Epigenetic programming by maternal behavior

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.

[1]  Shakti Sharma,et al.  Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[2]  I. Weaver,et al.  Early Environmental Regulation of Hippocampal Glucocorticoid Receptor Gene Expression: Characterization of Intracellular Mediators and Potential Genomic Target Sites , 2004, Annals of the New York Academy of Sciences.

[3]  Shakti Sharma,et al.  Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. , 1997, Science.

[4]  Anurag A. Agrawal,et al.  Phenotypic Plasticity in the Interactions and Evolution of Species , 2001, Science.

[5]  S. Schreiber,et al.  Vasopressin-induction of the immediate early gene, NGFI-A, in cultured hippocampal glial cells. , 1998, Brain research. Molecular brain research.

[6]  A. Razin,et al.  CpG methylation, chromatin structure and gene silencing—a three‐way connection , 1998, The EMBO journal.

[7]  C. Allis,et al.  Histone acetyltransferases. , 2001, Annual review of biochemistry.

[8]  S. Clark,et al.  High sensitivity mapping of methylated cytosines. , 1994, Nucleic acids research.

[9]  M. Meaney,et al.  5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. , 2000, Molecular endocrinology.

[10]  H. Cedar,et al.  Effect of regional DNA methylation on gene expression. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Szyf,et al.  Demethylase Activity Is Directed by Histone Acetylation* , 2001, The Journal of Biological Chemistry.

[12]  K. Fuxe,et al.  Mapping and computer assisted morphometry and microdensitometry of glucocorticoid receptor immunoreactive neurons and glial cells in the rat central nervous system , 1994, Neuroscience.

[13]  M. Meaney,et al.  Nongenomic transmission across generations of maternal behavior and stress responses in the rat. , 1999, Science.

[14]  M. Joëls,et al.  Brain corticosteroid receptor balance in health and disease. , 1998, Endocrine reviews.

[15]  A. Razin,et al.  Methylation of HoxA5 and HoxB5 and its relevance to expression during mouse development. , 2003, Gene.

[16]  L. E. McDonald,et al.  A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Milbrandt,et al.  A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. , 1987, Science.

[18]  A. Razin,et al.  Distribution of 5-methylcytosine in chromatin. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Fox,et al.  Maternal effects as adaptations , 1998 .

[20]  Shakti Sharma,et al.  Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. , 1996, Developmental neuroscience.

[21]  C. Sapienza,et al.  Parental imprinting of genes. , 1990, Scientific American.

[22]  M. Meaney,et al.  Postnatal Handling Increases the Expression of cAMP-Inducible Transcription Factors in the Rat Hippocampus: The Effects of Thyroid Hormones and Serotonin , 2000, The Journal of Neuroscience.

[23]  J. Stern.  Offspring-induced nurturance: animal-human parallels. , 1997, Developmental psychobiology.

[24]  S. Levine.  The Ontogeny of the Hypothalamic‐Pituitary‐Adrenal Axis. The Influence of Maternal Factors a , 1994, Annals of the New York Academy of Sciences.

[25]  A. Fleminga,et al.  Neurobiology of mother – infant interactions : experience and central nervous system plasticity across development and generations , 1999 .

[26]  T. R. Hebbes,et al.  Chromatin immunoprecipitation assays in acetylation mapping of higher eukaryotes. , 1999, Methods in enzymology.

[27]  J. Squire,et al.  Relationships between maternal behavior of SHR and WKY dams and adult blood pressures of cross-fostered F1 pups. , 1989, Developmental psychobiology.

[28]  D H Aitken,et al.  Neonatal handling alters adrenocortical negative feedback sensitivity and hippocampal type II glucocorticoid receptor binding in the rat. , 1989, Neuroendocrinology.

[29]  M. Meaney,et al.  Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. , 2001, Annual review of neuroscience.

[30]  K. Fuxe,et al.  Glial and Neuronal Glucocorticoid Receptor Immunoreactive Cell Populations in Developing, Adult, and Aging Brain a , 1994, Annals of the New York Academy of Sciences.

[31]  M. Meaney,et al.  Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor. , 2002, Brain research. Developmental brain research.

[32]  A. Mar,et al.  Variations in maternal care in the rat as a mediating influence for the effects of environment on development , 2003, Physiology & Behavior.

[33]  J. T. Kadonaga.  Eukaryotic Transcription: An Interlaced Network of Transcription Factors and Chromatin-Modifying Machines , 1998, Cell.