Epigenetic Vestiges of Early Developmental Adversity: Childhood Stress Exposure and DNA Methylation in Adolescence

Abstract Genome-wide passive DNA demethylation in cleavage-stage mouse embryos is related to the cytoplasmic localization of the maintenance methyltransferase DNMT1. However, recent studies provided evidences of the nuclear localization of DNMT1 and its contribution to the maintenance of methylation levels of imprinted regions and other genomic loci in early embryos. Using the DNA adenine methylase identification method, we identified Dnmt1-binding regions in four- and eight-cell embryos. The unbiased distribution of Dnmt1 peaks in the genic regions (promoters and CpG islands) as well as the absence of a correlation between the Dnmt1 peaks and the expression levels of the peak-associated genes refutes the active participation of Dnmt1 in the transcriptional regulation of genes in the early developmental period. Instead, Dnmt1 was found to associate with genomic retroelements in a greatly biased fashion, particularly with the LINE1 (long interspersed nuclear elements) and ERVK (endogenous retrovirus type K) sequences. Transcriptomic analysis revealed that the transcripts of the Dnmt1-enriched retroelements were overrepresented in Dnmt1 knockdown embryos. Finally, methyl-CpG-binding domain sequencing proved that the Dnmt1-enriched retroelements, which were densely methylated in wild-type embryos, became demethylated in the Dnmt1-depleted embryos. Our results indicate that Dnmt1 is involved in the repression of retroelements through DNA methylation in early mouse development.

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The Dual Impact of Early and Concurrent Life Stress on Adults’ Diurnal Cortisol Patterns: A Prospective Study

Psychological Science ◽

10.1177/0956797619833664 ◽

2019 ◽

Vol 30 (5) ◽

pp. 739-747 ◽

Cited By ~ 14

Author(s):

Ethan S. Young ◽

Allison K. Farrell ◽

Elizabeth A. Carlson ◽

Michelle M. Englund ◽

Gregory E. Miller ◽

...

Keyword(s):

Life Stress ◽

High Stress ◽

Early Life Stress ◽

Stress Exposure ◽

Childhood Stress ◽

Major Life ◽

Diurnal Cortisol ◽

A Prospective Study ◽

Cumulative Model

Major life stress often produces a flat diurnal cortisol slope, an indicator of potential long-term health problems. Exposure to stress early in childhood or the accumulation of stress across the life span may be responsible for this pattern. However, the relative impact of life stress at different life stages on diurnal cortisol is unknown. Using a longitudinal sample of adults followed from birth, we examined three models of the effect of stress exposure on diurnal cortisol: the cumulative model, the biological-embedding model, and the sensitization model. As its name implies, the cumulative model focuses on cumulative life stress. In contrast, the biological-embedding model implicates early childhood stress, and the sensitization model posits that current life stress interacts with early life stress to produce flat diurnal cortisol slopes. Our analyses are consistent with the sensitization model, as they indicate that the combination of high stress exposure early in life and high current stress predict flat diurnal cortisol slopes. These novel findings advance understanding of diurnal cortisol patterns and point to avenues for intervention.

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The Developmental Psychopathology of Stress Exposure in Childhood

The Oxford Handbook of Stress and Mental Health ◽

10.1093/oxfordhb/9780190681777.013.12 ◽

2018 ◽

pp. 264-286

Author(s):

Jenalee R. Doom ◽

Dante Cicchetti

Keyword(s):

Individual Differences ◽

Developmental Psychopathology ◽

Institutional Care ◽

Risk And Resilience ◽

Stress Exposure ◽

Severe Stress ◽

Childhood Stress ◽

Future Directions ◽

Effective Interventions ◽

And Behavior

This chapter reviews how the field of developmental psychopathology has shaped research on risk and resilience processes in the context of childhood stress. The central tenets of developmental psychopathology, including its transdisciplinary and multilevel nature, equifinality and multifinality, developmental cascades, and the interaction of risk and protective factors across development, guide research aiming to understand individual differences in response to stressors during childhood. Various stressors that children experience, including maltreatment, poverty, institutional care, malnutrition, and environmental exposures, can lead to different effects on biology and behavior depending on the type, timing, chronicity, and severity of the stressor. Genetics, psychobiology, and neurophysiology have been incorporated into this research to enhance our understanding of individual differences in functioning following childhood stress. Future directions include more fully incorporating sex differences into studies of childhood stress and utilizing research in this area to create effective interventions for children experiencing severe stress.

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Early Developmental and Evolutionary Origins of Gene Body DNA Methylation Patterns in Mammalian Placentas

PLoS Genetics ◽

10.1371/journal.pgen.1005442 ◽

2015 ◽

Vol 11 (8) ◽

pp. e1005442 ◽

Cited By ~ 57

Author(s):

Diane I. Schroeder ◽

Kartika Jayashankar ◽

Kory C. Douglas ◽

Twanda L. Thirkill ◽

Daniel York ◽

...

