Synergy of Homocysteine, MicroRNA, and Epigenetics: A Novel Therapeutic Approach for Stroke

Homocysteine (Hcy) is a thiol-containing amino acid formed during methionine metabolism. Elevated level of Hcy is known as hyperhomocysteinemia (HHcy). HHcy is an independent risk factor for cerebrovascular diseases such as stroke, dementia, Alzheimer’s disease, etc. Stroke, which is caused by interruption of blood supply to the brain, is one of the leading causes of death and disability in a number of people worldwide. The HHcy causes an increased carotid artery plaque that may lead to ischemic stroke but the mechanism is currently not well understood. Though mutations or polymorphisms in the key genes of Hcy metabolism pathway have been well elucidated in stroke, emerging evidences suggested epigenetic mechanisms equally play an important role in stroke development such as DNA methylation, chromatin remodeling, RNA editing, noncoding RNAs (ncRNAs), and microRNAs (miRNAs). However, there is no review available yet that describes the role of genetics and epigenetics during HHcy in stroke. The current review highlights the role of genetics and epigenetics in stroke during HHcy and the role of epigenetics in its therapeutics. The review also highlights possible epigenetic mechanisms, potential therapeutic molecules, putative challenges, and approaches to deal with stroke during HHcy.     

Epigenetic determinism in science and society

The epigenetic “revolution” in science cuts across many disciplines, and it is now one of the fastest-growing research areas in biology. Increasingly, claims are made that epigenetics research represents a move away from the genetic determinism that has been prominent both in biological research and in understandings of the impact of biology on society. We discuss to what extent an epigenetic framework actually supports these claims. We show that, in contrast to the received view, epigenetics research is often couched in language as deterministic as genetics research in both science and the popular press. We engage the rapidly emerging conversation about the impact of epigenetics on public discourse and scientific practice, and we contend that the notion of epigenetic determinism – or the belief that epigenetic mechanisms determine the expression of human traits and behaviors – matters for understandings of the influence of biology and society on population health.     

Population epigenetics

Our knowledge of the mechanisms that specify and propagate epigenetic states of gene expression is expanding rapidly; however, the significance of variation in epigenetic states at the population level remains largely unexplored. Population epigenetics, emerging as an active subfield at the interface of molecular genetics, genomics, and population biology, addresses questions concerning the prevalence and importance of epigenetic variation in the natural world.     

Epigenetics and cell cycle regulation in cystogenesis

The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of “PKD epigenetics” and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.     

Epigenetic gene regulation in stem cells and correlation to cancer

Through the classic study of genetics, much has been learned about the regulation and progression of human disease. Specifically, cancer has been defined as a disease driven by genetic alterations, including mutations in tumor-suppressor genes and oncogenes, as well as chromosomal abnormalities. However, the study of normal human development has identified that in addition to classical genetics, regulation of gene expression is also modified by ‘epigenetic’ alterations including chromatin remodeling and histone variants, DNA methylation, the regulation of polycomb group proteins, and the epigenetic function of non-coding RNA. These changes are modifications inherited during both meiosis and mitosis, yet they do not result in alterations of the actual DNA sequence. A number of biological questions are directly influenced by epigenetics, such as how does a cell know when to divide, differentiate or remain quiescent, and more importantly, what happens when these pathways become altered? Do these alterations lead to the development and/or progression of cancer? This review will focus on summarizing the limited current literature involving epigenetic alterations in the context of human cancer stems cells (CSCs). The extent to which epigenetic changes define cell fate, identity, and phenotype are still under intense investigation, and many questions remain largely unanswered. Before discussing epigenetic gene silencing in CSCs, the different classifications of stem cells and their properties will be introduced. This will be followed by an introduction to the different epigenetic mechanisms. Finally, there will be a discussion of the current knowledge of epigenetic modifications in stem cells, specifically what is known from rodent systems and established cancer cell lines, and how they are leading us to understand human stem cells.     

