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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    • "The glucocorticoid receptor gene (NR3C1) was another candidate gene that was highlighted in our analyses. The glucocorticoid receptor has been shown to interact with several key circadian proteins and to have an important role in integrating the regulatory input of environmental signals into the pathways of circadian genes (Yan et al. 2008; Reddy et al. 2012). We identified additional genes involved in regulating circadian pathways (PPARGC1A and MAGEL2) (Liu et al. 2007; McClung 2007 ) and genes encoding several glutamate and GABA receptors (e.g. "
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    • "The innermost circle shows the motif occurrences in the mitochondrial genome for each factor as black vertical bars. (A) CREB; (B) STAT3; (C) GR in A549 cells treated with different concentrations of dexamethasone (Dex) [60], [61]; (D) ERα in untreated (DMSO) ECC1 cells and ECC1 cells treated with bisphenol A (BPA), genistein (Gen) or 17β-estradiol (E2) [31]; (E) IRF3; (F) NFκB in GM12878 cells treated with TNFα [37]. The reads per million (RPM) tracks are shown, scaled to the maximum signal level (for both strands) for each dataset. "
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