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首页> 外文期刊>Molecular and Cellular Biology >TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4
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TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4

机译：孤儿核受体肝细胞核因子4从DNA和染色质模板的TRAP / SMCC /介导的转录激活。

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The orphan nuclear receptor hepatocyte nuclear factor 4 (HNF-4) regulates the expression of many liver-specific genes both during development and in the adult animal. Towards understanding the molecular mechanisms by which HNF-4 functions, we have established in vitro transcription systems that faithfully recapitulate HNF-4 activity. Here we have focused on the coactivator requirements for HNF-4, especially for the multicomponent TRAP/SMCC/Mediator complex that has emerged as the central regulatory module of the transcription apparatus. Using a system that has been reconstituted from purified transcription factors, as well as one consisting of unfractionated nuclear extract from which TRAP/SMCC/Mediator has been depleted by specific antibodies, we demonstrate a strong dependence of HNF-4 function on this coactivator. Importantly, we further show a TRAP/SMCC/Mediator-dependence for HNF-4 transcriptional activation from chromatin templates. The latter involves cooperation with the histone acetyltransferase-containing coactivator p300, in accord with a synergistic mode of action of the two divergent coactivators. We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically. This interaction likely involves primary HNF-4 activation function 2 (AF-2)-dependent interactions with the TRAP220 subunit of TRAP/SMCC/Mediator and secondary (AF-2-independent) interactions with TRAP170/RGR1. Finally, recruitment experiments using immobilized templates strongly suggest that the functional consequences of the physical interaction probably are manifested at a postrecruitment step in the activation pathway.
机译：孤儿核受体肝细胞核因子4（HNF-4）调节发育过程中和成年动物中许多肝脏特异性基因的表达。为了了解HNF-4发挥作用的分子机制，我们建立了忠实概述HNF-4活性的体外转录系统。在这里，我们集中讨论了HNF-4的共激活剂要求，特别是对于多组分TRAP / SMCC / Mediator复合物，该复合物已成为转录设备的中央调控模块。使用已从纯化的转录因子重建的系统，以及由未分离的核提取物组成的系统，其中TRAP / SMCC / Mediator已被特异性抗体耗尽，我们证明了HNF-4功能对这种共激活剂的强烈依赖性。重要的是，我们进一步显示了染色质模板对HNF-4转录激活的TRAP / SMCC /介体依赖性。后者涉及与含组蛋白乙酰转移酶的共激活因子p300的合作，这与两种不同的共激活因子的协同作用方式一致。我们还表明，HNF-4和TRAP / SMCC /介体可以发生物理相互作用。这种相互作用可能涉及与TRAP / SMCC /介体的TRAP220亚基的主要HNF-4激活功能2（AF-2）依赖的相互作用，以及与TRAP170 / RGR1的次级（AF-2独立）的相互作用。最后，使用固定模板的招募实验强烈表明，物理相互作用的功能后果可能在激活途径中的招募后步骤中体现出来。

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