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

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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