Med25 Is Required for RNA Polymerase II Recruitment to Specific Promoters, Thus Regulating Xenobiotic and Lipid Metabolism in Human Liver
Med25 Is Required for RNA Polymerase II Recruitment to Specific Promoters, Thus Regulating Xenobiotic and Lipid Metabolism in Human Liver
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DOI：
10.1128/mcb.00847-10
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发表时间：
2011-02-01
影响因子：
5.3
通讯作者：
Goldstein, Joyce A.
中科院分区：
文献类型：
--
作者：
Rana, Ritu;Surapureddi, Sailesh;Goldstein, Joyce A.
肝细胞核因子4 α（HNF 4 α）控制许多关键代谢途径的表达，并且介体复合物在将RNA聚合酶II（Pol II）募集到这些基因启动子中占据中心作用。人类肝脏中受损的转录HNF4 α网络是许多病理状况的原因，例如药物代谢改变、脂肪肝和糖尿病。在这里，我们报告说，Med25，一个相关的成员的调解人复合物，是需要的协会HNF4 α与调解人，它的几个辅因子，和RNA Pol II。此外，内源性Med25水平的增加和减少反映在转录复合物的组成、Pol II募集和HNF 4 α结合靶基因的表达中。Med25的一个新特征是它赋予“选择性”。Med25只影响HNF4 α靶基因的一个重要子集，这些基因选择性地调节药物和脂质代谢。这些结果定义了Med25和介体复合物在调节异生物质代谢和脂质稳态中的作用。
Hepatocyte nuclear factor 4 alpha (HNF4 alpha) controls the expression of many critical metabolic pathways, and the Mediator complex occupies a central role in recruiting RNA polymerase II (Pol II) to these gene promoters. An impaired transcriptional HNF4 alpha network in human liver is responsible for many pathological conditions, such as altered drug metabolism, fatty liver, and diabetes. Here, we report that Med25, an associated member of the Mediator complex, is required for the association of HNF4 alpha with Mediator, its several cofactors, and RNA Pol II. Further, increases and decreases in endogenous Med25 levels are reflected in the composition of the transcriptional complex, Pol II recruitment, and the expression of HNF4 alpha-bound target genes. A novel feature of Med25 is that it imparts "selectivity." Med25 affects only a significant subset of HNF4 alpha target genes that selectively regulate drug and lipid metabolism. These results define a role for Med25 and the Mediator complex in the regulation of xenobiotic metabolism and lipid homeostasis.