The Russian Biological Student Microscopes

Our out-of-school practical exercise was designed to bring upper secondary school students in contact with one of the most exciting and expanding topics in biology today: epigenetics. In school, students only study the basics in genetics and the respective investigation techniques as provided by the syllabus. For a practical exercise in epigenetics, however, they need additional knowledge. Hence, they are introduced to the subject of epigenetics and its molecular mechanisms. Students are asked to examine the different DNA methylation conditions of lambda DNA using both a restriction assay and gel electrophoresis in an out-of-school laboratory. DNA methylation is one of the major epigenetic mechanisms which have significant effects on gene expression; studies on monozygotic twins have shown that it is influenced by the environment. This exercise enables students to correctly identify the different methylation conditions of distributed lambda DNA samples. In doing so, they receive a first introduction to one epigenetic mechanism. The necessity for students to experience science in out-of-school settings has been shown by several scholars. The practical exercise we are proposing in this article was elaborated for such learning opportunities for upper secondary students to gain insight into contemporary science issues.     

How to localize epigenetics in the landscape of biological research?

Today, epigenetics is a very fashionable field of research. Modification of DNA by methylation, and of chromatin by histone modification or substitution represents a major fraction of the studies; but this special issue shows that epigenetic studies are very diverse, and not limited to the study of chromatin. What is common behind these different uses of the word epigenetics? A brief historical survey shows that epigenetics was invented twice, with different meanings: in the 1940s, by Conrad Waddington, as the study of the relations between the genotype and the phenotype; in the 1960s, as the global mechanisms of gene regulation involved in differentiation and development; what is common is that an approach distinct from genetics was in both cases considered as necessary because genetic models were incapable to address these problems. A good way to appreciate the relations between genetics and epigenetics is to realize that the main aim of organisms is to reproduce, and to consider the way organisms perform this task. Genetics is the precise means organisms have invented to reproduce the structure of their macromolecular components; the genome is also used to control the level and place of this reproduction. All the other means organisms have used to reproduce were more or less the result of tinkering, and constitute the field of epigenetics, with its diversity and richness.     

Epigenetics in osteoarthritis: Novel spotlight

Osteoarthritis (OA) is the most common type of arthritis and no longer is considered as an absolute consequence of joint mechanical use (wear and tear); rather recent data demonstrate the pivotal role of inflammatory mediators in the development and progression of this disease. This multifactorial disease results from several environmental and inherited factors. Genetic cannot solely explain all the contribution share of inheritance and, this way, it is speculated that epigenetics can play a role, too. Moreover, environmental factors can induce local epigenetic changes. The epigenetic contribution to OA pathogenesis occurs at all of its levels, DNA methylation, histone modification, microRNA, and long noncoding RNA. In fact, during early phases of OA pathogenesis, environmental factors employ epigenetic mechanisms to provide a positive feedback for the OA-related pathogenic mechanisms and pathways with an ultimate outcome of a well-established clinical OA. These epigenetic changes stay during clinical disease and prevent the body natural healing and regenerative processes to work properly, resulting in an incurable disease condition. In this review article, we aimed to have an overview on the studies performed with regard to understanding the role of epigenetics in the etiopathogenesis of OA and highlighted the importance of such kind of regulatory mechanisms within this context.     

Translational Epigenetics: Clinical Approaches to Epigenome Therapeutics for Cancer

Cancer epigenetics research is now entering an exciting phase of translational epigenetics whereby novel epigenome therapeutics is being developed for application in clinical settings. Epigenetics refers to all heritable and potentially reversible changes in gene or genome functioning that occurs without altering the nucleotide sequence of the DNA. A range of different epigenetic “marks” can activate or repress gene expression. While epigenetic alterations are associated with most cancers, epigenetic dysregulation can also have a causal role in cancer etiology. Epigenetically disrupted stem or progenitor cells could have an early role in neoplastic transformations, while perturbance of epigenetic regulatory mechanisms controlling gene expression in cancer-relevant pathways will also be a contribution factor. The reversibility of epigenetic marks provides the possibility that the activity of key cancer genes and pathways can be regulated as a therapeutic approach. The growing availability of a range of chemical agents which can affect epigenome functioning has led to a range of epigenetic-therapeutic approaches for cancer and intense interest in the development of second-generation epigenetic drugs (epi-drugs) which would have greater specificity and efficacy in clinical settings. The latest developments in this exciting arena of translational cancer epigenetics were presented at a recent conference on “Epigenetics and New Therapies in Cancer” at the Spanish National Cancer Research Center (CNIO), Spain.     

