The glucocorticoid receptor (NR3C1, also known as GR) binds to specific DNA sequences and directly induces transcription of anti-inflammatory genes that contribute to cytokine repression, frequently in cooperation with NF-kB. Whether inflammatory repression also occurs through local interactions between GR and inflammatory gene regulatory elements has been controversial. Here, using global run-on sequencing (GRO-seq) in human airway epithelial cells, we show that glucocorticoid signaling represses transcription within 10 min. Many repressed regulatory regions reside within "hyper-ChIPable" genomic regions that are subject to dynamic, yet nonspecific, interactions with some antibodies. When this artifact was accounted for, we determined that transcriptional repression does not require local GR occupancy. Instead, widespread transcriptional induction through canonical GR binding sites is associated with reciprocal repression of distal TNF-regulated enhancers through a chromatin-dependent process, as evidenced by chromatin accessibility and motif displacement analysis. Simultaneously, transcriptional induction of key anti-inflammatory effectors is decoupled from primary repression through cooperation between GR and NF-kB at a subset of regulatory regions. Thus, glucocorticoids exert bimodal restraints on inflammation characterized by rapid primary transcriptional repression without local GR occupancy and secondary anti-inflammatory effects resulting from transcriptional cooperation between GR and NF-kB.

中文翻译：

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糖皮质激素与 TNF 串扰的新生转录物分析定义了初级和协同炎症抑制。

糖皮质激素受体 (NR3C1，也称为 GR) 与特定的 DNA 序列结合，并直接诱导有助于细胞因子抑制的抗炎基因转录，通常与 NF-kB 合作。炎症抑制是否也通过 GR 和炎症基因调控元件之间的局部相互作用发生一直存在争议。在这里，我们在人气道上皮细胞中使用全局连续测序 (GRO-seq)，表明糖皮质激素信号在 10 分钟内抑制转录。许多受抑制的调节区域位于“超可芯片化”基因组区域内，这些区域受动态但非特异性与某些抗体相互作用的影响。当考虑到这个工件时，我们确定转录抑制不需要本地 GR 占用。反而，通过经典 GR 结合位点的广泛转录诱导与通过染色质依赖过程对远端 TNF 调节增强子的相互抑制相关，染色质可及性和基序置换分析证明了这一点。同时，通过 GR 和 NF-kB 在调节区域子集中的合作，关键抗炎效应子的转录诱导与初级抑制分离。因此，糖皮质激素对炎症具有双峰抑制作用，其特点是在没有局部 GR 占据的情况下快速初级转录抑制，以及 GR 和 NF-kB 之间的转录合作产生的次级抗炎作用。