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Abstract:
Psychosocial stress triggers a set of behavioral, neural, hormonal, and
molecular responses that can be a driving force for survival when
adaptive and time-limited, but may also contribute to a host of disease
states if dysregulated or chronic. The beneficial or detrimental effects
of stress are largely mediated by the hypothalamic-pituitary axis, a
highly conserved neurohormonal cascade that culminates in systemic
secretion of glucocorticoids. Glucocorticoids activate the
glucocorticoid receptor, a ubiquitous nuclear receptor that not only
causes widespread changes in transcriptional programs, but also induces
lasting epigenetic modifications in many target tissues. While the
epigenome remains sensitive to stressors throughout life, we propose two
key principles that may govern the epigenetics of stress and
glucocorticoids along the lifespan: first, the presence of distinct life
periods, during which the epigenome shows heightened plasticity to
stress exposure, such as in early development and at advanced age; and,
second, the potential of stress-induced epigenetic changes to accumulate
throughout life both in select chromatin regions and at the genome-wide
level. These principles have important clinical and translational
implications, and they show striking parallels with the existence of
sensitive developmental periods and the cumulative impact of stressful
experiences on the development of stress-related phenotypes. We hope
that this conceptual mechanistic framework will stimulate fruitful
research that aims at unraveling the molecular pathways through which
our life stories sculpt genomic function to contribute to complex
behavioral and somatic phenotypes.
