FROM MATERNAL CARE TO GENE EXPRESSION: DNA METHYLATION AND THE MATERNAL PROGRAMMING OF STRESS RESPONSES

Abstract

Maternal care of pups influences the development of hypothalamic‐pituitary‐ adrenal (HPA) responses to stress in the rat. Thus, the adult offspring of mothers which naturally show an increased frequency of pup licking=grooming and arched back nursing (i.e., high LG-ABN mothers) show more modest HPA responses to stress. These effects are, in part, mediated by changes in hippocampal glucocorticoid receptor (GR) expression which mediates glucocorticoid negative feedback regulation of CRF expression. The effects of maternal care on GR expression in the neonate are associated with increased expression of the transcription factor NGFI-A and enhanced activation of GR gene expression through a neuron-specific promoter on exon 1 (exon 1Z) of the GR gene. In adulthood, the offspring of the high LG-ABN mothers show decreased methylation of the exon 1Z sequence. Using NaBis mapping of individual CpG sites we found hypomethylation of the NGFI-A consensus sequence on exon 1Z. The results of gel-shift assay with differentially methylated oligo nucleotide sequences containing the NGFI-A consensus site show that the pattern of hypomethylation apparent in the offspring of high LG-ABN mothers is associated with increased NGFI-A binding. These findings suggest that maternal behavior increases NGFI-A expression in infancy resulting in differential methylation of selected DNA sites and thus stable, long-term differences in gene expression over the lifespan.