Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epigenetic programming by maternal behavior

This article has been updated

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Maternal care alters cytosine methylation of GR promoter.
Figure 2: Chromatin immunoprecipitation analysis of the association between histone H3-K9 acetylation and NGFI-A binding to the exon 17 GR sequence in hippocampal tissue from adult offspring of high- and low-LG-ABN mothers (n = 4 animals/group).
Figure 3: HDAC inhibitior (TSA) eliminates maternal effect on histone acetylation and NGFI-A binding.
Figure 4: TSA effects on cytosine methylation.
Figure 5: TSA eliminates the maternal effect on hippocampal GR expression and HPA responses to stress.

Accession codes

Accessions

GenBank/EMBL/DDBJ

Change history

  • 27 July 2004

    added footnote and footnote references to figures within text; updated Figure 1; corrected online date made to issue version of PDF

Notes

  1. *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.

References

  1. Agrawal, A.A. Phenotypic plasticity in the interactions and evolution of species. Science 294, 321–326 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Rossiter, M.C. Maternal Effects as Adaptations (eds. Fox, T.A. & Mousseau, C.W.) (Oxford University Press, London, 1999).

    Google Scholar 

  3. Levine, S. The ontogeny of the hypothalamic-pituitary-adrenal axis. The influence of maternal factors. Ann. NY Acad. Sci. 746, 275–293 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Fleming, A.S., O'Day, D.H. & Kraemer, G.W. Neurobiology of mother-infant interactions: experience and central nervous system plasticity across development and generations. Neurosci. Biobehav. Rev. 23, 673–685 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Meaney, M.J. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24, 1161–1192 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Stern, J.M. Offspring-induced nurturance: animal-human parallels. Dev. Psychobiol. 31, 19–37 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Liu, D. et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Caldji, C. et al. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc. Natl. Acad. Sci. USA 95, 5335–5340 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Francis, D., Diorio, J., Liu, D. & Meaney, M.J. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286, 1155–1158 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Myers, M.M., Brunelli, S.A., Shair, H.N., Squire, J.M. & Hofer, M.A. Relationships between maternal behavior of SHR and WKY dams and adult blood pressures of cross-fostered F1 pups. Dev. Psychobiol. 22, 55–67 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. De Kloet, E.R., Vreugdenhil, E., Oitzl, M.S. & Joels, M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301 (1998).

    CAS  PubMed  Google Scholar 

  12. Meaney, M.J., Aitken, D.H., Viau, V., Sharma, S. & Sarrieau, A. Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat. Neuroendocrinology 50, 597–604 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Weaver, I.C. et al. Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Mol. Cell. Endocrinol. 185, 205–218 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Meaney, M.J. et al. Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J. Neurosci. 20, 3926–3935 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Laplante, P., Diorio, J. & Meaney, M.J. Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor. Brain Res. Dev. Brain Res. 139, 199–203 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. McCormick, J.A. et al. 5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol. Endocrinol. 14, 506–517 (2000).

    CAS  PubMed  Google Scholar 

  17. Kadonaga, J.T. Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell 92, 307–313 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Razin, A. CpG methylation, chromatin structure and gene silencing- a three-way connection. Embo J. 17, 4905–4908 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Keshet, I., Yisraeli, J. & Cedar, H. Effect of regional DNA methylation on gene expression. Proc. Natl. Acad. Sci. USA 82, 2560–2564 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Razin, A. & Cedar, H. Distribution of 5-methylcytosine in chromatin. Proc. Natl. Acad. Sci. USA 74, 2725–2728 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Clark, S.J., Harrison, J., Paul, C.L. & Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 22, 2990–2997 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Frommer, M. et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc. Natl. Acad. Sci. USA 89, 1827–1831 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cintra, A. et al. Mapping and computer assisted morphometry and microdensitometry of glucocorticoid receptor immunoreactive neurons and glial cells in the rat central nervous system. Neuroscience 62, 843–897 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Cintra, A. et al. Glial and neuronal glucocorticoid receptor immunoreactive cell populations in developing, adult, and aging brain. Ann. NY Acad. Sci. 746, 42–63 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Brinton, R.D., Yamazaki, R., Gonzalez, C.M., O'Neill, K. & Schreiber, S.S. Vasopressin-induction of the immediate early gene, NGFI-A, in cultured hippocampal glial cells. Brain Res. Mol. Brain Res. 57, 73–85 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Sapienza, C. Parental imprinting of genes. Sci. Am. 263, 52–60 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. Hershko, A.Y., Kafri, T., Fainsod, A. & Razin, A. Methylation of HoxA5 and HoxB5 and its relevance to expression during mouse development. Gene 302, 65–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Meaney, M.J. et al. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev. Neurosci. 18, 49–72 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Roth, S.Y., Denu, J.M. & Allis, C.D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Cervoni, N. & Szyf, M. Demethylase activity is directed by histone acetylation. J. Biol. Chem. 276, 40778–40787 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Milbrandt, J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238, 797–799 (1987).

    Article  CAS  PubMed  Google Scholar 

  32. Champagne, F.A., Francis, D.D., Mar, A. & Meaney, M.J. Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol. Behav. 79, 359–371 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Crane-Robinson, C., Myers, F.A., Hebbes, T.R., Clayton, A.L. & Thorne, A.W. Chromatin immunoprecipitation assays in acetylation mapping of higher eukaryotes. Methods Enzymol. 304, 533–547 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Moshe Szyf or Michael J Meaney.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weaver, I., Cervoni, N., Champagne, F. et al. Epigenetic programming by maternal behavior. Nat Neurosci 7, 847–854 (2004). https://doi.org/10.1038/nn1276

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1276

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing