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Aim: To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores., Methods: DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes., Results: We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes., Conclusion: ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, potential interactions between DNA methylation and genetic background in relation to ME/CFS have not been examined. In this study we explored this association by characterizing the epigenetic (~480 thousand CpG loci) and genetic (~4.3 million SNPs) variation between cohorts of ME/CFS patients and healthy controls. We found significant associations of DNA methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism. Finally, we found significant correlations of genotypes with methylation modifications associated with ME/CFS. The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS.

Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months. Symptoms fail to dissipate after sufficient rest and have major effects on the daily functioning of CFS sufferers. CFS is a multi-system disease with a heterogeneous patient population showing a wide variety of functional disabilities and its biological basis remains poorly understood. Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored. We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences. Gene ontology (GO) and network analysis of differentially methylated genes was performed to determine potential biological pathways showing changes in DNA methylation in CFS. We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology.

Assessment of methylation state of DNA extracted from brain is becoming one of the most investigated issues in the study of epigenetics and psychopathology. pH effects in brain are known to affect gene transcription, though pH effects on DNA methylation state are unknown. We demonstrate in vitro using an artificially methylated plasmid that DNA methylation state remains stable, even under extreme pH conditions. Next, using two different genomic regions from human DNA, we assess methylation state from both cortical and sub-cortical brain regions using subjects with varying pH levels. No correlation was found between DNA methylation state and pH. These results suggest that DNA methylation state is stable in post-mortem brain.

Background: Alterations in gene expression in the suicide brain have been reported and for several genes DNA methylation as an epigenetic regulator is thought to play a role. rRNA genes, that encode ribosomal RNA, are the backbone of the protein synthesis machinery and levels of rRNA gene promoter methylation determine rRNA transcription., Methodology/principal Findings: We test here by sodium bisulfite mapping of the rRNA promoter and quantitative real-time PCR of rRNA expression the hypothesis that epigenetic differences in critical loci in the brain are involved in the pathophysiology of suicide. Suicide subjects in this study were selected for a history of early childhood neglect/abuse, which is associated with decreased hippocampal volume and cognitive impairments. rRNA was significantly hypermethylated throughout the promoter and 5' regulatory region in the brain of suicide subjects, consistent with reduced rRNA expression in the hippocampus. This difference in rRNA methylation was not evident in the cerebellum and occurred in the absence of genome-wide changes in methylation, as assessed by nearest neighbor., Conclusions/significance: This is the first study to show aberrant regulation of the protein synthesis machinery in the suicide brain. The data implicate the epigenetic modulation of rRNA in the pathophysiology of suicide.

Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with obesity during pregnancy show alterations that are detectable at birth. Epigenetic mechanisms such as DNA methylation modifications have been proposed to mediate prenatal programming. We investigated DNA methylation signatures in male and female infants from mothers with a normal Body Mass Index (BMI 18.5–24.9 kg/m2) compared to mothers with obesity (BMI≥30 kg/m2). BMI was measured during the first prenatal visit from women recruited into the Ontario Birth Study (OBS) at Mount Sinai Hospital in Toronto, ON, Canada. DNA was extracted from neonatal dried blood spots collected from heel pricks obtained 24 hours after birth at term (total n = 40) from women with a normal BMI and women with obesity matched for parity, age, and neonatal sex. Reduced representation bisulfite sequencing was used to identify genomic loci associated with differentially methylated regions (DMRs) in CpG-dense regions most likely to influence gene regulation. DMRs were predominantly localized to intergenic regions and gene bodies, with only 9% of DMRs localized to promoter regions. Genes associated with DMRs were compared to those from a large publicly available cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC; total n = 859). Hypergeometric tests revealed a significant overlap in genes associated with DMRs in the OBS and ALSPAC cohorts. PTPRN2, a gene involved in insulin secretion, and MAD1L1, which plays a role in the cell cycle and tumor suppression, contained DMRs in males and females in both cohorts. In males, KEGG pathway analysis revealed significant overrepresentation of genes involved in endocytosis and pathways in cancer, including IGF1R, which was previously shown to respond to diet-induced metabolic stress in animal models and in lymphocytes in the context of childhood obesity. These preliminary findings are consistent with Developmental Origins of Health and Disease paradigm, which posits that adverse prenatal exposures set developmental health trajectories. [ABSTRACT FROM AUTHOR]

Effects of stresses associated with extremely preterm birth may be biologically "recorded" in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (Mage = 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults (Mage = 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions. [ABSTRACT FROM AUTHOR]

Predation is a key organizing force in ecosystems. The threat of predation may act to programme the endocrine hypothalamic-pituitary-adrenal axis during development toprepare offspring for the environment theyare likely to encounter. Such effects are typically investigated through the measurement of corticosteroids (Cort). Corticosteroid-binding globulin (CBG) plays a key role in regulating the bioavailability of Cort, with only free unbound Cort being biologically active. We investigated the effects of prenatal predator odour exposure (POE) inmice on offspring CBG and its impact onCort dynamics before, during and after restraint stress in adulthood. POEmales, but not females, had significantly higher serumCBG at baseline and during restraint and lower circulating levels of Free Cort. Restraint stresswas associated with reduced liver transcript abundance of SerpinA6 (CBG-encoding gene) only in control males. POE did not affect SerpinA6 promoterDNAmethylation. Our results indicate that prenatal exposure to a natural stressor led to increased CB Glevels, decreased per cent of Free Cort relative to total and inhibited restraint stress-induced downregulation of CBG transcription. These changes suggest an adaptive response to a high predator risk environment in males but not females that could buffer male offspring from chronic Cort exposure. [ABSTRACT FROM AUTHOR]

Long‐term sequelae of extremely low birth weight (ELBW; ≤1000 g) may contribute to accelerated biological aging. This hypothesis was examined by analyzing a range of risk factors with a molecular age marker in adults born at ELBW or normal birth weight (NBW; ≥2500 g). DNAm age—the weighted average of DNA methylation at 353 cytosine–phosphate–guanine (CpG) sites from across the genome—was derived from a sample of 45 ELBW (Mage = 32.35 years) and 47 NBW control (Mage = 32.44 years) adults, using the Illumina 850k BeadChip Array. At two assessments undertaken 9 years apart (at 23 and 32 years), cumulative risks were summed from six domains with potential to affect physiological and psychological health: resting respiratory sinus arrhythmia, blood pressure, basal cortisol, grip strength, body mass index, and self‐esteem. At age 32 years, cumulative risks were differentially associated with epigenetic age in ELBW survivors (interaction, p < 0.01). For each additional risk factor they possessed, ELBW survivors (B = 1.43) were biologically 2.16 years older than NBW adults (B = –0.73), by the fourth decade of life. Developmental change, epigenetic maintenance, and intervention targets are discussed. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Extremely low birth weight (ELBW) (<1000 g) survivors are exposed to elevated levels of physiologic stress during their lives and may be susceptible to accelerated aging. Using the oldest known longitudinally followed cohort of ELBW survivors, we compared biological aging in this group using an epigenetic clock to a sample of matched normal birth weight (NBW) (>2500 g) control participants. METHODS: Buccal cells were collected from 45 ELBW survivors and 49 NBW control participants at 30 to 35 years of age. Epigenetic age was calculated from the weighted average of DNA methylation at 353 cytosine-phosphate-guanine sequence within DNA sites, by using the Illumina Infinium Human Methylation EPIC 850k BeadChip array. RESULTS: Before and after statistically adjusting for neurosensory impairment and the presence of chronic health conditions, a significant sex by birth weight group interaction was observed in the 353-site epigenetic-clock assay (P = .03), whereby ELBW men had a significantly older epigenetic age than NBW men (4.6 years; P = .01). Women born at ELBW were not found to be epigenetically older than their NBW peers. CONCLUSIONS: The results of this study suggest that prenatal exposures may play an important role in aging, and that men born preterm may experience accelerated aging relative to their peers. We further highlight the need to monitor and promote the health of preterm survivors, with a particular focus on healthy aging across the life span. [ABSTRACT FROM AUTHOR]

Early life maternal care received has a profound effect on later-life behaviour in adult offspring, and previous studies have suggested epigenetic mechanisms are involved. Changes in thyroid hormone receptor signalling may be related to differences in maternal care received and DNA methylation modifications. We investigated the effects of variations in temperature exposure (a proxy of maternal contact) and licking-like tactile stimulation on these processes in week-old female rat pups. We assessed thyroid hormone receptor signalling by measuring circulating triiodothyronine and transcript abundance of thyroid hormone receptors and the thyroid hormone-responsive genes DNA methyltransferase 3a and oxytocin in the paraventricular nucleus of the hypothalamus. DNA methylation of the oxytocin promoter was assessed in relation to changes in thyroid hormone receptor binding. Repeated room temperature exposure was associated with a decrease in thyroid hormone receptor signalling measures relative to nest temperature exposure, while acute room temperature exposure was associated with an increase. Repeated room temperature exposure also increased thyroid hormone receptor binding and DNA methylation at the oxytocin promoter. These findings suggest that repeated room temperature exposure may affect DNA methylation levels as a consequence of alterations in thyroid hormone receptor signalling. [ABSTRACT FROM AUTHOR]

It has been approximately 30 years since the seminal discoverie s of David Barker and his colleagues, and research is beginning to unravel the mechanisms that underlie developmental programming. The early environment of the embryo, foetus and newborn have been clearly linked to altered hypothalamic-pituit ary-adrenal (HPA) function and related behaviours through the juvenile period and into adulthood. A number of recent studies have shown that these effects can pass across multiple generations. The HPA axis is highly responsive to the environment, impacts both central and peripheral systems and is critical to health in a wide variety of contexts. Mechanistic studies in animals are linking early exposures to adversity wit h changes in gene regulatory mechanisms, including modifications of DNA methylation and altered levels of miRNA. Similar associations are emerging from recent human s tudies. These findings suggest that epigenetic mechanisms represent a fundamental link between adverse early environments and developmental programming of later disease. The underlying biological mechanisms that connect the perinatal environment wi th modified long-term health outcomes represent an intensive area of research. Indeed, opportunities for early interventions must identify the relevant environmental factors and their molecular targets. This new knowledge will likely assist in the identifica tion of individuals who are at risk of developing poor outcomes and for whom early interven tion is most effective. [ABSTRACT FROM AUTHOR]

The mother is the major interface between the offspring and its prenatal environment. Prenatal toxins and stress-inducing physical agents are important factors programming the developmental trajectory of mammals that likely involve epigenetic modifications. However, prenatal stressors commonly-used in the laboratory (e.g. prenatal restraint stress and prenatal chronic variable stress) are typically administered at high intensities. These exposures typically lead to pathological phenotypes supporting the development origin of health and disease hypothesis. In this review, we compare the phenotypic outcomes of these commonly-used prenatal stressors to an ecologically-relevant, psychogenic stressor that has been present over evolutionary times, predator or predator cues presence. Prenatal stress by predator threat results in behavioral, physiological, endocrine, transcript abundance and epigenetic (DNA methylation) modifications. These phenotypic modifications are consistent with developmental forecasting according to the Predictive Adaptive Response hypothesis, yielding adaptive responses in environments where such predation stress is present. The evidence described in this review suggests that the type of prenatal stress agent and its intensity modifies the phenotype expressed, which can range from adaptive to pathological. Prenatal Bisphenol A exposure studies are presented as an example where graded intensities (concentrations) of prenatal toxin exposure can be compared directly. Finally, we emphasize the importance of studying both sexes in these studies, as sex differences appear to be a common feature of the response to prenatal stress. [ABSTRACT FROM AUTHOR]

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined. Methods: We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results. Results: We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci. Conclusions: Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/ CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population. [ABSTRACT FROM AUTHOR]

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Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCOR-TICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin a, p, and y gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience. [ABSTRACT FROM AUTHOR]

Abstract: An organism''s behavioral and physiological and social milieu influence and are influenced by the epigenome, which is composed predominantly of chromatin and the covalent modification of DNA by methylation. Epigenetic patterns are sculpted during development to shape the diversity of gene expression programs in the organism. In contrast to the genetic sequence, which is determined by inheritance and is virtually identical in all tissues, the epigenetic pattern varies from cell type to cell type and is potentially dynamic throughout life. It is postulated here that different environmental exposures, including early parental care, could impact epigenetic patterns, with important implications for mental health in humans. Because epigenetic programming defines the state of expression of genes, epigenetic differences could have the same consequences as genetic polymorphisms. Yet in contrast to genetic sequence differences, epigenetic alterations are potentially reversible. This review will discuss basic epigenetic mechanisms and how epigenetic processes early in life might play a role in defining inter-individual trajectories of human behavior. In this regard, we will examine evidence for the possibility that epigenetic mechanisms can contribute to later-onset neurological dysfunction and disease. [Copyright &y& Elsevier]

