Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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*Note: In the version of this article originally published online, in Figure 1, the label of the y axis was omitted: it should read "C-methylation (%)". In Figure 2, the panels were misidentified: the top two Southern blot panels in the immunoprecipitation analysis data should be identified as "a", the bottom two Southern blot panels as "b" and the graph as "c". In Figure 3, the legend text referred incorrectly to the panels: the legend should refer to the blots (beginning in the second sentence) as "a" and the graph (last sentence) as "b". In Figure 5, the panels were misidentified: the western blots and the graph immediately below them should be identified as "a" and the graph of corticosterone response as "b". In addition, in panel b, the units were listed incorrectly on the y axis: the correct units should be "μg/dl". In the Methods section, in the description of "Sodium bisufite mapping", the description of the thermocycler protocol listed the annealing temperature incorrectly: the annealing temperature should be 56 °C.
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These studies were supported by a grant from the Canadian Institutes for Health Research (CIHR) to M.J.M. and M.S. and from the National Cancer Institute of Canada to M.S. M.J.M. is supported by a CIHR Senior Scientist award and the project was supported by a Distinguished Investigator Award (M.J.M.) from the National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD).
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