Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.
Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.
Stavreva
Diana A
DA
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-5055, USA.
Wiench
Malgorzata
M
John
Sam
S
Conway-Campbell
Becky L
BL
McKenna
Mervyn A
MA
Pooley
John R
JR
Johnson
Thomas A
TA
Voss
Ty C
TC
Lightman
Stafford L
SL
Hager
Gordon L
GL
D000305:Adrenal Cortex Hormones / Q000097:blood / Q000494:pharmacology*; D000315:Adrenalectomy; D000818:Animals; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D000305:Adrenal Cortex Hormones; D018832:Molecular Chaperones; D011965:Receptors, Glucocorticoid; D049452:Green Fluorescent Proteins; D012319:RNA Polymerase II
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