer immunology, with great implications for the future of the field. This perspective offers a view on how this synthesis is impacting both the understanding and treatment of cancer using adjuvant immunomodulatory modalities in the context of surgical, radiotherapeutic and chemotherapeutic interventions which are present standards of care. With the revolutions in immunochemotherapy and immunoradiotherapy coming this decade, the next great challenge faced by the field will be how to identify simple, cost effective and broadly applicable solutions that do not rely deeply on personalized characters, in an effort to minimize the daunting complexity and costs of a problem that challenges not only physicians and patients but also health care systems and insurers caring for aging populations in the developed world.
Although both nutrition and chemicals are important environmental factors modulating epigenetic changes, they are commonly studied separately by researchers in different fields. However, these two environmental factors cannot be separated from each other in the real world because a number of chemical agents contaminate food chains.
We propose a unifying mechanism that can link epigenetic alterations in relation to DNA hypomethylation due to chemical agents and to nutrient deficiency or imbalance, emphasizing the importance of an integrative approach in the field of environmental epidemiology.
Methyl groups from S-adenosylmethionine (SAM) are needed for DNA methylation. Diets low in sources of methyl groups can lead to global DNA hypomethylation by impairing synthesis of SAM. However, even without nutritional deficiency, enhanced need to synthesize glutathi-one (GSH) can impair synthesis of SAM and perturb DNA methylation, because the methylation cycle and the GSH synthesis pathways are biochemically linked. Exposure to environmental chemicals is a common situation in which the need for GSH synthesis is enhanced, because GSH is consumed to conjugate diverse chemicals. Given that GSH conjugation happens at any chemical dose, this hypothesis is relevant even at exposures below the high doses that cause toxicologic responses.
At present, general populations are exposed to a large number of chemicals, each at a very low dose. Thus, DNA hypomethylation due to chemical exposure may be common in modern societies and can synergistically interact with nutrition-induced DNA hypomethylation.
chemicals; DNA hypomethylation; epigenetics; glutathione; nutrient; persistent organic pollutants
Epigenetics refers to alterations in gene expression due to modifications in histone acetylation and DNA methylation at the promoter regions of genes. Unlike genetic mutations, epigenetic alterations are not due to modifications in the gene primary nucleotide sequence. The importance of epigenetics in the initiation and progression of breast cancer has led many investigators to incorporate this novel and exciting field in breast cancer drug development. Several drugs that target epigenetic alterations, including inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT), are currently approved for treatment of hematological malignancies and are available for clinical investigation in solid tumors. In this manuscript, we review the critical role of epigenetics in breast cancer including the potential for epigenetic alterations to serve as biomarkers determining breast cancer prognosis and response to therapy. We highlight initial promising results to date with use of epigenetic modifiers in patients with breast cancer and the ongoing challenges involved in the successful establishment of these agents for the treatment of breast cancer.
Epigenetics; Breast cancer; DNA methyltransferase inhibitor (DNMT); Histone deacetylase inhibitor (HDAC)
biologists have taken the view that an understanding
of development is irrelevant to theories of evolution.
However, the integration of several disciplines in
recent years suggests that this position is wrong. The
capacity of the organism to adapt to challenges from
the environment can set up conditions that affect the
subsequent evolution of its descendants. Moreover,
molecular events arising from epigenetic processes can
be transmitted from one generation to the next and
influence genetic mutation. This in turn can
facilitate evolution in the conditions in which
epigenetic change was first initiated.
Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer.
epigenetic regulation; DNA methylation; histone modification; radiation exposure; cancer; colon cancer
Neuropsychiatric disorders affect a large segment of the human population and result in large costs to society. The majority of such disorders have unknown underlying causes. Recent evidence suggests an important role for epigenetic regulation in the emergence of neuropsychiatric disease. Epigenetics may provide a link between genetic and environmental factors and behavior. Epigenetic signaling involves changes on the structure of chromatin; such changes are often triggered and maintained by the post-translational modification of chromatin proteins and/or DNA. Recent proteomic technologies have enabled the study of epigenetic mechanisms in a high-throughput manner. This review will provide an overview of the major epigenetic pathways and modern techniques for their study, before focusing on experimental evidence supporting a strong role for epigenetics in selected psychiatric disorders such as depression, schizophrenia and drug addiction. These results highlight a great need for the inclusion of the proteomic characterization of epigenetic mechanisms in the study of gene/disease associations in psychiatric disorders.
Epigenetics; chromatin; histone modification; DNA methylation; neuropsychiatric disorders
The pathogenic origin of autoimmune diseases can be traced to both genetic susceptibility and epigenetic modifications arising from exposure to the environment. Epigenetic modifications influence gene-expression and alter cellular functions without modifying the genomic sequence. CpG-DNA methylation, histone-tail modifications, and micro-RNAs (miRNAs) are the main epigenetic mechanisms of gene regulation. Understanding the molecular mechanisms that are involved in the pathophysiology of autoimmune diseases is essential for the introduction of effective, target-directed, and tolerated therapies. In this review, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune disorders while focusing on systemic lupus erythematosus (SLE). We discuss future directions in basic research, autoimmune diagnostics, and applied therapy.