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Dynamic DNA methylation programs persistent adverse effects of early-life stress

Nature Neuroscience volume 12, pages 1559–1566 (2009)Cite this article

An Erratum to this article was published on 01 May 2010

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Abstract

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.

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Figure 1: Endocrine and behavioral consequences of ELS depend on sustained AVP expression.
Figure 2: Selective methylation of the intergenic region of the Avp gene.
Figure 3: ELS induces hypomethylation of the Avp enhancer.
Figure 4: Enhancer methylation represses Avp expression as a result of MeCP2 occupancy.
Figure 5: CaMKII relieves MeCP2 occupancy and repression of the Avp enhancer.
Figure 6: ELS induces phosphorylation of MeCP2 in parvocellular PVN neurons.
Figure 7: ELS reduces MeCP2 occupancy at the Avp enhancer.

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Change history

  • 03 December 2009

    In the version of this article initially published, on page 2, left column, the phrase “…and typically cluster in glucocorticoid-rich regions called CpG islands (CGIs)” should be “…and typically cluster in GC-rich regions called CpG islands (CGIs)”. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. Hoffmann and R. Stoffel for their excellent technical assistance, A. Varga and B. Wörle for help with animal care, N. Sousa, J.-P. Schülke, T. Bettecken, F. Roselli and R. Spanagel for support. We thank S. Aventis for supplying SSR149415. This work was funded by the European Union (CRESCENDO – European Union contract number LSHM-CT-2005-018652 to O.F.X.A. and D.S.) and the Deutsche Forschungsgemeinschaft (SP 386/4-2 to D.S.).

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Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany

    Chris Murgatroyd, Alexandre V Patchev, Yonghe Wu, Vincenzo Micale, Yvonne Bockmühl, Dieter Fischer, Florian Holsboer, Carsten T Wotjak, Osborne F X Almeida & Dietmar Spengler

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Contributions

The study was conceived and designed by D.S. and O.F.X.A. C.M. and D.S. designed and interpreted the molecular studies that were carried out by C.M., Y.W., Y.B. and D.F., A.V.P. and O.F.X.A. were responsible for the neuroendocrine studies and A.V.P. and V.M. carried out the behavioral experiments under the guidance of C.T.W. C.M., A.V.P., F.H., O.F.X.A. and D.S. wrote the paper, with input from all of the other authors.

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Correspondence to Dietmar Spengler.

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Murgatroyd, C., Patchev, A., Wu, Y. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12, 1559–1566 (2009). https://doi.org/10.1038/nn.2436

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