Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

2015 ◽  
Vol 27 (1) ◽  
pp. 123-135 ◽  
Author(s):  
Rick H. A. van der Doelen ◽  
Ilse A. Arnoldussen ◽  
Hussein Ghareh ◽  
Liselot van Och ◽  
Judith R. Homberg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Serotonin Transporter ◽  
Life Stress ◽  
Early Life ◽  
Gene Promoter ◽  
Early Life Stress ◽  
Corticotropin Releasing Factor ◽  
Mrna Levels ◽  
Gene Variation ◽  
Gene Environment

AbstractThe interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

scholarly journals Early-Life Stress Reduces DNA Methylation of the Pomc Gene in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1751-1762 ◽  
Author(s):  
Yonghe Wu ◽  
Alexandre V. Patchev ◽  
Guillaume Daniel ◽  
Osborne F.X. Almeida ◽  
Dietmar Spengler
Keyword(s):  
Dna Methylation ◽  
Life Stress ◽  
Early Life ◽  
Binding Protein ◽  
Early Life Stress ◽  
Neuroendocrine Cells ◽  
Mrna Levels ◽  
Male Mice ◽  
Pomc Mrna ◽  
Pomc Gene

Early-life stress (ELS) increases the vulnerability thresholds for stress-related diseases such as major depression and anxiety by inducing alterations in the structure and function of neural circuits and endocrine pathways. We previously demonstrated the contribution of epigenetic mechanisms to the long-term programming of the hypothalamo-pituitary-adrenal axis activity following ELS exposure in male mice. Here, ELS comprising daily separation of pups from their dams on postnatal days 1–10 was observed to up-regulate the expression of the pituitary proopiomelanocortin (Pomc) gene; POMC serves as a prohormone for ACTH, a key mediator of the adrenocortical response to stress. Detailed analysis revealed that the increase in Pomc mRNA levels results from a reduction in DNA methylation at a critical regulatory region of the Pomc gene; interestingly, this change occurs with some delay after ELS and persists for up to 1 year. Using a Pomc-expressing pituitary cell line (AtT20), we confirmed a role for DNA methylation in restraining Pomc expression under resting conditions: specifically, we show that CpG site-specific methylation of the Pomc promoter represses Pomc mRNA transcription. Further, we show high-affinity binding of methyl-CpG binding protein-2 to the distal promoter of Pomc, suggesting that methyl-CpG binding protein-2 acts in association with the chromatin modifiers histone deacetylase 2 and DNA methyltransferase 1 to repress Pomc gene expression. Collectively, these experiments contribute to our understanding of the mechanisms through which environmental cues are translated into stable changes (“cellular memory”) in neuroendocrine cells.

Serotonin Transporter Gene Variation is Associated with Alcohol Sensitivity in Rhesus Macaques Exposed to Early-Life Stress

2003 ◽  
Vol 27 (5) ◽  
pp. 812-817 ◽  
Author(s):  
Christina S. Barr ◽  
Timothy K. Newman ◽  
Michelle L. Becker ◽  
Maribeth Champoux ◽  
Klaus Peter Lesch ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Life Stress ◽  
Early Life ◽  
Rhesus Macaques ◽  
Early Life Stress ◽  
Serotonin Transporter Gene ◽  
Transporter Gene ◽  
Alcohol Sensitivity ◽  
Gene Variation

scholarly journals Early-life stress, corticotropin-releasing factor, and serotonin transporter gene: A pilot study

2011 ◽  
Vol 36 (2) ◽  
pp. 289-293 ◽  
Author(s):  
Jeremy D. Coplan ◽  
Chadi G. Abdallah ◽  
Joan Kaufman ◽  
Joel Gelernter ◽  
Eric L.P. Smith ◽  
...  
Keyword(s):  
Pilot Study ◽  
Serotonin Transporter ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Corticotropin Releasing Factor ◽  
Serotonin Transporter Gene ◽  
Transporter Gene

scholarly journals Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins

2012 ◽  
Vol 43 (9) ◽  
pp. 1813-1823 ◽  
Author(s):  
I. Ouellet-Morin ◽  
C. C. Y. Wong ◽  
A. Danese ◽  
C. M. Pariante ◽  
A. S. Papadopoulos ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Serotonin Transporter ◽  
Life Stress ◽  
Monozygotic Twins ◽  
Early Life Stress ◽  
Serotonin Transporter Gene ◽  
Bullying Victimization ◽  
Transporter Gene ◽  
Twin Design ◽  
Response To Stress

BackgroundChildhood adverse experiences are known to induce persistent changes in the hypothalamic–pituitary–adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear.MethodWe tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994–1995 cohort of families with twins.ResultsBullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children's genetic makeup or their shared familial environments because of the study design. Bullied twins also showed increasing methylation levels between the age of 5 years, prior to bullying victimization, and the age of 10 years whereas no such increase was detected in non-bullied twins across time. Moreover, children with higher SERT methylation levels had blunted cortisol responses to stress.ConclusionsOur study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNA methylation at a specific cytosine–phosphate–guanine (CpG) site in the SERT promoter and HPA functioning and suggests that these two systems may be functionally associated.

scholarly journals A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 4892-4900 ◽  
Author(s):  
Courtney J. Rice ◽  
Curt A. Sandman ◽  
Mohammed R. Lenjavi ◽  
Tallie Z. Baram
Keyword(s):  
Mouse Model ◽  
Paraventricular Nucleus ◽  
Life Stress ◽  
Early Life ◽  
Molecular Mechanisms ◽  
Early Life Stress ◽  
Plasma Corticosterone ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Basal Plasma

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.

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