TY - JOUR
T1 - Genome-wide epigenetic regulation by early-life trauma
AU - Labonté, Benoit
AU - Suderman, Matt
AU - Maussion, Gilles
AU - Navaro, Luis
AU - Yerko, Volodymyr
AU - Mahar, Ian
AU - Bureau, Alexandre
AU - Mechawar, Naguib
AU - Szyf, Moshe
AU - Meaney, Michael J.
AU - Turecki, Gustavo
PY - 2012/7
Y1 - 2012/7
N2 - 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.
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.
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U2 - 10.1001/archgenpsychiatry.2011.2287
DO - 10.1001/archgenpsychiatry.2011.2287
M3 - Article
C2 - 22752237
AN - SCOPUS:84855300158
SN - 0003-990X
VL - 69
SP - 722
EP - 731
JO - Archives of general psychiatry
JF - Archives of general psychiatry
IS - 7
ER -