Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis
Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis
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人肝脏中转录因子与细胞色素 P450 和 UDP-葡萄糖醛酸基转移酶 1A 表达和活性的关系：共表达网络分析
DOI：
10.1208/s12248-016-9990-2
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发表时间：
2017
期刊：
影响因子：
4.5
通讯作者：
Tang Lan
中科院分区：
文献类型：
--
作者：
Zhong Shilong;Han Weichao;Hou Chuqi;Liu Junjin;Wu Lili;Liu Menghua;Liang Zhi;Lin Haoming;Zhou Lili;Liu Shuwen;Tang Lan
细胞色素P450(Cyps)和UDP-葡萄糖醛酸基转移酶(UGT)在外源和内源化合物的代谢中起着重要作用。转录因子(转录因子)可增强或降低细胞色素P450和谷氨酰胺转运蛋白的基因转录。本研究旨在探索参与人肝脏UGTS/CyPS调控网络的新型转录因子。首先计算了3种不同的人肝脏表达谱(n = 640)中683个关键转录因子和Cys/UGT的转录水平之间的相关性。有监督加权相关网络分析(SWGCNA)用于确定所选TF中的HUB基因。在30例中国患者的肝组织标本中，对17种已定义的Tf、Cyps/UGTs的表达和活性之间的关系进行了评估。GreysWGCNA模块中阳性对照(如PPARA、NR1I2、NR1I3)和HUB TF(NFIA、NR3C2和AR)与CyPS/UGTS的表达显著正相关。与肿瘤或炎症相关的转录因子(TEAD4、NFKB2和NFKB1)与CYP2C9/CYP2E1/UGT1A9的mRNA表达呈负相关。此外，NR1I2、NR1I3、AR、TEAD4和NFKB2对CYP450/UGT1A基因转录的影响转化为对酶活性的中度影响。据我们所知，这是第一次整合基因表达总括(GEO)数据集和监督加权相关网络分析(SWGCNA)来定义潜在与Cyps/UGts相关的转录因子。我们检测到几个新的转录因子参与了人类肝脏细胞色素P450和糖基化终产物的调节网络。进一步的验证和研究可能揭示其调控CyPS/UGTS的确切机制。
Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs. The relationship among 17 defined TFs, CYPs/UGTs expression, and activity were evaluated in 30 liver samples from Chinese patients. The positive controls (e.g., PPARA, NR1I2, NR1I3) and hub TFs (NFIA, NR3C2, and AR) in the GreysWGCNA Module were significantly and positively associated with CYPs/UGTs expression. And the cancer- or inflammation-related TFs (TEAD4, NFKB2, and NFKB1) were negatively associated with mRNA expression of CYP2C9/CYP2E1/UGT1A9. Furthermore, the effect of NR1I2, NR1I3, AR, TEAD4, and NFKB2 on CYP450/UGT1A gene transcription translated into moderate influences on enzyme activities. To our knowledge, this is the first study to integrate Gene Expression Omnibus (GEO) datasets and supervised weighted correlation network analysis (sWGCNA) for defining TFs potentially related to CYPs/UGTs. We detected several novel TFs involved in the regulatory network of hepatic CYPs and UGTs in humans. Further validation and investigation may reveal their exact mechanism of CYPs/UGTs regulation.