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. 2011 Nov;25(8):1548-53.
doi: 10.1016/j.bbi.2011.05.001. Epub 2011 May 11.

DNA Methylation as a Risk Factor in the Effects of Early Life Stress

Free PMC article

DNA Methylation as a Risk Factor in the Effects of Early Life Stress

Erin L Kinnally et al. Brain Behav Immun. .
Free PMC article


Epigenetic marks (e.g., DNA 5-methylcytosine [5mC] content or CpG methylation) within specific gene regulatory regions have been demonstrated to play diverse roles in stress adaptation and resulting health trajectories following early adversity. Yet the developmental programming of the vast majority of the epigenome has not yet been characterized, and its role in the impact of early stress largely unknown. In the present study, we investigated the relationships among early life stress, whole-epigenome and candidate stress pathway gene (serotonin transporter, 5-HTT) methylation patterns, and adult behavioral stress adaptation in a non-human primate model. Early in life, experimental variable foraging demand (VFD) stress or control conditions were administered to two groups each of 10 female bonnet macaques (Macaca radiata) and their mothers. As adults (3-13 years of age), these females were assessed for behavioral adaptation to stress across four conditions of increasing intensity. Blood DNA 5-HTT 5mC status was determined using sodium bisulfite pyrosequencing and total 5mC content was determined using ELISA. Neither stress reactivity nor DNA methylation differed based on early life stress. However, we found that both greater 5-HTT and whole-genome 5mC was associated with enhanced behavioral stress reactivity following early life stress, but not control conditions. Therefore, regardless of developmental origin, greater DNA methylation conferred a genomic background of "risk" in the context of early stress. We suggest that this may arise from constrained plasticity in gene expression needed for stress adaptation early in development. This risk may have wider implications for psychological and physical stress adaptation and health.

Conflict of interest statement

Conflict of Interest Statement: JDC received grants from Pfizer, GlaxoSmithKline, Bristol Myers Squibb, Eli Lilly, Astra Zeneca. JJM received unrelated grants from GSK and Novartis.


Figure 1
Figure 1
5-HTT CpG methylation moderates the effects of early life stress on behavioral stress reactivity. Higher 5-HTT CpG methylation was associated with higher reactivity scores in adults that experienced VFD stress as infants (F (1, 19) = 4.756, p = .023, adjusted R2 = .283). This effect is likely due to higher ratios of 5-methylcytosine across the epigenome, as they also confer risk for poorer stress adaptation (F (1,19) = 6.695, p = .008, adjusted R2 = .375).

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