RT Journal
A1 Labonté B, Suderman M, Maussion G, et al
T1 GEnome-wide epigenetic regulation by early-life trauma
JF Archives of General Psychiatry
JO Archives of General Psychiatry
YR 2012
FD July 1
VO 69
IS 7
SP 722
OP 731
DO 10.1001/archgenpsychiatry.2011.2287
UL http://dx.doi.org/10.1001/archgenpsychiatry.2011.2287
AB 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.