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Heatmap for selected genes showing methylation levels (hypomethylation -blue; hypermethylation -orange) across individual subjects classified into the low (green) and high (red) ETV categories. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
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Exposure to violence (ETV) has been linked to epigenomics mechanisms such as DNA methylation (DNAm). We used epigenetic profiling of blood collected from 32 African American young adult males who lived in Washington DC to determine if changes in DNAm at CpG sites affiliated with nervous and immune system were associated with exposure to violence. P...
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Background
Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se,...
Citations
... Several studies have reported that methylation of BDNF is associated with exposure to adversity and trauma across the life course [49,50]. This includes events and circumstances such as childhood stressors, community crime, domestic violence, and combat. ...
A recent epigenetic measure of aging has developed based on human cortex tissue. This cortical clock (CC) dramatically outperformed extant blood-based epigenetic clocks in predicting brain age and neurological degeneration. Unfortunately, measures that require brain tissue are of limited utility to investigators striving to identify everyday risk factors for dementia. The present study investigated the utility of using the CpG sites included in the CC to formulate a peripheral blood-based cortical measure of brain age (CC-Bd). To establish the utility of CC-Bd, we used growth curves with individually varying time points and longitudinal data from a sample of 694 aging African Americans. We examined whether three risk factors that have been linked to cognitive decline—loneliness, depression, and BDNFm—predicted CC-Bd after controlling for several factors, including three new-generation epigenetic clocks. Our findings showed that two clocks—DunedinPACE and PoAm—predicted CC-BD, but that increases in loneliness and BDNFm continued to be robust predictors of accelerated CC-Bd even after taking these effects into account. This suggests that CC-Bd is assessing something more than the pan-tissue epigenetic clocks but that, at least in part, brain health is also associated with the general aging of the organism.
... In humans, rare variants in DSCAML1 are associated with several neurodevelopmental disorders, including autism spectrum disorder, cortical abnormality, and epilepsy (Iossifov et al., 2014;Karaca et al., 2015;Hayase et al., 2020;Ogata et al., 2021). Genetic and epigenetic studies also implicate DSCAML1 in the stress response to violent experiences (Caramillo et al., 2015;Saadatmand et al., 2021). However, the relationship between DSCAML1 and the stress axis remains unknown. ...
... Using zebrafish as a vertebrate model for the ontogenesis of the stress axis, we found that dscaml1 deficiency results in CRH neuron deficits and dysfunction of the stress axis. Genetic perturbations of DSCAML1 are seen in patients suffering from a wide range of mental health disorders, including intellectual disability, autism spectrum disorder, schizophrenia, epilepsy, and stress disorder (Iossifov et al., 2014;Caramillo et al., 2015;Karaca et al., 2015;Hayase et al., 2020;Ogata et al., 2021;Saadatmand et al., 2021). Developmental deficits in the stress axis may contribute to the etiology of these disorders. ...
The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. In dscaml1 mutant animals, hypothalamic CRH neurons had higher crhb (the CRH homolog in zebrafish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically, dscaml1 mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of human DSCAML1-linked neuropsychiatric disorders.
... One study revealed that histone deacetylases and methyl-CpG-binding protein 2 (MeCP2) inhibit repetitive behaviors through regulation of the Sapap3 gene [128]. Additionally, recent studies have also reported an association between altered methylation of SAPAP1 and stress responses to violence [129] and a link between epigenetic dysregulation of SAPAP4 and early-onset cerebellar ataxia [23,130]. Identified as a target of the BDassociated microRNA miR-1908-5p N/A Neural progenitor cells BD patients [127] Abbreviations: AD, Alzheimer's disease; BD, bipolar disorder; PTSD, post-traumatic stress disorder. ...
Excitatory (glutamatergic) synaptic transmission underlies many aspects of brain activity and the genesis of normal human behavior. The postsynaptic scaffolding proteins SAP90/PSD-95-associated proteins (SAPAPs), which are abundant components of the postsynaptic density (PSD) at excitatory synapses, play critical roles in synaptic structure, formation, development, plasticity, and signaling. The convergence of human genetic data with recent in vitro and in vivo animal model data indicates that mutations in the genes encoding SAPAP1–4 are associated with neurological and psychiatric disorders, and that dysfunction of SAPAP scaffolding proteins may contribute to the pathogenesis of various neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, obsessive compulsive disorders, Alzheimer’s disease, and bipolar disorder. Here, we review recent major genetic, epigenetic, molecular, behavioral, electrophysiological, and circuitry studies that have advanced our knowledge by clarifying the roles of SAPAP proteins at the synapses, providing new insights into the mechanistic links to neurodevelopmental and neuropsychiatric disorders.
The enduring influence of early life social environments on lifelong wellbeing, health, and behavioral trajectories has garnered extensive attention in the fields of epidemiology and social sciences. Moreover, within the realm of psychiatric genetics, the concept of “gene-environment” interactions has shed light on how the early social environment may modulate the impact of genetic variants on later-life behavioral phenotypes. This interaction posits that while two individuals may both carry a risk allele for a particular behavioral phenotype, its manifestation may occur solely in a person who experienced childhood adversity.
The existence of a statistical interaction between early environments and genetic variants suggests that environmental factors may operate through mechanisms that impact gene function. Epigenetics, a complex interplay of biochemical processes, orchestrates gene expression variations across different tissues, times, and spatial contexts without altering the underlying gene sequence. This phenomenon facilitates cellular differentiation in multicellular organisms, enabling one genome to yield diverse phenotypes in various tissues and organs during embryonal and postnatal development.
Nearly two decades ago, it was hypothesized that epigenetic mechanisms which enable creating diverse phenotypes from one genome, might serve as the intermediaries linking early life social exposures to later-life physiological and behavioral outcomes. This chapter delves into a discussion of both animal data and human studies that substantiate this association, offering insights into the potential functional consequences of such links. The primary focus of this chapter centers on DNA methylation, a robust and extensively investigated epigenetic mechanism in this domain.
El maltrato infantil es un problema de salud pública e incluye todos los tipos de maltrato, físico o psicológico, abuso sexual, desatención, negligencia y explotación comercial o de otro tipo que causen o puedan causar un daño a la salud, desarrollo o dignidad del niño. Los niños víctimas de maltrato presentan mayor riesgo de depresión, ansiedad, trastorno bipolar, síndrome de estrés postraumático, diabetes mellitus, hipertensión arterial, enfisema, enfermedad pulmonar obstructiva crónica, bronquitis crónica, migrañas, lumbalgia, problemas de visión, accidente cerebrovascular, neoplasias, tabaquismo, obesidad, desnutrición, síndrome de fatiga crónica en la edad adulta, artritis, enfermedad intestinal y otras enfermedades autoinmunes. Esto puede ser explicado en parte por alteraciones moleculares principalmente epigenéticas, específicamente por metilación en el ADN. La principal alteración molecular encontrada fue la metilación asociada a los genes relacionados con el eje hipotálamo-pituitaria-adrenal, vías de neurotransmisores, del sistema inmunológico, así como el acortamiento de los telómeros. En conclusión, se debe de trabajar en crear conciencia y, en consecuencia, estrategias específicas para respetar los derechos de los niños. La información disponible fue consultada mediante una búsqueda bibliográfica en español e inglés en las bases de datos PubMed, INEGI, Google Scholar y revistas como Lancet y Nature hasta el 7 de enero de 2022. Las palabras claves que se utilizaron para la búsqueda por separado y combinadas fueron “Violencia”, “epigenética”, “metilación”, “violencia intrafamiliar”, “abuso infantil”, “ADN”, “trastorno” “maltrato”.
