Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription

Abstract

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.

60 YEARS OF NEUROENDOCRINOLOGY: Glucocorticoid dynamics: insights from mathematical, experimental and clinical studies

“…3D), with the ACTH pulse amplitude increasing throughout the day as result of the circadian input from the SCN, via regulation of circadian secretion of CRH (Watts et al 2004). Given that pulsatility of CORT is important for maintaining optimal transcription of glucocorticoid regulated genes (Stavreva et al 2009), we decided to investigate whether pulsatile ACTH is important for optimal transcription of ACTH-responsive …”

Rhythms Within Rhythms: The Importance of Oscillations for Glucocorticoid Hormones

“…Ultradian oscillations of CORT induce cyclic GR-mediated pulses of gene transcription, both in vitro and in vivo, which differ from the response to equivalent constant levels of the ligand (Stavreva et al 2009;Conway-Campbell et al 2012;McMaster et al 2011). Indeed, gene pulsing of the clock gene period 1 occurs in vivo in response to physiological pulses, both in the liver (Stavreva et al 2009) and in the hippocampus .…”

“…Ultradian oscillations of CORT induce cyclic GR-mediated pulses of gene transcription, both in vitro and in vivo, which differ from the response to equivalent constant levels of the ligand (Stavreva et al 2009;Conway-Campbell et al 2012;McMaster et al 2011). Indeed, gene pulsing of the clock gene period 1 occurs in vivo in response to physiological pulses, both in the liver (Stavreva et al 2009) and in the hippocampus . In addition to these genomic effects, glucocorticoids have rapid non-genomic effects on neuronal activity in the brain (Karst et al 2005;Evanson et al 2010;Hill and Tasker 2012), with rapid effects on both excitatory and inhibitory inputs to the hippocampus (Karst et al 2005), and evidence for a specific effect on the insertion of Ca 2+ -permeable AMPA receptors into synapses (Whitehead et al 2013).…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…In contrast, the high affinity MR already responds to low glucocorticoid levels and its signalling activity appears to be more sustained (reviewed in [88]). These dynamics have consequences for gene expression: For the M a n u s c r i p t GR, it has been shown that pulsatile glucocorticoid signals can lead to different induction levels and expression dynamics of GR target genes compared with those observed under continuous stimulation [149]. It will be interesting to examine links between the circadian and ultradian changes in glucocorticoid levels, the different dynamic signalling properties of GR and MR, as well as the regulation of cell proliferation and survival.…”

“…Hamsters carrying a mutation which shortens their circadian period also present a reduced ultradian corticosterone pulse frequency [174]. Conversely, steady state transcription levels of the glucocorticoid inducible clock gene per1 are different under constant versus pulsatile GC treatments [149]. These examples suggest that, at least in some cases, the circadian clock and the circadian-ultradian GC rhythms may be interdependent.…”