Epigenetics, miRNAs, and human cancer: a new chapter in human gene regulation

Cancer is a genetic and epigenetic disease. MicroRNAs (miRNAs), a class of small noncoding RNAs, have been shown to be deregulated in many diseases including cancer. An intertwined connection between epigenetics and miRNAs has been supported by the recent identification of a specific subgroup of miRNAs called “epi-miRNAs” that can directly and indirectly modulate the activity of the epigenetic machinery. The complexity of this connection is enhanced by the epigenetic regulation of miRNA expression that generates a fine regulatory feedback loop. This review focuses on how epigenetics affects the miRNome and how the recently identified epi-miRNAs regulate the epigenome in human cancers, ultimately contributing to human carcinogenesis.     

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.     

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.     

Effect of maternal zinc deficiency on offspring health: The epigenetic impact

BackgroundZinc deficiency is associated with adverse effects on maternal health and pregnancy outcomes. These consequences have been reported over the years from zinc supplementation trials and observational studies whereby outcomes of maternal, foetal and infant health were measured. Owing to the importance of zinc in the functions of epigenetic enzymes, pre-clinical studies have shown that its deficiency could disrupt biological activities that involve epigenetic mechanisms in offspring. Thus, this review assessed the link between epigenetics and the effects of maternal zinc deficiency on the offspring’s health in animal studies.MethodsResearch articles were retrieved without date restriction from PubMed, Web of Science, ScienceDirect, and Google Scholar databases, as well as reference lists of relevant articles. The search terms used were “zinc deficiency”, “maternal zinc deficiency”, “epigenetics”, and “offspring.” Six studies met the eligibility criteria and were reviewed.ResultsAll the eligible studies reported maternal zinc deficiency and observed changes in epigenetic markers on the progeny during prenatal and postnatal stages of development. The main epigenetic markers reported were global and gene specific methylation and/ or acetylation. The epigenetic changes led to mortality, disruption in development, and risk of later life diseases.ConclusionMaternal zinc deficiency is associated with epigenetic modifications in offspring, which induce pathologies and increase the risk of later life diseases. More research and insight into the epigenetic mechanisms could spring up new approaches to combat the associated disease conditions.     

Mapping the new molecular landscape: social dimensions of epigenetics

Epigenetics is the study of changes in gene expression caused by mechanisms other than changes in the DNA itself. The field is rapidly growing and being widely promoted, attracting attention in diverse arenas. These include those of the social sciences, where some researchers have been encouraged by the resonance between imaginaries of development within epigenetics and social theory. Yet, sustained attention from science and technology studies (STS) scholars to epigenetics and the praxis it propels has been lacking. In this article, we reflexively consider some of the ways in which epigenetics is being constructed as an area of biomedical novelty and discuss the content and logics underlying the ambivalent promises being made by scientists working in this area. We then reflect on the scope, limits and future of engagements between epigenetics and the social sciences. Our discussion is situated within wider literatures on biomedicine and society, the politics of “interventionist STS”, and on the problems of “caseness” within empirical social science.     

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.     

Epigenetic metaphors: an interdisciplinary translation of encoding and decoding

Looking at the new and often disputed science of epigenetics, we examined the challenges faced by scientists when they communicate scientific research to the public. We focused on the use of metaphors to illustrate notions of epigenetics and genetics. We studied the “encoding” by epigeneticists and “decoding” in focus groups with diverse backgrounds. We observed considerable overlap in the dominant metaphors favored by both researchers and the lay public. However, the groups differed markedly in their interpretations of which metaphors aided understanding or not. We conclude by discussing the role of metaphors and their interpretations in the context of a shift from pre-deterministic genomic metaphors to more active, dynamic and nuanced epigenetic metaphors. These reflections on the choice of metaphors and differences in encoding/decoding are important for science communication and scientific boundary-maintenance.     

Environmental Values,Human Nature,and Economic Democracy

Recent social science indicates that the public at large behave more ethically, and favor environmental protection more strongly, than do the wealthiest minority. Yet the latter group exerts predominant control over the economy. This suggests that shifting power away from this minority and onto the majority would yield a better ecology. In this paper I spell out the implications of these considerations for “economic democracy” (ED), a well-developed alternative to capitalism that shifts power from wealthy shareholders onto ordinary citizens and workers. I contrast this rationale for ED with some thinkers’ defense of “sustainable capitalism”, and with others’ ecological arguments for ED based on economic stability and self-interest, rather than ethical behavior per se.     

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.     

The Legal Status of Cats in New Zealand: A Perspective on the Welfare of Companion,Stray, and Feral Domestic Cats (Felis catus)

Pinpointing and safeguarding the welfare status of domestic cats is problematic, especially in New Zealand where cats are introduced predators with significant impact on indigenous fauna. Usually the identification of welfare status depends on conservational, legal, and public attitudes that are often contrasting. Cats may rapidly transgress definitions placed on them, confounding attempts to categorize them. In 1 generation, cats can move from a human-dependent state (“stray” or “companion”) to wild (“feral”). Often this categorization uses arbitrary behavioral and or situational parameters; consequent treatment and welfare protection for these cats are similarly affected. Terminology used to describe cats is not equitable across research. However, the New Zealand Animal Welfare (Companion Cats) Code of Welfare 2007 seeks to create a new definition of the terms companion, stray, and feral. It distinguishes between cats who live within and without human social constructs. This legislation mandates that cats in human environments or indirectly dependent on humans cannot be classified as feral. Such definitions may prove vital when safeguarding the welfare of free-living domestic cats and cat colonies.     

Plant epigenetics: phenotypic and functional diversity beyond the DNA sequence

Phenotypic variation determines the capacity of plants to adapt to changing environments and to colonize new habitats. Deciphering the mechanisms contributing to plant phenotypic variation and their effects on plant ecological interactions and evolutionary dynamics is thus central to all biological disciplines. In the past few decades, research on plant epigenetics is showing that (1) epigenetic variation is related to phenotypic variation and that some epigenetic marks drive major phenotypic changes in plants; (2) plant epigenomes are highly diverse, dynamic, and can respond rapidly to a variety of biotic and abiotic stimuli; (3) epigenetic variation can respond to selection and therefore play a role in adaptive evolution. Yet, current information in terms of species, geographic ranges, and ecological contexts analyzed so far is too limited to allow for generalizations about the relevance of epigenetic regulation in phenotypic innovation and plant adaptation across taxa. In this report, we contextualize the potential role of the epigenome in plant adaptation to the environment and describe the latest research in this field presented during the symposium “Plant epigenetics: phenotypic and functional diversity beyond the DNA sequence” held within the Botany 2020 conference framework in summer 2020.     

Ecological plant epigenetics: Evidence from model and non‐model species,and the way forward

Growing evidence shows that epigenetic mechanisms contribute to complex traits, with implications across many fields of biology. In plant ecology, recent studies have attempted to merge ecological experiments with epigenetic analyses to elucidate the contribution of epigenetics to plant phenotypes, stress responses, adaptation to habitat, and range distributions. While there has been some progress in revealing the role of epigenetics in ecological processes, studies with non‐model species have so far been limited to describing broad patterns based on anonymous markers of DNA methylation. In contrast, studies with model species have benefited from powerful genomic resources, which contribute to a more mechanistic understanding but have limited ecological realism. Understanding the significance of epigenetics for plant ecology requires increased transfer of knowledge and methods from model species research to genomes of evolutionarily divergent species, and examination of responses to complex natural environments at a more mechanistic level. This requires transforming genomics tools specifically for studying non‐model species, which is challenging given the large and often polyploid genomes of plants. Collaboration among molecular geneticists, ecologists and bioinformaticians promises to enhance our understanding of the mutual links between genome function and ecological processes.     

Metaphors in search of a target: the curious case of epigenetics

Carrying out research in genetics and genomics and communicating about them would not be possible without metaphors such as “information,” “code,” “letter” or “book.” Genetic and genomic metaphors have remained relatively stable for a long time but are now beginning to shift in the context of synthetic biology and epigenetics. This article charts the emergence of metaphors in the context of epigenetics, first through collecting some examples of metaphors in scientific and popular writing and second through a systematic analysis of metaphors used in two UK broadsheets. Findings show that while source domains for metaphors can be identified, such as our knowledge of electrical switches or of bookmarks, it is difficult to pinpoint target domains for such metaphors. This may be indicative both of struggles over what epigenetics means for scientists (natural and social) and of difficulties associated with talking about this, as yet, young field in the popular press.     

Neural and behavioral epigenetics; what it is,and what is hype

The ability to examine epigenetic mechanisms in the brain has become readily available over the last 20 years. This has led to an explosion of research and interest in neural and behavioral epigenetics. Of particular interest to researchers, and indeed the lay public, is the possibility that epigenetic processes, such as changes in DNA‐methylation and histone modification, may provide a biochemical record of environmental effects. This has led to some fascinating insights into how molecular changes in the brain can control behavior. However, some of this research has also attracted controversy and, as is dealt with here, some overblown claims. This latter problem is partly linked to the shifting sands of what is defined as ‘epigenetics’. In this review, I provide an overview of what exactly epigenetics is, and what is hype, with the aim of opening up a debate as to how this exciting field moves forward.     

