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

机译：过敏性糖皮质激素反应特别调节周期1和昼夜节律基因的表达。

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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.
机译：糖皮质激素通过结合和激活糖皮质激素受体（GR）来调节基因表达。虽然配体亲和力决定了反应的整体敏感性，但其他蛋白质作用于基因组以调节某些基因的敏感性。然而，剂量特异性糖皮质激素应答的基因组范围和特异性尚不清楚。我们显示，剂量特异性糖皮质激素反应在基因组规模上具有极高的特异性，能够在与夜间夜间最低点一致的浓度下清楚地表达单一基因，即第1期的昼夜节律基因（ PER1 ）。人的皮质醇。我们将 PER1 响应映射到单个GR绑定位点。特定的GR结合序列不影响灵敏度，我们将响应归因于在相同基因座中发挥作用的其他转录因子和染色质可及性的组合。 PER1 过敏反应元件在小鼠中是保守的，我们在其中发现垂体细胞中 Per1 的类似上调。 PER1 的针对性和瞬时过表达导致数小时后对其他昼夜节律基因的调节，表明 PER1 的超敏表达影响昼夜节律基因的表达。这些发现表明，过敏性GR结合发生在整个基因组中，驱动靶向基因的表达，并且可能对周围昼夜节律的内分泌介导很重要。

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