Genome-wide Epigenetic Regulation by Early-Life Trauma

TLDR

DNA methylation mediates genome adaptation to environmental influences, with early‑life adversity linked to methylation changes in rodents and humans. The study aims to identify genome‑wide DNA methylation changes caused by early‑life trauma. The authors profiled promoter methylation by MeDIP‑array in hippocampal tissue from 41 French‑Canadian men, compared methylation with mRNA expression, validated differences in neuronal and nonneuronal fractions, and examined functional effects with luciferase assays. The study found 362 promoters differentially methylated in abused subjects, with 248 hyper‑ and 114 hypo‑methylated sites, mainly in neurons, and identified ALS2 as the most significant gene whose hypermethylation reduced promoter activity and hippocampal expression.

Abstract

<h3>Context</h3>Our genome adapts to environmental influences, in part through epigenetic mechanisms, including DNA methylation. Variations in the quality of the early environment are associated with alterations in DNA methylation in rodents, and recent data suggest similar processes in humans in response to early-life adversity.<h3>Objective</h3>To determine genome-wide DNA methylation alterations induced by early-life trauma.<h3>Design</h3>Genome-wide study of promoter methylation in individuals with severe abuse during childhood.<h3>Patients, Setting, and Main Outcome Measures</h3>Promoter DNA methylation levels were profiled using methylated DNA immunoprecipitation followed by microarray hybridization in hippocampal tissue from 41 French-Canadian men (25 with a history of severe childhood abuse and 16 control subjects). Methylation profiles were compared with corresponding genome-wide gene expression profiles obtained by messenger RNA microarrays. Methylation differences between groups were validated on neuronal and nonneuronal DNA fractions isolated by fluorescence-assisted cell sorting. Functional consequences of site-specific promoter methylation were assessed by luciferase assays.<h3>Results</h3>We identified 362 differentially methylated promoters in individuals with a history of abuse compared with controls. Among these promoters, 248 showed hypermethylation and 114 demonstrated hypomethylation. Validation and site-specific quantification of DNA methylation in the 5 most hypermethylated gene promoters indicated that methylation differences occurred mainly in the neuronal cellular fraction. Genes involved in cellular/neuronal plasticity were among the most significantly differentially methylated, and, among these, Alsin (ALS2) was the most significant finding. Methylated ALS2 constructs mimicking the methylation state in samples from abused suicide completers showed decreased promoter transcriptional activity associated with decreased hippocampal expression of ALS2 variants.<h3>Conclusion</h3>Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.