ChIPing the cistrome of PXR in mouse liver.
ChIPing the cistrome of PXR in mouse liver.
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DOI：
10.1093/nar/gkq654
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发表时间：
2010-12
影响因子：
14.9
通讯作者：
Klaassen CD
中科院分区：
文献类型：
--
作者：
Cui JY;Gunewardena SS;Rockwell CE;Klaassen CD
PXR是外源性生物质在肝脏中代谢和处置的关键调节因子。然而，关于体内PXR DNA结合特征，或者PXR如何在全基因组范围内调节新的直接靶点，人们知之甚少。因此，我们在整个小鼠基因组中生成了肝脏PXR结合的路线图[染色质免疫沉淀（ChIP）-Seq]。最常见的PXR DNA结合基序是具有4 bp间隔区的AGTTCA样直接重复序列[直接重复序列（DR）-4）]。令人惊讶的是，还存在具有5 bp周期性间隔区的高基序出现，形成PXR结合的新DR-（5 n + 4）模式。PXR结合与基因激活的表观遗传标记（组蛋白-H3 K4-二甲基化）重叠，但不与基因抑制的表观遗传标记（DNA甲基化或组蛋白-H3 K27-三甲基化）重叠（ChIP芯片）。给予PXR激动剂后，大多数PXR直接靶基因的mRNA变化与PXR结合增加相关。具体而言，增加PXR结合触发关键药物代谢酶和转运蛋白的反式激活。这些基因的mRNA诱导在PXR缺失小鼠中不存在。目前的工作提供了小鼠基因组中PXR DNA结合特征的第一个体内证据，为预测和进一步了解PXR在肝脏中的多方面作用铺平了道路。
The pregnane X receptor (PXR) is a key regulator of xenobiotic metabolism and disposition in liver. However, little is known about the PXR DNA-binding signatures in vivo, or how PXR regulates novel direct targets on a genome-wide scale. Therefore, we generated a roadmap of hepatic PXR bindings in the entire mouse genome [chromatin immunoprecipitation (ChIP)-Seq]. The most frequent PXR DNA-binding motif is the AGTTCA-like direct repeat with a 4bp spacer [direct repeat (DR)-4)]. Surprisingly, there are also high motif occurrences with spacers of a periodicity of 5 bp, forming a novel DR-(5n + 4) pattern for PXR binding. PXR-binding overlaps with the epigenetic mark for gene activation (histone-H3K4-di-methylation), but not with epigenetic marks for gene suppression (DNA methylation or histone-H3K27-tri-methylation) (ChIP-on-chip). After administering a PXR agonist, changes in mRNA of most PXR-direct target genes correlate with increased PXR binding. Specifically, increased PXR binding triggers the trans-activation of critical drug-metabolizing enzymes and transporters. The mRNA induction of these genes is absent in PXR-null mice. The current work provides the first in vivo evidence of PXR DNA-binding signatures in the mouse genome, paving the path for predicting and further understanding the multifaceted roles of PXR in liver.
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影响因子：
3.5
作者：
Cui, Yue Julia;Yeager, Ronnie L.;Klaassen, Curtis D.
通讯作者：
Klaassen, Curtis D.
影响因子：
11.4
作者：
LI, H;CAPETANAKI, Y
通讯作者：
CAPETANAKI, Y
影响因子：
3.8
作者：
Guzelian, Jeffrey;Barwick, Joyce L.;Guzelian, Philip S.
通讯作者：
Guzelian, Philip S.
影响因子：
46.9
作者：
Ji, Hongkai;Jiang, Hui;Ma, Wenxiu;Johnson, David S.;Myers, Richard M.;Wong, Wing H.
通讯作者：
Wong, Wing H.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J