Keyword(s):

Dna Methylation ◽

Gene Body ◽

Evolutionary Origins ◽

Methylation Patterns ◽

Early Developmental

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Supplementation of Maturation Medium with Folic Acid Affects DNA Methylation of Porcine Oocytes and Histone Acetylation of Early Developmental Stage Embryos

Journal of Mammalian Ova Research ◽

10.1274/jmor.30.109 ◽

2013 ◽

Vol 30 (3) ◽

pp. 109-116

Author(s):

Daichi Sato ◽

Kouta Sakurai ◽

Yasunori Monji ◽

Takehito Kuwayama ◽

Hisataka Iwata

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Developmental Stage ◽

Histone Acetylation ◽

Early Developmental Stage ◽

Maturation Medium ◽

Early Developmental

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Epigenetic mechanisms in the development of behavior: Advances, challenges, and future promises of a new field

Development and Psychopathology ◽

10.1017/s0954579413000618 ◽

2013 ◽

Vol 25 (4pt2) ◽

pp. 1279-1291 ◽

Cited By ~ 46

Author(s):

Tania L. Roth

Keyword(s):

Dna Methylation ◽

Social Stress ◽

Treatment Strategies ◽

Traumatic Experiences ◽

Future Research ◽

Epigenetic Alterations ◽

Stress Exposure ◽

The Past ◽

Gene Environment

AbstractIn the past decade, there have been exciting advances in the field of behavioral epigenetics that have provided new insights into a biological basis of neural and behavioral effects of gene–environment interactions. It is now understood that changes in the activity of genes established through epigenetic alterations occur as a consequence of exposure to environmental adversity, social stress, and traumatic experiences. DNA methylation in particular has thus emerged as a leading candidate biological pathway linking gene–environment interactions to long-term and even multigenerational trajectories in behavioral development, including the vulnerability and resilience to psychopathology. This paper discusses what we have learned from research using animal models and from studies in which the translation of these findings has been made to humans. Studies concerning the significance of DNA methylation alterations in outcomes associated with stress exposure later in life and dysfunction in the form of neuropsychiatric disorders are highlighted, and several avenues of future research are suggested that promise to advance our understanding of epigenetics both as a mechanism by which the environment can contribute to the development of psychiatric disorders and as an avenue for more effective intervention and treatment strategies.

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Childhood stress exposure among preadolescents with and without family histories of substance use disorders.

Psychology of Addictive Behaviors ◽

10.1037/adb0000020 ◽

2015 ◽

Vol 29 (1) ◽

pp. 192-200 ◽

Cited By ~ 9

Author(s):

Nora E. Charles ◽

Stacy R. Ryan ◽

Ashley Acheson ◽

Charles W. Mathias ◽

Yuanyuan Liang ◽

...

Keyword(s):

Substance Use ◽

Substance Use Disorders ◽

Stress Exposure ◽

Childhood Stress ◽

Family Histories

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Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820842116 ◽

2019 ◽

Vol 117 (38) ◽

pp. 23280-23285 ◽

Cited By ~ 19

Author(s):

Nadine Provençal ◽

Janine Arloth ◽

Annamaria Cattaneo ◽

Christoph Anacker ◽

Nadia Cattane ◽

...

Keyword(s):

Dna Methylation ◽

Messenger Rna ◽

Fetal Brain ◽

Transcriptional Response ◽

Hippocampal Neurogenesis ◽

Stress Exposure ◽

Long Term Effects ◽

Transcriptional Responses ◽

Cpg Dinucleotides ◽

Fetal Brain Development

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn’s cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

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Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: A prospective longitudinal study

Development and Psychopathology ◽

10.1017/s095457941700147x ◽

2017 ◽

Vol 29 (5) ◽

pp. 1895-1903 ◽

Cited By ~ 19

Author(s):

Madeline B. Harms ◽

Rasmus Birn ◽

Nadine Provencal ◽

Tobias Wiechmann ◽

Elisabeth B. Binder ◽

...

Keyword(s):

Inhibitory Control ◽

Life Stress ◽

Early Life ◽

Binding Protein ◽

Early Life Stress ◽

Stress Exposure ◽

Childhood Stress ◽

Fk506 Binding Protein ◽

Wide Range ◽

Prospective Longitudinal

AbstractIndividuals who have experienced high levels of childhood stress are at increased risk for a wide range of behavioral problems that persist into adulthood, yet the neurobiological and molecular mechanisms underlying these associations remain poorly understood. Many of the difficulties observed in stress-exposed children involve problems with learning and inhibitory control. This experiment was designed to test individuals' ability to learn to inhibit responding during a laboratory task. To do so, we measured stress exposure among a community sample of school-aged children, and then followed these children for a decade. Those from the highest and lowest quintiles of childhood stress exposure were invited to return to our laboratory as young adults. At that time, we reassessed their life stress exposure, acquired functional magnetic resonance imaging data during an inhibitory control task, and assayed these individuals' levels of methylation in the FK506 binding protein 5 (FKBP5) gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorsolateral prefrontal cortex between error and correct trials during inhibition. This effect was associated only with childhood stress exposure and not by current levels of stress in adulthood. In addition, FKBP5 methylation mediated the association between early life stress and inhibition-related prefrontal activity. These findings are discussed in terms of using multiple levels of analyses to understand the ways in which adversity in early development may affect adult behavioral adaptation.

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