Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.
McGowan
Patrick O
PO
Douglas Mental Health University Institute, 6875 LaSalle Boulevard, Montreal, Quebec, H4H 1R3, Canada.
Sasaki
Aya
A
D'Alessio
Ana C
AC
Dymov
Sergiy
S
Labonté
Benoit
B
Szyf
Moshe
M
Turecki
Gustavo
G
Meaney
Michael J
MJ
D000328:Adult; D054523:Adult Survivors of Child Abuse / Q000523:psychology*; D001483:Base Sequence; D002460:Cell Line; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D013405:Suicide / Q000523:psychology; D055815:Young Adult
C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid