Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.
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Charmandari E, Chrousos GP, Lambrou GI, Pavlaki A, Koide H, Ng SS, Kino T
Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.
PLoS One. 2011;6(9):e25612. doi: 10.1371/journal.pone.0025612. Epub 2011 Sep 28.
- PubMed ID
- 21980503 [ View in PubMed]
- Abstract
CONTEXT AND OBJECTIVE: Circulating cortisol fluctuates diurnally under the control of the "master" circadian CLOCK, while the peripheral "slave" counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR) at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans. DESIGN AND PARTICIPANTS: We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs) obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs) as non-synchronized controls. RESULTS: GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. CONCLUSIONS: Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Glucocorticoid receptor P04150 Details - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Hydrocortisone Approved Vet Approved ARNTL 406 downregulated Hydrocortisone results in decreased expression of ARNTL mRNA 11p15.3 Hydrocortisone Approved Vet Approved CRY1 1407 upregulated Hydrocortisone results in increased expression of CRY1 mRNA 12q23.3 Hydrocortisone Approved Vet Approved DUSP1 1843 upregulated Hydrocortisone results in increased expression of DUSP1 mRNA 5q35.1 Hydrocortisone Approved Vet Approved IL1A 3552 downregulated Hydrocortisone results in decreased expression of IL1A mRNA 2q14.1 Hydrocortisone Approved Vet Approved NR3C1 2908 downregulated Hydrocortisone results in decreased expression of NR3C1 mRNA 5q31.3 Hydrocortisone Approved Vet Approved PER1 5187 upregulated Hydrocortisone results in increased expression of PER1 mRNA 17p13.1 Hydrocortisone Approved Vet Approved RORA 6095 upregulated Hydrocortisone results in increased expression of RORA mRNA 15q22.2 Hydrocortisone Approved Vet Approved TNF 7124 downregulated Hydrocortisone results in decreased expression of TNF mRNA 6p21.33 Hydrocortisone Approved Vet Approved ZFP36 7538 upregulated Hydrocortisone results in increased expression of ZFP36 mRNA 19q13.1