DNA methylation impacts on learning and memory in aging

Learning and memory are two of the fundamental cognitive functions that confer us the ability to accumulate knowledge from our experiences. Although we use these two mental skills continuously, understanding the molecular basis of learning and memory is very challenging. Methylation modification of DNA is an epigenetic mechanism that plays important roles in regulating gene expression, which is one of the key processes underlying the functions of cells including neurons. Interestingly, a genome-wide decline in DNA methylation occurs in the brain during normal aging, which coincides with a functional decline in learning and memory with age. It has been speculated that DNA methylation in neurons might be involved in memory coding. However, direct evidence supporting the role of DNA methylation in memory formation is still under investigation. This particular function of DNA methylation has not drawn wide attention despite several important studies that have provided supportive evidence for the epigenetic control of memory formation. To facilitate further exploration of the epigenetic basis of memory function, we will review existing studies on DNA methylation that are related to the development and function of the nervous system. We will focus on studies illustrating how DNA methylation regulates neural activities and memory formation via the control of gene expression in neurons, and relate these studies to various age-related neurological disorders that affect cognitive functions.     

Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation.

Fine-tuning of neuronal connections during development is regulated through environmental interactions. Some fine-tuning occurs through changes in gene expression and/or epigenetic gene-specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S-adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short-term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene-specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi-factorial psychiatric disorders. For example, L-methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This gene's protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimer's disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.     

The Role of Epigenetics in Aging and Autoimmunity

The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low-grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here, we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.     

Aberrant T cell ERK pathway signaling and chromatin structure in lupus

Human systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies to nuclear components with subsequent immune complex formation and deposition in multiple organs. A combination of genetic and environmental factors is required for disease development, but how the environment interacts with the immune system in genetically predisposed hosts to cause lupus is unclear. Recent evidence suggests that environmental agents may alter T cell chromatin structure and gene expression through effects on DNA methylation, a repressive epigenetic mechanism promoting chromatin inactivation, to cause lupus in people with the appropriate genetic background. DNA methylation is regulated by ERK pathway signaling, and abnormalities in ERK pathway signaling may contribute to immune dysfunction in lupus through epigenetic effects on gene expression. This article reviews current evidence for epigenetic abnormalities, and in particular DNA demethylation, in the pathogenesis of idiopathic and some forms of drug-induced lupus, and how impaired ERK pathway signaling may contribute to the development of human lupus through effects on T cell DNA methylation.     

Regional-specific global cytosine methylation and DNA methyltransferase expression in the adult rat hippocampus

Recent observations suggest that DNA methylation plays an important role in memory and long-term potentiation (LTP) in the hippocampus and is involved in programming the offspring epigenome in response to maternal care. Global DNA methylation is believed to be stable postnatally and to be similar across tissues in the adult mammal. It has also been a long held belief that DNA methyltransferases (DNMTs) play a very limited role in postmitotic tissues. Recent data suggests a more dynamic role for DNA methylation in the brain postnatally, therefore we examined the global state of methylation and the expression of the known DNMTs in the different regions of the hippocampus. We observed strikingly different levels of global methylation in the adult rat dentate gyrus (DG) and CA1 region in comparison with the CA2 and CA3 regions. mRNA levels of DNA methyltransferases exhibited similar regional specificity and were correlated with global DNA methylation levels. These regional differences in global methylation and expression of the DNA methylation machinery in the adult brain are consistent with the emerging hypothesis that DNA methylation may play a dynamic physiological role in the adult brain.     

Exercise training and DNA methylation in humans

The response to exercise training (trainability) has been shown to have a strong heritable component. There is growing evidence suggesting that traits such as trainability do not only depend on the genetic code, but also on epigenetic signals. Epigenetic signals play an important role in the modulation of gene expression, through mechanisms such as DNA methylation and histone modifications. There is an emerging evidence to show that physical activity influences DNA methylation in humans. The present review aims to summarize current knowledge on the link between DNA methylation and physical activity in humans. We have critically reviewed the literature and only papers focused on physical activity and its influence on DNA methylation status were included; a total of 25 papers were selected. We concluded that both acute and chronic exercises significantly impact DNA methylation, in a highly tissue‐ and gene‐specific manner. This review also provides insights into the molecular mechanisms of exercise‐induced DNA methylation changes, and recommendations for future research.     

Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation

Alterations in the epigenetic modulation of gene expression have been implicated in several developmental disorders, cancer, and recently, in a variety of mental retardation and complex psychiatric disorders. A great deal of effort is now being focused on why the nervous system may be susceptible to shifts in activity of epigenetic modifiers. The answer may simply be that the mammalian nervous system must first produce the most complex degree of developmental patterning in biology and hardwire cells functionally in place postnatally, while still allowing for significant plasticity in order for the brain to respond to a rapidly changing environment. DNA methylation and histone deacetylation are two major epigenetic modifications that contribute to the stability of gene expression states. Perturbing DNA methylation, or disrupting the downstream response to DNA methylation – methyl-CpG-binding domain proteins (MBDs) and histone deacetylases (HDACs) – by genetic or pharmacological means, has revealed a critical requirement for epigenetic regulation in brain development, learning, and mature nervous system stability, and has identified the first distinct gene sets that are epigenetically regulated within the nervous system. Epigenetically modifying chromatin structure in response to different stimuli appears to be an ideal mechanism to generate continuous cellular diversity and coordinate shifts in gene expression at successive stages of brain development – all the way from deciding which kind of a neuron to generate, through to how many synapses a neuron can support. Here, we review the evidence supporting a role for DNA methylation and histone deacetylation in nervous system development and mature function, and present a basis from which to understand how the clinical use of HDAC inhibitors may impact nervous system function.     

DNA methylation and autoimmune disease

DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well.     

Alteration of methylation status in archival DNA samples: A qualitative assessment by methylation specific polymerase chain reaction

DNA methylation is an epigenetic mechanism that regulates gene expression, which also facilitates genomic imprinting. Genomic imprinting is responsible for differential expression of genes based on parent of origin. Altered methylation of parental alleles results in imprinting disorders diagnosed by methylation specific polymerase chain reaction (MS-PCR) technique. With increasing evidence of genes under epigenetic influence, methylation studies are extensively performed on archival samples. To evaluate effect of storage and storage conditions on DNA methylation, a systematic MS-PCR based analysis was planned on an imprinted gene, SNRPN, located on chromosome 15q11.2. It was assessed by MS-PCR on fresh, 4 −20, and −80°C stored DNA samples for different time periods for systematic evaluation of methylation status. Technical factors like type of sample processing, method of DNA isolation, primer region polymorphism, sample heterogeneity were also evaluated. DNA methylation was observed to be altered for SNRPN gene after storage at −80°C from 2 months onwards. Long-term storage of DNA at −80°C results in altered DNA methylation status. This may lead to false MS-PCR diagnosis of imprinting disorders. Our proof of concept study should be followed with quantitative validation since the findings have critical implications in the present era of biobanking.     

The hippocampal memory indexing theory

The hippocampal formation (comprising the hippocampus proper, the dentate gyrus, and the subiculum) has been repeatedly implicated in information storage models of the mammalian brain. The precise nature of the hippocampal role in the storage of information has, however, remained elusive. Here it is proposed that the role of the hippocampus is to form and retain an index of neocortical areas activated by experiential events. The hippocampal index, thus, represents those unique cortical regions activated by specific events. The neuronal mechanism underlying the memory index is hypothesized to be long-term potentiation. It is asserted that the reactivation of the stored hippocampal memory index will serve to also reactivate the associated unique array of neocortical areas and thus will result in a memorial experience. This hippocampal reactivation of a neocortical array may also be involved in establishing a cortically based memory trace.     

Hippocampus development and function: role of epigenetic factors and implications for cognitive disease

Lagali PS, Corcoran CP, Picketts DJ. Hippocampus development and function: role of epigenetic factors and implications for cognitive disease. The hippocampus is a primary region of the brain controlling the formation of memories and learned behaviours. The ability to learn or form a memory requires a neuron to translate a transient signal into gene expression changes that have a long‐lasting effect on synapse activity and connectivity. Numerous studies over the past decade have detailed changes in epigenetic modifications under various learning paradigms to support a role for chromatin remodelling in these processes. Moreover, the identification of mutations in epigenetic regulators as the cause of mental retardation or intellectual disability (MR/ID) disorders further strengthens their importance to learning and memory. Animal models for many of these disorders are emerging and advancing our understanding of the molecular mechanisms linking epigenetic regulation and cognitive function. Here, we review how chromatin remodelling proteins implicated in MR/ID contribute to the development of the hippocampus and memory formation.     

Could decitabine treatment impair memory functions in humans?

