The Hypersensitive Glucocorticoid Response Specifically Regulates Period 1 and Expression of Circadian Genes
- 1 September 2012
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 32 (18), 3756-3767
- https://doi.org/10.1128/mcb.00062-12
Abstract
Glucocorticoids regulate gene expression by binding and activating the glucocorticoid receptor (GR). While ligand affinity determines the global sensitivity of the response, additional proteins act on the genome to tune sensitivity of some genes. However, the genomic extent and specificity of dose-specific glucocorticoid responses are unknown. We show that dose-specific glucocorticoid responses are extraordinarily specific at the genomic scale, able to distinctly express a single gene, the circadian rhythm gene for Period 1 (PER1), at concentrations consistent with the nighttime nadir of human cortisol. We mapped the PER1 response to a single GR binding site. The specific GR binding sequence did not impact sensitivity, and we instead attributed the response to a combination of additional transcription factors and chromatin accessibility acting in the same locus. The PER1 hypersensitive response element is conserved in the mouse, where we found similar upregulation of Per1 in pituitary cells. Targeted and transient overexpression of PER1 led to regulation of additional circadian rhythm genes hours later, suggesting that hypersensitive expression of PER1 impacts circadian gene expression. These findings show that hypersensitive GR binding occurs throughout the genome, drives targeted gene expression, and may be important to endocrine mediation of peripheral circadian rhythms.This publication has 74 references indexed in Scilit:
- Cryptochromes mediate rhythmic repression of the glucocorticoid receptorNature, 2011
- Dynamic Exchange at Regulatory Elements during Chromatin Remodeling Underlies Assisted Loading MechanismCell, 2011
- Transcription Factor AP1 Potentiates Chromatin Accessibility and Glucocorticoid Receptor BindingMolecular Cell, 2011
- Chromatin accessibility pre-determines glucocorticoid receptor binding patternsNature Genetics, 2011
- Rescue of Obesity-Induced Infertility in Female Mice due to a Pituitary-Specific Knockout of the Insulin ReceptorCell Metabolism, 2010
- Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcriptionNature, 2009
- Modulation of transcription parameters in glucocorticoid receptor-mediated repressionMolecular and Cellular Endocrinology, 2008
- Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genesThe Journal of Steroid Biochemistry and Molecular Biology, 2008
- FoxA1 Translates Epigenetic Signatures into Enhancer-Driven Lineage-Specific TranscriptionCell, 2008
- Regulation of Gluconeogenesis by Krüppel-like Factor 15Cell Metabolism, 2007