Dynamic DNA methylation programs persistent adverse effects of early-life stress.
Adverse early life events can induce long-lasting changes in physiology and behavior. We found that early-life stress (ELS) in mice caused enduring hypersecretion of corticosterone and alterations in passive stress coping and memory. This phenotype was accompanied by a persistent increase in arginine vasopressin (AVP) expression in neurons of the hypothalamic paraventricular nucleus and was reversed by an AVP receptor antagonist. Altered Avp expression was associated with sustained DNA hypomethylation of an important regulatory region that resisted age-related drifts in methylation and centered on those CpG residues that serve as DNA-binding sites for the methyl CpG-binding protein 2 (MeCP2). We found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.
Murgatroyd
Chris
C
Max Planck Institute of Psychiatry, Munich, Germany.
Patchev
Alexandre V
AV
Wu
Yonghe
Y
Micale
Vincenzo
V
Bockmühl
Yvonne
Y
Fischer
Dieter
D
Holsboer
Florian
F
Wotjak
Carsten T
CT
Almeida
Osborne F X
OF
Spengler
Dietmar
D
D000818:Animals; D000831:Animals, Newborn; D001127:Arginine Vasopressin / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D019175:DNA Methylation / Q000502:physiology*; D003863:Depression / Q000235:genetics / Q000503:physiopathology*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000166:cytology / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology*; D010641:Phenotype; D010766:Phosphorylation / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D001127:Arginine Vasopressin; D003345:Corticosterone