Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
J Steroid Biochem Mol Biol. 2021 Jun;210:105873. doi: 10.1016/j.jsbmb.2021.105873. Epub 2021 Mar 17.
Glucocorticoid (GC) receptor (GR) is a key transcription factor (TF) that regulates vital metabolic and anti-inflammatory processes. We have identified BCL6 corepressor (BCOR) as a dexamethasone-stimulated interaction partner of GR. BCOR is a component of non-canonical polycomb repressor complex 1.1 (ncPCR1.1) and linked to different developmental disorders and cancers, but the role of BCOR in GC signaling is poorly characterized. Here, using ChIP-seq we show that, GC induces genome-wide redistribution of BCOR chromatin binding towards GR-occupied enhancers in HEK293 cells. As assessed by RNA-seq, depletion of BCOR altered the expression of hundreds of GC-regulated genes, especially the ones linked to TNF signaling, GR signaling and cell migration pathways. Biotinylation-based proximity mapping revealed that GR and BCOR share several interacting partners, including nuclear receptor corepressor NCOR1. ChIP-seq showed that the NCOR1 co-occurs with both BCOR and GR on a subset of enhancers upon GC treatment. Simultaneous depletion of BCOR and NCOR1 influenced GR target gene expression in a combinatorial and gene-specific manner. Finally, we show using live cell imaging that the depletion of BCOR together with NCOR1 markedly enhances cell migration. Collectively, our data suggest BCOR as an important gene and pathway selective coregulator of GR transcriptional activity.
糖皮质激素（GC）受体（GR）是一种关键的转录因子（TF），可调节重要的代谢和抗炎过程。我们已经确定 BCL6 核心抑制因子（BCOR）是地塞米松刺激的 GR 相互作用伙伴。BCOR 是非典型多梳抑制复合物 1.1（ncPCR1.1）的组成部分，与不同的发育障碍和癌症有关，但 BCOR 在 GC 信号转导中的作用尚未得到充分表征。在这里，我们使用 ChIP-seq 表明，GC 诱导 BCOR 染色质结合在 HEK293 细胞中向 GR 占据的增强子的全基因组重新分布。如 RNA-seq 评估所示，BCOR 的耗竭改变了数百个 GC 调节基因的表达，特别是与 TNF 信号、GR 信号和细胞迁移途径相关的基因。基于生物素化的邻近图谱显示，GR 和 BCOR 共享几个相互作用的伙伴，包括核受体共抑制因子 NCOR1。ChIP-seq 显示，NCOR1 与 BCOR 和 GR 一起在 GC 处理后的一组增强子上共同出现。BCOR 和 NCOR1 的同时耗竭以组合和基因特异性的方式影响 GR 靶基因表达。最后，我们通过活细胞成像表明，BCOR 与 NCOR1 的共耗竭显著增强了细胞迁移。总的来说，我们的数据表明 BCOR 是 GR 转录活性的重要基因和途径选择性共调节因子。
