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

Abstract

Ke X, McKnight RA, Maniar LE, Sun Y, Callaway CW, Majnik A, Lane RH, Cohen SS. IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus. Am J Physiol Regul Integr Comp Physiol 309: R119 -R127, 2015. First published May 13, 2015 doi:10.1152/ajpregu.00495.2014.-Intrauterine growth restriction (IUGR) increases the risk for neurodevelopment delay and neuroendocrine reprogramming in both humans and rats. Neuroendocrine reprogramming involves the glucocorticoid receptor (GR) gene that is epigenetically regulated in the hippocampus. Using a wellcharacterized rodent model, we have previously shown that IUGR increases GR exon 1.7 mRNA variant and total GR expressions in male rat pup hippocampus. Epigenetic regulation of GR transcription may involve chromatin remodeling of the GR gene. A key chromatin remodeler is Brahma-related gene-1(Brg1), a member of the ATPdependent SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Brg1 regulates gene expression by affecting nucleosome repositioning and recruiting transcriptional components to target promoters. We hypothesized that IUGR would increase hippocampal Brg1 expression and binding to GR exon 1.7 promoter, as well as alter nucleosome positioning over GR promoters in newborn male pups. Further, we hypothesized that IUGR would lead to accumulation of specificity protein 1 (Sp1) and RNA pol II at GR exon 1.7 promoter. Indeed, we found that IUGR increased Brg1 expression and binding to GR exon 1.7 promoter. We also found that increased Brg1 binding to GR exon 1.7 promoter was associated with accumulation of Sp1 and RNA pol II carboxy terminal domain pSer-5 (a marker of active transcription). Furthermore, the transcription start site of GR exon 1.7 was located within a nucleosome-depleted region. We speculate that changes in hippocampal Brg1 expression mediate GR expression and subsequently trigger neuroendocrine reprogramming in male IUGR rats.intrauterine growth restriction; Brahma-related gene 1; glucocorticoid receptor; hippocampus UTEROPLACENTAL INSUFFICIENCY (UPI) leads to intrauterine growth restriction (IUGR) and complicates up to 4 -6% of all pregnancies in developed countries (13). IUGR predisposes affected newborns toward poor neurological outcomes and impaired neuroendocrine programming (18,20,46,67,71). 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

Alterations in expression of imprinted genes from the H19/IGF2 loci in a multigenerational model of intrauterine growth restriction (IUGR)

“…This fetal programming is associated with epigenomic alterations 1–5 and has been demonstrated to occur across multiple generations. 12–17 Therefore, the identification of effective interventions during gestation to stop the cycle of the adult onset of disease is essential to ameliorate not only the health of the individual, but that of future generations.…”

“…We and others have shown that IUGR is associated with epigenetic alterations in many tissues including liver. 12–15, 5, 16, 17 Methylation levels are sensitive to the availability of the nutrients in the one carbon metabolism pathway including methionine, folic acid and choline. 18 We therefore hypothesize that supplementation of the maternal diet with components of the one carbon metabolism pathway during gestation would be associated with changes in gene-specific DNA methylation levels in the offspring.…”

Intrauterine growth restriction is not associated with decreased exercise capacity in adolescents with congenital heart disease

“…In summary, just as there are data that prenatal stressors and IUGR are associated with epigenetic modifications, there is evidence that the beneficial effects of physical activity are mediated through epigenetic modifications. [50][51][52][53][54][55] We speculate that IUGR may mediate epigenetic changes to genes involved in cardiorespiratory fitness, which may obscure response to exercise regimens. IUGR may act as a primary insult initiating epigenetic modifications.…”

Early life nutrition and brain development: breakthroughs, challenges and new horizons

“…The list of nutrients identified to cause changes to DNA methylation in early life has been growing. These early Intrauterine growth restriction H4K20 histone methylation of DUSP gene (51) Activation of glucocorticoid receptor with increased BDNF DNA CpG methylation and histone acetylation (52) Long-chain PUFA Alters DNA CpG methylation of BDNF gene (53) Alters CpG methylation genome-wide (54)…”