Acetylation-mediated epigenetic regulation of glucocorticoid receptor activity: circadian rhythm-associated alterations of glucocorticoid actions in target tissues.

Glucocorticoids influence organ functions through the glucocorticoid receptor, a protein acetylated and deacetylated by several histone acetyltransferases and deacetylases. We reported that the circadian rhythm-related transcription factor "Clock", a key component of the biological CLOCK with inherent histone acetyltransferase activity, acetylates glucocorticoid receptor lysines within its hinge region--a "lysine cluster" containing a KXKK motif--and represses its transcriptional activity. This Clock-induced repression of the glucocorticoid receptor activity is inversely phased to the diurnally circulating glucocorticoids and may act as a local counter regulatory mechanism to the actions of these hormones. Importantly, uncoupling of the central CLOCK-regulated hypothalamic-pituitary-adrenal axis and peripheral CLOCK-mediated alterations of glucocorticoid action, such as chronic stress and frequent trans-time zone travel or night-shift work, may cause functional hypercortisolism and contribute to various pathologies. Thus, acetylation-mediated epigenetic regulation of the glucocorticoid receptor may be essential for the maintenance of proper time-integrated glucocorticoid action, significantly influencing human well-being and longevity.