The Hypersensitive Glucocorticoid Response Specifically Regulates Period 1 and Expression of Circadian Genes

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2012; 32(18):3756-67. DOI: 10.1128/MCB.00062-12
Source: PubMed


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.

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