title: Genome-wide epigenetic regulation by early-life trauma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Childhood adversity is associated with epigenetic alterations in the promoters of several genes in hippocampal neurons.
authors: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.
authors: Benoit
authors: B
authors: Labonté
authors: Matt
authors: M
authors: Suderman
authors: Gilles
authors: G
authors: Maussion
authors: Luis
authors: L
authors: Navaro
authors: Volodymyr
authors: V
authors: Yerko
authors: Ian
authors: I
authors: Mahar
authors: Alexandre
authors: A
authors: Bureau
authors: Naguib
authors: N
authors: Mechawar
authors: Moshe
authors: M
authors: Szyf
authors: Michael J
authors: MJ
authors: Meaney
authors: Gustavo
authors: G
authors: Turecki
mesh_terms: D000328:Adult; D002648:Child; D002649:Child Abuse; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D016678:Genome; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008016:Life Change Events; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic