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

Tomoshige Kino, George P. Chrousos

Research output: Contribution to journalReview article

36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalMolecular and Cellular Endocrinology
Volume336
Issue number1-2
DOIs
Publication statusPublished - 10 Apr 2011
Externally publishedYes

Fingerprint

Acetylation
Glucocorticoid Receptors
Circadian Rhythm
Epigenomics
Glucocorticoids
Tissue
Histone Acetyltransferases
Lysine
Clocks
Histone Deacetylases
Cushing Syndrome
Pathology
Hinges
Transcription Factors
Maintenance
Hormones
Proteins

Keywords

  • Acetylation
  • Circadian rhythm
  • Clock
  • Histone acetyltransferase (HAT)
  • Histone deacetylase (HDAC)
  • Hypothalamic-pituitary-adrenal (HPA) axis
  • Sirt1

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Biochemistry

Cite this

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N2 - 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.

AB - 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.

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