The role of epigenetic mechanisms in cognitive functions and neurological/psychiatric disorders has been studied in a number of studies recently. One of these mechanisms is DNA methylation, for which DNA methyltransferases (DNMT) are responsible. Decitabine, or 5-aza-2′-deoxycytidine, is a cytosine-analog DNMT inhibitor and is used in the treatment of certain myelodysplastic syndromes (MDS) subsets. Several studies address the role of DNA methylation and negative effects of decitabine on memory formation and consolidation in animals. We, therefore, hypothesize that standard decitabine treatment for MDS in patients without dementia might cause learning and memory deficits. A clinical trial is proposed to test the hypothesis which could support the role of DNA methylation in cognitive abilities of humans.     

Neuronal mechanisms of executive control by the prefrontal cortex

Executive function is considered to be a product of the coordinated operation of various processes to accomplish a particular goal in a flexible manner. The mechanism or system responsible for the coordinated operation of various processes is called executive control. Impairments caused by damage to the prefrontal cortex are often called dysexecutive syndromes. Therefore, the prefrontal cortex is considered to play a significant role in executive control. Prefrontal participation to executive control can be partly explained by working memory that includes mechanisms for temporary active storage of information and processing stored information. For the prefrontal cortex to exert executive control, neuronal mechanisms for temporary storage of information and dynamic and flexible interactions among them are necessary. In this article, we present the presence of dynamic and flexible changes in the strength of functional interaction and extensive functional interactions among temporal information-storage processes in the prefrontal cortex. In addition, recent imaging studies show dynamic changes in functional connectivity between the prefrontal cortex and other cortical and subcortical structures depending upon the characteristics or the temporal context of the task. These observations indicate that the examination of dynamic and flexible modulation in neuronal interaction among prefrontal neurons as well as between the prefrontal cortex and other cortical and subcortical areas is important for explaining how the prefrontal cortex exerts executive control.     

Impact of aging on DNA methylation

The biochemistry of aging is complex, with biologically significant changes occurring in proteins, lipids and nucleic acids. One of these changes is in the methylation of DNA. DNA methylation is a mechanism modifying gene expression. The methylation of sequences in or near regulatory elements can suppress gene expression through effects on DNA binding proteins and chromatin structure. Both increases and decreases in methylation occur with aging, depending on the tissue and the gene. These changes can have pathologic consequences, contributing to the development of malignancies and autoimmunity with aging, and possibly to other disorders as well. Thus, while aging can impact on DNA methylation, the changes in DNA methylation can also impact on aging. This review summarizes current evidence for changes in the methylation status of specific genes with aging, their impact on diseases that develop with aging, and mechanisms that may contribute to the altered DNA methylation patterns. As this field is still developing, it is anticipated that new knowledge will continue to accumulate rapidly.     

DNA methylation, imprinting and cancer

It is well known that a variety of genetic changes influence the development and progression of cancer. These changes may result from inherited or spontaneous mutations that are not corrected by repair mechanisms prior to DNA replication. It is increasingly clear that so called epigenetic effects that do not affect the primary sequence of the genome also play an important role in tumorigenesis. This was supported initially by observations that cancer genomes undergo changes in their methylation state and that control of parental allele-specific methylation and expression of imprinted loci is lost in several cancers. Many loci acquiring aberrant methylation in cancers have since been identified and shown to be silenced by DNA methylation. In many cases, this mechanism of silencing inactivates tumour suppressors as effectively as frank mutation and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis. In contrast to mutations which are essentially irreversible, methylation changes are reversible, raising the possibility of developing therapeutics based on restoring the normal methylation state to cancer-associated genes. Development of such therapeutics will require identifying loci undergoing methylation changes in cancer, understanding how their methylation influences tumorigenesis and identifying the mechanisms regulating the methylation state of the genome. The purpose of this review is to summarise what is known about these issues.     

Generating long‐lived CD8+ T‐cell memory: Insights from epigenetic programs

T‐cell‐based immunological memory has the potential to provide the host with life‐long protection against pathogen reexposure and thus offers tremendous promise for the design of vaccines targeting chronic infections or cancer. In order to exploit this potential in the design of new vaccines, it is necessary to understand how and when memory T cells acquire their poised effector potential, and moreover, how they maintain these properties during homeostatic proliferation. To gain insight into the persistent nature of memory T‐cell functions, investigators have turned their attention to epigenetic mechanisms. Recent efforts have revealed that many of the properties acquired among memory T cells are coupled to stable changes in DNA methylation and histone modifications. Furthermore, it has recently been reported that the delineating features among memory T cells subsets are also linked to distinct epigenetic events, such as permissive and repressive histone modifications and DNA methylation programs, providing exciting new hypotheses regarding their cellular ancestry. Here, we review recent studies focused on epigenetic programs acquired during effector and memory T‐cell differentiation and discuss how these data may shed new light on the developmental path for generating long‐lived CD8⁺ T‐cell memory.