Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322.
Proc Natl Acad Sci U S A. 2021 Jul 27;118(30). doi: 10.1073/pnas.2024685118.
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls the tissue- and gene-specific transactivation and transrepression of thousands of target genes. Distinct GR DNA-binding sequences with activating or repressive activities have been identified, but how they modulate transcription in opposite ways is not known. We show that GR forms phase-separated condensates that specifically concentrate known coregulators via their intrinsically disordered regions (IDRs) in vitro. A combination of dynamic, multivalent (between IDRs) and specific, stable interactions (between LxxLL motifs and the GR ligand-binding domain) control the degree of recruitment. Importantly, GR DNA binding directs the selective partitioning of coregulators within GR condensates such that activating DNAs cause enhanced recruitment of coactivators. Our work shows that condensation controls GR function by modulating coregulator recruitment and provides a mechanism for the up- and down-regulation of GR target genes controlled by distinct DNA recognition elements.
糖皮质激素受体（GR）是一种配体调节转录因子（TF），可控制数千个靶基因的组织和基因特异性转录激活和转录抑制。已经确定了具有激活或抑制活性的不同 GR DNA 结合序列，但它们如何以相反的方式调节转录尚不清楚。我们表明，GR 在体外形成相分离的凝聚物，通过其固有无序区域（IDR）特异性浓缩已知的共调节剂。动态、多价（IDR 之间）和特定、稳定的相互作用（LxxLL 基序和 GR 配体结合域之间）的组合控制募集的程度。重要的是，GR DNA 结合指导共调节剂在 GR 凝聚物内的选择性分区，使得激活 DNA 导致共激活剂的募集增强。我们的工作表明，凝聚作用通过调节共调节剂的募集来控制 GR 的功能，并为受不同 DNA 识别元件控制的 GR 靶基因的上调和下调提供了一种机制。
