Epigenetics of stress adaptations in the brain

Recent findings in epigenetics shed new light on the regulation of gene expression in the central nervous system (CNS) during stress. The most frequently studied epigenetic mechanisms are DNA methylation, histone modifications and microRNA activity. These mechanisms stably determine cell phenotype but can also be responsible for dynamic molecular adaptations of the CNS to stressors. The limbic–hypothalamic–pituitary–adrenal axis (LHPA) is the primary circuit that initiates, regulates and terminates a stress response. The same brain areas that control stress also react to stress dynamically and with long-term consequences. One of the biological processes evoking potent adaptive changes in the CNS such as changes in behavior, gene activity or synaptic plasticity in the hippocampus is psychogenic stress. This review summarizes the current data regarding the epigenetic basis of molecular adaptations in the brain including genome-wide epigenetic changes of DNA methylation and particular genes involved in epigenetic responses that participate in the brain response to chronic psychogenic stressors. It is concluded that specific epigenetic mechanisms in the CNS are involved in the stress response.     

Epigenetics in nucleotide repeat expansion disorders

Over the past 20 years, nucleotide repeat expansion disorders have informed our broader understanding of neurodevelopmental and neurodegenerative disease. This is especially true with regard to the contributions of epigenetic mechanisms to neurologic disease pathogenesis. In this review, the authors describe a few of the myriad ways in which epigenetic processes underlie aspects of repeat expansion disorder pathophysiology and discuss how therapies targeted at epigenetic modulation hold promise for many of these disorders.     

Epileptogenesis: Can the Science of Epigenetics Give Us Answers?

Epigenetic mechanisms are regulatory processes that control gene expression changes involved in multiple aspects of neuronal function, including central nervous system development, synaptic plasticity, and memory. Recent evidence indicates that dysregulation of epigenetic mechanisms occurs in several human epilepsy syndromes. Despite this discovery of a potential role for epigenetic mechanisms in epilepsy, few studies have fully explored their contribution to the process of epilepsy development known as epileptogenesis. The purpose of this article is to discuss recent findings suggesting that the process of epileptogenesis may alter the epigenetic landscape, affecting the gene expression patterns observed in epilepsy. Future studies focused on a better characterization of these aberrant epigenetic mechanisms hold the promise of revealing novel treatment options for the prevention and even the reversal of epilepsy.The underlying cause of epilepsy in patients is still largely unknown, leaving 1 to 2% of the population without a cure and making the search for new treatments ever more urgent. Current treatment options for the epilepsies have been largely focused on and are effective at controlling seizure activity in most cases; however, cures for these disorders have been elusive. This is largely owing to the very complex progression of the disease state and the multiple inherited and acquired factors that can influence the onset and progression of epilepsy disorders. An emerging idea is that exploring epigenetic mechanisms, including covalent modifications of histones and DNA, may provide insight into how inherited or acquired alterations in the steady-state expression patterns of genes in the brain contribute to epileptogenesis.During the past decade the science of epigenetics has advanced our understanding of the complex relationship between genetic and environmental factors that orchestrate expression of genes under numerous physiologic conditions. Accordingly, aberrant epigenetic regulation of genes has been implicated in several CNS disorders, including stroke, Alzheimer disease, schizophrenia, and depression (1, 2). Epilepsy is no exception, in that abnormalities in the expression and regulation of epigenetic factors offer a provocative locus for the integration of common pathways that may reveal novel insights into the development of this disease.     

Epigenetics and Biomarkers in the Staging of Neuropsychiatric Disorders

Epigenetics, or alterations in the phenotype or gene expression due to mechanisms other than changes in the underlying DNA sequence, reflects the sensitivity and responsiveness of human and animal brains in constantly varying circumstances regulating gene expression profiles that define the biomarkers and present the ultimate phenotypical outcomes, such as cognition and emotion. Epigenetics is associated with functionally relevant alterations to the genome in such a fashion that under the particular conditions of early, adolescent, and adult life, environmental signals may activate intracellular pathways that remodel the “epigenome,” triggering changes in gene expression and neural function. Thus, genetic influences in neuropsychiatric disorders that are subject to clinical staging, epigenetics in schizophrenia, epigenetic considerations in the expression of sensorimotor gating resulting from disease conditions, biomarkers of drug use and addiction, current notions on the role of dopamine in schizophrenia spectrum disorders, and the discrete interactions of biomarkers in persistent memory were to greater or lesser extents reflected upon. The relative contributions of endophenotypes and epistasis for mediating epigenetic phenomena and the outcomes as observed in the analysis of biomarkers appear to offer a multitude of interactive combinations to further complicate the labyrinthine machinations of diagnosis, intervention, and prognosis.     