Epigenetics of Host–Pathogen Interactions: The Road Ahead and the Road Behind

A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g., cancer). With the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing. Despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. Yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. The phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. Moreover, pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. The significance of epigenetic modifications may, however, go beyond providing a mechanistic basis for host and pathogen plasticity. Epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. In addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. Here, we review the evidence available for the role epigenetics on host–pathogen interactions, and the utility and versatility of the epigenetic technologies available that can be cross-applied to host–pathogen studies. We conclude with recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.     

CpG Island Hypermethylation of Tumor Suppressor microRNAs in Human Cancer

In the last few years, microRNAs have started a revolution in molecular biology and emerged as key players in the cancer process. For these reasons, it is extremely important to understand the physiological and disease-associated mechanisms underlying the regulation of these small, single-stranded RNAs. Thus, it was merely a matter of time before microRNAs and epigenetics coincided. In cancer, aberrant DNA hypermethylation of tumor suppressor genes, global genomic DNA hypomethylation, and disruption of the histone modification patterns are the main epigenetic alterations, and have consequently been widely studied. Some microRNAs are downregulated in cancer and act as bona fide tumor suppressor genes, and this knowledge led to the proposal of the hypothesis that miRNAs could be silenced by epigenetic mechanisms. It has recently been shown that miR-127 and miR-124a, two putative tumor suppressor miRNAs, are methylated in tumor cells. Epigenomic tools can be effectively used in the search for new methylated tumor suppressor microRNAs. Furthermore, this aberrant methylation can be reversed by epigenetic drugs, such as DNA demethylating agents and histone deacetylase inhibitors, restoring microRNA expression levels and reverting the tumoral phenotype. In the coming years we will come to realize more fully the relevance of this expected encounter between two forces – epigenetics and microRNAs – that are currently at the forefront of biology.     

Hot topics in epigenetic mechanisms of aging: 2011

Aging is a complex process that results in compromised biological functions of the organism and increased susceptibility to disease and death. Although the molecular basis of aging is currently being investigated in many experimental contexts, there is no consensus theory to fully explain the aging process. Epigenetic factors, including DNA methylation, histone modifications, and microRNA expression, may play central roles in controlling changes in gene expression and genomic instability during aging. In this Hot Topic review, we first examine the mechanisms by which these epigenetic factors contribute to aging in diverse eukaryotic species including experimental models of yeasts, worms, and mammals. In a second section, we will emphasize in the mammalian epigenetic alterations and how they may affect human longevity by altering stem cell function and/or somatic cell decline. The field of aging epigenetics is ripe with potential, but is still in its infancy, as new layers of complexity are emerging in the epigenetic network. As an example, we are only beginning to understand the relevance of non-coding genome to organism aging or the existence of an epigenetic memory with transgenerational inheritance. Addressing these topics will be fundamental for exploiting epigenetics phenomena as markers of aging-related diseases or as therapeutic targets.     

What obesity research tells us about epigenetic mechanisms

The pathophysiology of obesity is extremely complex and is associated with extensive gene expression changes in tissues throughout the body. This situation, combined with the fact that all gene expression changes are thought to have associated epigenetic changes, means that the links between obesity and epigenetics will undoubtedly be vast. Much progress in identifying epigenetic changes induced by (or inducing) obesity has already been made, with candidate and genome-wide approaches. These discoveries will aid the clinician through increasing our understanding of the inheritance, development and treatment of obesity. However, they are also of great value for epigenetic researchers, as they have revealed mechanisms of environmental interactions with epigenetics that can produce or perpetuate a disease state. Here, we will review the evidence for four mechanisms through which epigenetics contributes to obesity: as downstream effectors of environmental signals; through abnormal global epigenetic state driving obesogenic expression patterns; through facilitating developmental programming and through transgenerational epigenetic inheritance.     

Epigenetic inheritance,prions and evolution

The field of epigenetics has grown explosively in the past two decades or so. As currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in DNA sequence, but alter the way that information encoded in DNA is utilized. The bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. However, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducing organisms or mitotically in asexually reproducing ones. Such transgenerational epigenetic inheritance (TEI) raises obvious questions about a possible evolutionary role for epigenetic ‘Lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. In this review I attempt a brief overview of the periodically reviewed and debated ‘classical’ TEI phenomena and their possible implications for evolution. The review then focusses on a less-discussed, unique kind of protein-only epigenetic inheritance mediated by prions. Much remains to be learnt about the mechanisms, persistence and effects of TEI. The jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.