Laboratory of Pharmacogenomics, Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland.
Int J Mol Sci. 2021 Apr 20;22(8):4258. doi: 10.3390/ijms22084258.
The glucocorticoid receptor (GR, also known as NR3C1) coordinates molecular responses to stress. It is a potent transcription activator and repressor that influences hundreds of genes. Enhancers are non-coding DNA regions outside of the core promoters that increase transcriptional activity via long-distance interactions. Active GR binds to pre-existing enhancer sites and recruits further factors, including EP300, a known transcriptional coactivator. However, it is not known how the timing of GR-binding-induced enhancer remodeling relates to transcriptional changes. Here we analyze data from the ENCODE project that provides ChIP-Seq and RNA-Seq data at distinct time points after dexamethasone exposure of human A549 epithelial-like cell line. This study aimed to investigate the temporal interplay between GR binding, enhancer remodeling, and gene expression. By investigating a single distal GR-binding site for each differentially upregulated gene, we show that transcriptional changes follow GR binding, and that the largest enhancer remodeling coincides in time with the highest gene expression changes. A detailed analysis of the time course showed that for upregulated genes, enhancer activation persists after gene expression changes settle. Moreover, genes with the largest change in EP300 binding showed the highest expression dynamics before the peak of EP300 recruitment. Overall, our results show that enhancer remodeling may not directly be driving gene expression dynamics but rather be a consequence of expression activation.
糖皮质激素受体 (GR，也称为 NR3C1) 协调对压力的分子反应。它是一种有效的转录激活剂和抑制剂，影响数百个基因。增强子是核心启动子之外的非编码 DNA 区域，通过长距离相互作用增加转录活性。活性 GR 结合到预先存在的增强子位点，并招募更多的因子，包括 EP300，这是一种已知的转录共激活因子。然而，GR 结合诱导的增强子重塑与转录变化之间的时间关系尚不清楚。在这里，我们分析了 ENCODE 项目的数据，该项目提供了人类 A549 上皮样细胞系在给予地塞米松后不同时间点的 ChIP-Seq 和 RNA-Seq 数据。本研究旨在研究 GR 结合、增强子重塑和基因表达之间的时间相互作用。通过研究每个上调基因的单个远端 GR 结合位点，我们表明转录变化紧随 GR 结合之后，最大的增强子重塑与基因表达变化的最大值同时发生。对时间过程的详细分析表明，对于上调基因，增强子激活在基因表达变化稳定后仍然存在。此外，EP300 结合变化最大的基因在 EP300 募集高峰之前表现出最高的表达动态。总的来说，我们的结果表明，增强子重塑可能不是基因表达动态的直接驱动因素，而是表达激活的结果。