Abstract: Phenotypic diversity is shaped by both genetic and epigenetic mechanisms that program tissue specific patterns of gene expression. Cells, including neurons, undergo massive epigenetic reprogramming during development through modifications to chromatin structure, and by covalent modifications of the DNA through methylation. There is evidence that these changes are sensitive to environmental influences such as maternal behavior and diet, leading to sustained differences in phenotype. For example, natural variations in maternal behavior in the rat that influence stress reactivity in offspring induce long-term changes in gene expression, including in the glucocorticoid receptor, that are associated with altered histone acetylation, DNA methylation, and NGFI-A transcription factor binding. These effects can be reversed by early postnatal cross-fostering, and by pharmacological manipulations in adulthood, including Trichostatin A (TSA) and l-methionine administration, that influence the epigenetic status of critical loci in the brain. Because levels of methionine are influenced by diet, these effects suggest that diet could contribute significantly to this behavioral plasticity. Recent data suggest that similar mechanisms could influence human behavior and mental health. Epidemiological data suggest indeed that dietary changes in methyl contents could affect DNA methylation and gene expression programming. Nutritional restriction during gestation could affect epigenetic programming in the brain. These findings provide evidence for a stable yet dynamic epigenome capable of regulating phenotypic plasticity through epigenetic programming. [Copyright &y& Elsevier]

The article presents a research investigating the epigenetics in mood disorders. It discusses several sets of data, including clinical studies relevant to depression, the role of histone modification in antidepressive treatment action, the role of DNA methylation in mood regulation, and DNA methylation analysis in the postmortem brain.

Human epidemiological studies and studies of animal models provide many examples by which early life experiences influence health in a long-term manner, a concept known as biological embedding. Such experiences can have profound impacts during periods of high plasticity in prenatal and early postnatal life. Epigenetic mechanisms influence gene function in the absence of changes in gene sequence. In contrast to the relative stability of gene sequences, epigenetic mechanisms appear, at least to some extent, responsive to environmental signals. To date, a few examples appear to clearly link early social experiences to epigenetic changes in pathways relevant for mental health in adulthood. Our recent work using high-throughput epigenomic techniques points to large-scale changes in gene pathways in addition to candidate genes involved in the response to psychosocial stress and neuroplasticity. Elucidation of which pathways are epigenetically labile under what conditions will enable a more complete understanding of how the epigenome can mediate environmental interactions with the genome that are relevant for mental health. In this mini-review, we provide examples of nascent research into the influence of early life experience on mental health outcomes, discuss evidence of epigenetic mechanisms that may underlie these effects, and describe challenges for research in this area. [ABSTRACT FROM AUTHOR]

Rat dams show natural variations in maternal care, licking and grooming (LG), that are associated with distinct behavioral and neural phenotypes in offspring. However, there has been limited research on the effects of differences in LG received by female pups and of variations in maternal care within the litter. Here, we investigated LG received by measuring active maternal care after pup retrieval of female offspring. We then examined locomotor activity, open field exploration, and restraint stress reactivity in adult female offspring. We also investigated the expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) and DNA methylation of the GR17 promoter in the hippocampus. High compared with low LG siblings and female offspring from high compared with low LG dams showed increased locomotor activity. High compared with low LG siblings also showed reduced anxiety behavior regardless of the overall level of LG received in the litter. Unexpectedly, both the lowest licked offspring from low LG litters and the highest licked offspring from high LG litters showed suppressed corticosterone (CORT) responses to stress. However, high LG offspring within Utters also showed increased expression of the GR gene, which was negatively correlated with the CORT response to restraint. DNA methylation at 2 CpG sites within GR17 promoter was significantly higher in high LG offspring. These differences in the response to maternal care both within- and between-litters were distinct in part from previous reports of between litter effects, potentially a result of the sex studied or the methods used to observe maternal care. [ABSTRACT FROM AUTHOR]