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Madejska, Arleta (2015): Stimulus-dependent glucocorticoid receptor signalling in early-life stressed mice. Dissertation, LMU München: Fakultät für Biologie



Epigenetic programming facilitates the adaptation of an organism to changes in the environment through lasting alterations in gene expression that underlie certain physical and behavioral phenotypes. Exposure to adverse events in early postnatal life is known to increase the risk for stress-related psychiatric disorders later on. Our previous studies showed that early-life stress (ELS) in mice caused by periodic infant-mother separation (MS) leads to increased hyperactivity of the HPA axis, reduced glucocorticoid feedback inhibition, and depressive-like behavior. Moreover, our work revealed ELS-induced hypomethylation of the arginine vasopressin (Avp) gene enhancer and pro-opiomelanocortin (Pomc) promoter. The aim of the study was to investigate whether ELS can also lead to epigenetic programming of the mouse glucocorticoid receptor (GR, Nr3c1). GR is a major feedback regulator of the hypothalamic-pituitary adrenal (HPA) stress axis and its expression is regulated by multiple promoters associated with its5’ untranslated first exons. Given the fact that the mouse GR promoter was only partly characterized, we aimed to determine its genomic structure. In addition, tissue distribution and absolute quantification of newly identified alternative first exon transcripts were analysed. Although most of the first exon transcripts were found to be widely expressed, some of them are shown to be differentially regulated by growth factor- and depolarization-induced signaling. In the present work we show also that mice with a history of maternal separation display up-regulated GR mRNA levels. This observation was confined to Crh-producing neurons in the hypothalamic paraventricular nucleus (PVN), which are principal effectors of the stress response. Moreover, elevated levels of GR are shown to be responsible for stronger induction of its downstream target genes (Fkbp5, Sgk1, and DUSP1), which suggests an enhanced transcriptional activity of the GR in ELS mice. This effect is supported by a higher occupancy of the GR at the glucocorticoid response elements (GREs), following corticosterone injection (i.p.). Finally, we report here that an enhanced level of GR expression in ELS mice is accompanied by an increased methylation of specific CpG residues at the CpG island shore region of the GR promoter. These ELS-responsive CpGs comprise a DNA binding site for the transcriptional repressor Yin Yang 1 (YY1). Given the high homology of the mouse and human GR promoter, and the conservation of the YY1 binding site, we conducted a methylation analysis of the hGR CpG island shore region in peripheral tissues and post mortem brain samples. Our findings might serve as a basis for comparing the methylation patterns in tissues from control subjects and patients with stress-related brain disorders.