Intrauterine growth retardation affects expression and epigenetic characteristics of the rat hippocampal glucocorticoid receptor gene

Abstract

Studies in humans and rats suggest that intrauterine growth retardation (IUGR) permanently resets the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis reprogramming may involve persistently altered expression of the hippocampal glucocorticoid receptor (hpGR), an important regulator of HPA axis reactivity. Persistent alteration of gene expression, long after the inciting event, is thought to be mediated by epigenetic mechanisms that affect mRNA and mRNA variant expression. GR mRNA variants in both humans and rats include eleven 5'-end variants and GRalpha, the predominant 3'-end variant. The 3'-end variants associated with glucocorticoid resistance in humans (GRbeta, GRgamma, GRA, and GRP) have not been reported in rats. We hypothesized that in the rat hippocampus IUGR would decrease total GR mRNA, increase GRbeta, GRgamma, GRA, and GRP, and affect epigenetics of the GR gene at birth (D0) and at 21 days of life (D21). IUGR increased hpGR and exon 1.7 hpGR mRNA in males at D0 and D21, associated with increased trimethyl H3/K4 at exon 1.7 at both time points. IUGR also increased hpGRgamma in males at D0 and D21, associated with increased acetyl H3/K9 at exon 3 at both time points. hpGRA increased in female IUGR rats at D0 and D21. In addition, our data support the existence of hpGRbeta and hpGRP in the rat. IUGR has sex-specific, persistent effects on GR expression and its histone code. We speculate that postnatal changes in hippocampal GR variant and total mRNA expression may underlie IUGR-associated HPA axis reprogramming.

Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta

“…Ke and colleagues demonstrated an increase in expression of some forms of GR in the hippocampus of IUGR rats. 17 Our data suggest an increase in DNA methylation of the exon 1F of the GR associated with LGA status, which would be consistent with the findings of Ke and colleagues. More research is needed to identify risk factors that may lead to the developmental outcome of high birthweight, as well as further elucidation of the role of the glucocorticoid pathways and other critical molecular mediators leading to this phenotype and the associated later onset disease risk including metabolic disorders.…”

“…[14][15][16][17][18][19] Both rat and human studies have shown an association between methylation of the hippocampal GR gene and early postnatal outcomes. 16 Early maternal care of rat pups leads to altered methylation status of the NGFI-A consensus binding site within the promoter of the GR gene in the hippocampus, and these changes have been linked to altered stress responses later in life, as well as to growth restriction in utero.…”

IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus

“…Neuroendocrine programming of the hypothalamo-pituitary axis (HPA) axis is regulated, in part, by the hippocampus (24,40). Multiple studies suggest that IUGR-induced neuroendocrine reprogramming involves altered glucocorticoid receptor (GR) expression in the hippocampus and dysregulation of HPA axis reactivity (24,34,42,43,74,75,80 …”

“…Exon 1.7 plays an important role in regulating hippocampus GR expression and programming the HPA axis sensitivity (14,48,50,77). Interestingly, UPI-induced IUGR specifically increases GR exon 1.7 mRNA variant expression in male rat pup hippocampus (34). However, the epigenetic mechanism that determines the specific upregulation of GR exon 1.7 variant remains unknown.…”

“…We hypothesized further that increased Brg1 binding would be associated with accumulations of Sp1 and RNA pol II CTD pSer-5 in GR exon 1.7 promoter, as well as repositioning of nucleosomes over GR promoters. To test these hypotheses, we used a well-characterized rat model of UPI-induced IUGR (31,33,34), which results in significantly lighter placental mass and pup body weights compared with controls (54,64). IUGR rat pups grow up to develop metabolic disorders and impaired neurodevelopment (4,8,12,39,62,79).…”