Finalism in Darwinian and Lamarckian Evolution: Lessons from Epigenetics and Developmental Biology

Finalist (teleological) implications have been described for both Darwinian and Lamarckian theories, even though finalism appears to be more commonly associated with Lamarckism. Biologists have focused on finding final causes to explain evolutionary novelties through, for example, applying the ??what for??? question to address experimental observations. Now epigenetics, together with developmental biology, may allow us to focus on the efficient causes leading to evolutionary change, asking the ??how??? question, considering environmental influences as inducers of genomic change. This is a whole under-studied dimension in evolutionary studies. In this paper, I discuss how epigenetics and developmental biology can help integrate two important ways in which the environment affects evolution: through inducing or through restricting the emergence of new phenotypes. I also discuss which aspects of both theories should be reconsidered in the face of current knowledge in epigenetics and where the emphasis of evolutionary experiments should be placed. Important goals of evolution related epigenetic studies should be: (i) to experimentally consider the separation among the origin of characters in a lineage and its further fixation, in order to address these processes in a proper dimension, (ii) to build the cause-effect relation between the factors inducing epigenetic changes and consequent changes in population parameters, and (iii) to consider that the arising of new characters is modulated by physiological and developmental constraints, and that this process is not related to a purpose or focused to solve an ecological, physiological or evolutionary challenge.     

Epigenetic regulation of immune escape genes in cancer

According to the concept of immune surveillance, the appearance of a tumor indicates that it has earlier evaded host defenses and subsequently must have escaped immunity to evolve into a full-blown cancer. Tumor escape mechanisms have focused mainly on mutations of immune and apoptotic pathway genes. However, data obtained over the past few years suggest that epigenetic silencing in cancer may be as frequent a cause of gene inactivation as are mutations. Here, we discuss the evidence that tumor immune evasion is mediated by non-mutational epigenetic events involving chromatin and that epigenetics collaborates with mutations in determining tumor progression. Since epigenetic changes are potentially reversible, the relative contribution of mutations and epigenetics, to the gene defects in any given tumor, may be a factor in determining the efficacy of treatments. We review new developments in basic chromatin mechanisms and in this context describe the rationale for the current use of epigenetic agents in cancer therapy and for a novel epigenetically generated tumor vaccine model. We emphasize that epigenetic cancer treatments are currently a ‘blunt-sword’ and suggest future directions for designing chromatin-based programs of potential value in the diagnosis and treatment of cancer.     

Environmental epigenetic modifications and reprogramming-recalcitrant genes

The term “environmental epigenetic modifications” refers to alterations in phenotype triggered by environmental stimuli via epigenetic mechanisms. Epidemiologic and animal model studies show that a subset of such environmental epigenetic marks may affect susceptibility to chronic diseases. A growing body of evidence regarding incompleteness of reprogramming indicates that the potential retention of pathogenic environmental epigenetics in human induced pluripotent stem cells (iPSCs) should be seriously considered. Given this possibility, the optimization of methods for the generation of human induc pluripotent stem cells may require the identification of epigenetically appropriate somatic cell sources. Similarly, techniques for controlling epigenetic modification by environmental factors may also play a critical role in the development of epigenetically stable sources of pluripotent stem cells.     

Maternal inheritance,epigenetics and the evolution of polyandry

Growing evidence indicates that females actively engage in polyandry either to avoid genetic incompatibility or to bias paternity in favor of genetically superior males. Despite empirical support for the intrinsic male quality hypothesis, the maintenance of variation in male fitness remains a conundrum for traditional "good genes" models of sexual selection. Here, we discuss two mechanisms of non-Mendelian inheritance, maternal inheritance of mitochondria and epigenetic regulation of gene expression, which may explain the persistence of variation in male fitness traits important in post-copulatory sexual selection. The inability of males to transmit mitochondria precludes any direct evolutionary response to selection on mitochondrial mutations that reduce or enhance male fitness. Consequently, mitochondrial-based variation in sperm traits is likely to persist, even in the face of intense sperm competition. Indeed, mitochondrial nucleotide substitutions, deletions and insertions are now known to be a primary cause of low sperm count and poor sperm motility in humans. Paradoxically, in the field of sexual selection, female-limited response to selection has been largely overlooked. Similarly, the contribution of epigenetics (e.g., DNA methylation, histone modifications and non-coding RNAs) to heritable variation in male fitness has received little attention from evolutionary theorists. Unlike DNA sequence based variation, epigenetic variation can be strongly influenced by environmental and stochastic effects experienced during the lifetime of an individual. Remarkably, in some cases, acquired epigenetic changes can be stably transmitted to offspring. A recent study indicates that sperm exhibit particularly high levels of epigenetic variation both within and between individuals. We suggest that such epigenetic variation may have important implications for post-copulatory sexual selection and may account for recent findings linking sperm competitive ability to offspring fitness.