Stimulus-dependent glucocorticoid receptor signalling in early-life stressed mice

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.