The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.

中文翻译：

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Ep300 与功能不同的糖皮质激素受体结合位点的隔离是快速基因激活和抑制的基础

对转录因子糖皮质激素受体 (GR) 的快速转录反应，包括基因激活或抑制，是由具有多个 GR 结合位点 (GBS) 的基因在大基因组距离上的空间关联介导的。然而，只有少数 GBS 具有独立的 GR 介导的激活能力，具有独立抑制活性的 GBS 很少见报道。为了了解 GR 的正面和负面影响，我们绘制了其基因靶标的调控环境。我们表明，GR 激活和抑制基因的染色质相互作用网络在空间上是分离的，并且其 GBS 和其他非 GBS 调控元件的特征和配置各不相同。GR 激活域中的 KLF4 通路和 GR 抑制域中的 STAT6 通路的收敛，对 GR 施加相反的转录效应，与激素应用无关。此外，ROR 和 Rev-erb 转录因子分别作为 GR 介导的基因激活的正向和负向调节因子。我们发现 GBS 和非 GBS 之间的空间串扰提供了一个物理平台，用于将 Ep300 共激活因子与 GR 激活和抑制基因区室中的非 GR 调节基因座隔离。虽然这允许快速基因抑制，但 Ep300 募集到 GBSs 在激活的隔室中特别有效，从而为基因诱导提供了基础。我们发现 GBS 和非 GBS 之间的空间串扰提供了一个物理平台，用于将 Ep300 共激活因子与 GR 激活和抑制基因区室中的非 GR 调节基因座隔离。虽然这允许快速基因抑制，但 Ep300 募集到 GBSs 在激活的隔室中特别有效，从而为基因诱导提供了基础。我们发现 GBS 和非 GBS 之间的空间串扰提供了一个物理平台，用于将 Ep300 共激活因子与 GR 激活和抑制基因区室中的非 GR 调节基因座隔离。虽然这允许快速基因抑制，但 Ep300 募集到 GBSs 在激活的隔室中特别有效，从而为基因诱导提供了基础。