Purpose of Review
There is a great deal of interest regarding the biological embedding of childhood trauma and social exposures through epigenetic mechanisms, including DNA methylation (DNAm), but a comprehensive understanding has been hindered by issues of limited reproducibility between studies. This review presents a summary of the literature on childhood trauma and DNAm, highlights issues in the field, and proposes some potential solutions.
Recent Findings
Investigations of the associations between DNAm and childhood trauma are commonly performed using candidate gene approaches, specifically involving genes related to neurological and stress pathways. Childhood trauma is defined in a wide range of ways in several societal contexts. However, although variations in DNAm are frequently found in stress-related genes, unsupervised epigenome-wide association studies (EWAS) have shown limited reproducibility both between studies and in relating these changes to exposures.
Summary
The reproducibility of childhood trauma DNAm studies, and the field of social epigenetics in general, may be improved by increasing sample sizes, standardizing variables, making use of effect size thresholds, collecting longitudinal and intervention samples, appropriately accounting for known confounding factors, and applying causal analysis wherever possible, such as “two-step epigenetic Mendelian randomization.”
The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress dysfunction and mental health disorders, it is critical to identify the molecular mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH-neuron development and stress axis function. In dscaml1 mutant animals, CRH neurons had higher stress axis-associated neuropeptide (crhb and avp) expression, increased cell number, decreased apoptosis, and reduced intercellular spacing as compared to controls. Time-lapse imaging showed that CRH neuron cell death is reduced in dscaml1 mutant animals, contributing to increased CRH neuron number. Physiologically, dscaml1 mutant animals had significantly higher baseline stress hormone (cortisol) levels and an attenuated response to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that stress axis dysregulation may contribute to the etiology of human DSCAML1-linked neuropsychiatric disorders.
Background
Low socioeconomic status neighborhood exposure to stress and violence may be sources of negative stimuli that poses significant health risks for children, adolescents and throughout the life course of an individual. The study aims to investigate if aberrant epigenetic DNA methylation changes may be a potential mechanism for regulating neighborhood exposures and health outcomes.
Methods
Exposure to environmental stressors identified in 98 young African American (AA) adults aged 18–25 years old from the Washington D.C., area were used in the study. We correlated the association between stress markers; cortisol, CRP, IgG, IGA, IgM, and self-reported exposure to violence and stress, with quantitative DNA methylation changes in a panel of gene-specific loci using saliva DNA.
Results
In all participants studied, the exposure to violence was significant and negatively correlated with DNA methylation of MST1R loci (p = 0.032; r = -0.971) and nominally significant with NR3C1 loci (p = 0.053; r = -0.948). In addition, we observed significant and negative correlation of DNA methylation changes of LINE 1 (p = 0.044; r = -0.248); NR3C 1 (p = 0.017; r = -0.186); MSTR 1 (p = 0.022; r = -0.192); and DRD 2 (p = 0.056; r = -0.184; albeit nominal significant correlation) with IgA expression. On the other hand, we observed a significant and position correlation of DNA methylation changes in DRD 2 (p = 0.037; r = 0.184) with IgG expression. When participants were stratified by sex, we observed in AA young male adults, significant DNA methylation changes of MST1R (p< 0.05) and association with exposure to violence and IgG level. We also observed significant DNA methylation levels of DRD2 (p< 0.05) and association with IgA, IgG, and cortisol level. Furthermore, we observed significant DNA methylation changes of NR3C1 (p< 0.05) with stress, IgA, and IgG in the male participants only. On the other hand, we only observed significant and a positive association of IgG with DNA methylation levels of ESR 1 (p = 0.041) in the young AA female participants.
Conclusion
Our preliminary observation of significant DNA methylation changes in neuronal and immune genes in saliva samples supports our recently published genome-wide DNA methylations changes in blood samples from young AA male adults indicating that saliva offers a non-invasive means for DNA methylation prediction of exposure to environmental stressors in a gender-specific manner.
