Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.
Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.
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DOI：
10.1093/nar/gkx509
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发表时间：
2017-08-21
影响因子：
14.9
通讯作者：
Ortlund EA
中科院分区：
文献类型：
--
作者：
Weikum ER;de Vera IMS;Nwachukwu JC;Hudson WH;Nettles KW;Kojetin DJ;Ortlund EA
糖皮质激素受体（GR）是一种配体调节的转录因子，控制广泛的基因网络的表达，驱动上调和下调。GR利用多种DNA结合依赖性和非依赖性机制来实现上下文特异性转录结果。不依赖DNA结合的机制涉及GR通过蛋白质-蛋白质相互作用与促炎性转录因子激活蛋白-1（AP-1）的连接。这一机制已成为GR介导的炎症基因反式阻遏的主要模型。然而，ChIP-seq数据一致显示GR占据AP-1应答元件（TREs），即使在不存在AP-1的情况下。因此，目前的模型不足以解释GR在这些网站上的行动。在这里，我们表明，GR调节炎症基因的一个子集在DNA结合依赖的方式。使用结构生物学和生物化学方法，我们表明，GR直接结合到TRE通过序列特异性接触到GR结合序列（GBS）半位点发现嵌入TRE基序。此外，我们表明，GR介导的反式阻遏观察TRE网站是DNA结合依赖。这代表了该领域的范式转变，表明GR使用多种机制来抑制炎症基因表达。这项工作进一步扩大了我们对这种复杂的多方面转录因子的理解。
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls the expression of extensive gene networks, driving both up- and down-regulation. GR utilizes multiple DNA-binding-dependent and -independent mechanisms to achieve context-specific transcriptional outcomes. The DNA-binding-independent mechanism involves tethering of GR to the pro-inflammatory transcription factor activator protein-1 (AP-1) through protein-protein interactions. This mechanism has served as the predominant model of GR-mediated transrepression of inflammatory genes. However, ChIP-seq data have consistently shown GR to occupy AP-1 response elements (TREs), even in the absence of AP-1. Therefore, the current model is insufficient to explain GR action at these sites. Here, we show that GR regulates a subset of inflammatory genes in a DNA-binding-dependent manner. Using structural biology and biochemical approaches, we show that GR binds directly to TREs via sequence-specific contacts to a GR-binding sequence (GBS) half-site found embedded within the TRE motif. Furthermore, we show that GR-mediated transrepression observed at TRE sites to be DNA-binding-dependent. This represents a paradigm shift in the field, showing that GR uses multiple mechanisms to suppress inflammatory gene expression. This work further expands our understanding of this complex multifaceted transcription factor.
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影响因子：
14.9
作者：
Flicek P;Ahmed I;Amode MR;Barrell D;Beal K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fairley S;Fitzgerald S;Gil L;García-Girón C;Gordon L;Hourlier T;Hunt S;Juettemann T;Kähäri AK;Keenan S;Komorowska M;Kulesha E;Longden I;Maurel T;McLaren WM;Muffato M;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ritchie GR;Ruffier M;Schuster M;Sheppard D;Sobral D;Taylor K;Thormann A;Trevanion S;White S;Wilder SP;Aken BL;Birney E;Cunningham F;Dunham I;Harrow J;Herrero J;Hubbard TJ;Johnson N;Kinsella R;Parker A;Spudich G;Yates A;Zadissa A;Searle SM
通讯作者：
Searle SM
影响因子：
30.8
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
DOI：
10.1016/0960-0760(92)90188-o
发表时间：
1992-09-01
影响因子：
4.1
作者：
CATO, ACB;KONIG, H;HERRLICH, P
通讯作者：
HERRLICH, P
影响因子：
16
作者：
John, Sam;Sabo, Peter J.;Hager, Gordon L.
通讯作者：
Hager, Gordon L.
影响因子：
13.8
作者：
Kadmiel M;Cidlowski JA
通讯作者：
Cidlowski JA