The glucocorticoid receptor is an important immunosuppressive drug target and metabolic regulator that acts as a ligand-gated transcription factor. Generally, GR’s anti-inflammatory effects are attributed to the silencing of inflammatory genes, while its adverse effects are ascribed to the upregulation of metabolic targets. GR binding directly to DNA is proposed to activate, whereas GR tethering to pro-inflammatory transcription factors is thought to repress transcription. Using mice with a point mutation in GR’s zinc finger, that still tether via protein–protein interactions while being unable to recognize DNA, we demonstrate that DNA binding is essential for both transcriptional activation and repression. Performing ChIP-Seq, RNA-Seq and proteomics under inflammatory conditions, we show that DNA recognition is required for the assembly of a functional co-regulator complex to mediate glucocorticoid responses. Our findings may contribute to the development of safer immunomodulators with fewer side effects.

中文翻译：

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糖皮质激素受体的抗炎功能需要与DNA结合。

糖皮质激素受体是重要的免疫抑制药物靶标和代谢调节剂，可作为配体门控转录因子。通常，GR的抗炎作用归因于炎症基因的沉默，而其不利作用归因于代谢靶标的上调。建议直接与DNA结合的GR可以激活，而与促炎转录因子相连的GR被认为可以抑制转录。使用GR的锌指中具有点突变的小鼠，该突变仍然通过蛋白质间相互作用而束缚，但无法识别DNA，我们证明了DNA结合对于转录激活和抑制都是必不可少的。在炎症条件下进行ChIP-Seq，RNA-Seq和蛋白质组学，我们表明，DNA识别是功能性协同调节复合物介导糖皮质激素应答所必需的。我们的发现可能有助于开发更安全，副作用更少的免疫调节剂。