Epigenetics and psychoneuroimmunology: Mechanisms and models

In this Introduction to the Named Series “Epigenetics, Brain, Behavior, and Immunity” an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome.     

Alzheimer's disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics

Several lines of evidence indicate that the etiology of late-onset Alzheimer's disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research suggests the importance of epigenetic mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD. There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD, and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures during early life and onset of Alzheimer's disease. There is also a lack of validated circulating epigenetics biomarkers and retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.     

Epigenetics Modifications in Large-Artery Atherosclerosis: A Systematic Review

ObjectivesIn recent years, the evidence of the relationship between epigenetics and acute ischemic stroke (AIS) were accumulating, however, the epigenetic characteristics that directs specifically towards the aetiology of large-artery atherosclerosis (LAA) remain ambiguous. The aim of this study was to highlight the overall evidence concerning the epigenetic mechanisms associated with the occurrence of LAA.Materials and methodsStudies that involve investigations related to epigenetic markers (DNA methylation and RNA modifications) and LAA were retrieved from eleven scientific publication databases. The studies were screened through the pre-set inclusion and exclusion criteria prior to the NOS evaluation.ResultsEligible studies (n=25) were evaluated. Of which, six reported on DNA methylation and 19 studies assessed RNA modifications (16 on miRNAs, two on lncRNAs, and one study on circRNA). Hypomethylation of MTRNR2L8 and ERα promoters; microRNAs (miR-7-2-3p, miR-16, miR-34a-5p, miR-126, miR-143, miR-200b, miR-223, miR-503, miR-1908, miR-146a rs2910164 C/G, miR-149 rs2292832 T/C, miR-200b rs7549819 T/C, miR-34a rs2666433); lncRNA of ZFAS1; and circRNA of hsa_circRNA_102488 were associated with LAA significantly.ConclusionCurrent systematic review highlighted hypomethylation of miRNAs and lncRNA might be the potential biomarkers for LAA.     

New horizons in the development of antiepileptic drugs: the search for new targets

The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g., after head trauma or stroke. Thus, there are at least three important goals for the future: (1) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (2) development of disease-modifying therapies, interfering with progression of epilepsy, and (3) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The Second Workshop on New Horizons in the Development of Antiepileptic Drugs explored these three goals for improved epilepsy therapy, with a focus on the search for new drug targets for prevention of epilepsy, for interfering with progression of epilepsy, and for interfering with drug resistance in epilepsy. A special topic dealt with gene expression analysis for target identification. Furthermore, pharmacological and non-pharmacological targets for curing epilepsy were explored. In this conference review, the current status of antiepileptic therapies is critically assessed, and innovative approaches for future therapies are highlighted.     

Idiopathic focal epilepsies: the “lost tribe”

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010 ), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many “treats” for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age‐related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow‐wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro‐temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau‐Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro‐clinical features warranting inclusion. In addition, a number of less well‐defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The term “benign” is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research. A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence‐free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice. Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the “unknown cause” classification and strongly suggest a genetic aetiology. The IFE are strongly age‐related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age‐related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state‐of‐the‐art thinking on the topics explored. The symposium led to the formation of international working groups under the umbrella of “Luke's Idiopathic Focal Epilepsy Project” to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high‐frequency oscillations, and parental resources (see www.childhood-epilepsy.org ). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.     

Modificaciones epigenéticas en las cefaleas

IntroductionMultiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target.MethodsWe performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA.ResultsA total of 15 English-language publications related to the above terms were obtained.ConclusionThere is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets.     

The omniscient placenta: Metabolic and epigenetic regulation of fetal programming

Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic–pituitary–adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment.     

Can mutation‐mediated effects occurring early in development cause long‐term seizure susceptibility in genetic generalized epilepsies?

Epilepsy has a strong genetic component, with an ever‐increasing number of disease‐causing genes being discovered. Most epilepsy‐causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here we review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub‐mesoscopic structural changes in GGE is also reviewed. Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub‐mesoscopic structural changes occur in GGE. The existence of sub‐mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. We also propose that presymptomatic treatment may be essential for limiting the long‐term consequences of disease‐causing mutations in genetic epilepsies.