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Original Article
July 2012

Genome-wide Epigenetic Regulation by Early-Life Trauma

Author Affiliations

Author Affiliations: McGill Group for Suicide Studies, Douglas Mental Health University Institute (Messrs Labonté and Mahar and Drs Maussion, Yerko, Mechawar, and Turecki), Department of Neurology and Neurosurgery (Messrs Labonté and Mahar and Drs Mechawar, Meaney, and Turecki), McGill Centre for Bioinformatics (Dr Suderman), Departments of Pharmacology and Therapeutics (Drs Suderman and Szyf) and Psychiatry (Drs Mechawar, Meaney, and Turecki), and McGill University, Montreal, Québec, Canada; Unitat de Genètica Molecular Institut de Biomedicina de València, Valencia, Spain (Mr Navaro); Centre de Recherche Robert-Giffard, Université Laval, Québec City, Québec, Canada (Dr Bureau); and Singapore Institute for Clinical Sciences, Singapore (Dr Meaney).

Arch Gen Psychiatry. 2012;69(7):722-731. doi:10.1001/archgenpsychiatry.2011.2287
Abstract

Context 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.

Objective To determine genome-wide DNA methylation alterations induced by early-life trauma.

Design Genome-wide study of promoter methylation in individuals with severe abuse during childhood.

Patients, Setting, and Main Outcome Measures 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.

Results 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.

Conclusion Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.

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