STAT5A and STAT5B have opposite correlations with drug response gene expression.
STAT5A and STAT5B have opposite correlations with drug response gene expression.
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DOI：
10.1016/j.bbrc.2016.06.011
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发表时间：
2016-10-14
影响因子：
3.1
通讯作者：
Liang F
中科院分区：
文献类型：
--
作者：
Lamba V;Jia B;Liang F
STAT 5A和STAT 5 B是重要的转录因子，其在调节几种重要的生理过程（包括增殖、存活、介导对细胞因子的应答）和调节药物应答基因（例如负责人体中大部分药物代谢反应的肝细胞色素P450（CYP））的性别差异中发挥关键作用。STAT 5A和STAT 5 b具有高度的序列同源性，并且据报道具有很大程度上相似的功能。然而，最近的研究表明，它们在调节基因表达方面也常常具有独特的作用。在这项研究中，我们评估了STAT 5A和STAT 5 B mRNA表达水平与几个关键的肝细胞色素P450（CYP）和肝转录因子（TF）的相关性，并评估了STAT 5A和5 b在介导这些CYP和TF的性别差异中的潜在作用。使用RNA测序（RNA-seq）在102例人肝脏样本（57例女性，45例男性）中进行了主要肝脏β亚型和转录因子的表达谱分析。在50份人类肝脏样本（25名女性，25名男性）的子集中获得了选定CYP和TF的真实的PCR基因表达数据，并用于验证RNA-seq结果。虽然STAT 5A与多种肝脏转录因子（包括NR 1 I2和HNF 4A）和DME（如CYP 3A 4和CYP 2C 19）的表达水平呈显著负相关，但观察到STAT 5 B表达与分析的几种CYP和TF呈正相关。由于STAT 5A和STAT 5 B已被证明在CYP的性别差异的调节中是重要的，我们还分析了STAT 5A和5 b分别与男性和女性中的CYP和TF的关联，并观察到STAT与几种CYP和TF的性别依赖性差异关联。来自真实的时间PCR验证的结果在很大程度上支持了我们的RNA-seq发现。同时使用RNA测序和真实的时间PCR，我们研究了STAT 5A和STAT 5 B mRNA表达与TNF和TF基因表达的关系。而STAT 5A与多种肝TF（包括NR 1 I2和HNF 4 α）和CYP（如CYP 1A 1）的表达水平呈显著负相关。观察到STAT 5 B表达与分析的大多数CYP/TF呈正相关，表明STAT 5A和STAT 5 b在调节肝脏药物反应基因表达方面具有潜在的不同和独特的作用。需要进一步的研究来阐明STAT 5A和5 b在调节CYP/TF中的潜在作用以及这些发现的潜在意义。
STAT5A and STAT5B are important transcription factors that play a key role in regulation of several important physiological processes including proliferation, survival, mediation of responses to cytokines and in regulating gender differences in drug response genes such as the hepatic cytochrome P450s (CYPs) that are responsible for a large majority of drug metabolism reactions in the human body. STAT5A and STAT5b have a high degree of sequence homology and have been reported to have largely similar functions. Recent studies have, however, indicated that they can also often have distinct and unique roles in regulating gene expression. In this study, we evaluated the association of STAT5A and STAT5B mRNA expression levels with those of several key hepatic cytochrome P450s (CYPs) and hepatic transcription factors (TFs) and evaluated the potential roles of STAT5A and 5b in mediating gender differences in these CYPs and TFs. Expression profiling for major hepatic CYP isoforms and transcription factors was performed using RNA sequencing (RNA-seq) in 102 human liver samples (57 female, 45 male). Real time PCR gene expression data for selected CYPs and TFs was available on a subset of 50 human liver samples (25 female, 25 male) and was used to validate the RNA-seq findings. While STAT5A demonstrated significant negative correlation with expression levels of multiple hepatic transcription factors (including NR1I2 and HNF4A) and DMEs such as CYP3A4 and CYP2C19, STAT5B expression was observed to demonstrate positive associations with several CYPs and TFs analyzed. As STAT5A and STAT5B have been shown to be important in regulation of gender differences in CYPs, we also analyzed STAT5A and 5b associations with CYPs and TFs separately in males and females and observed gender dependent differential associations of STATs with several CYPs and TFs. Results from the real time PCR validation largely supported our RNA-seq findings. Using both RNA sequencing and real time PCR, we examined the association of STAT5A and STAT5B mRNA expression with CYP and TF gene expression. While STAT5A demonstrated significant negative correlations with expression levels of multiple hepatic TFs (including NR1I2 and HNF4α) and CYPs (eg. CYP3A4, CYP2C19), STAT5B expression was observed to demonstrate positive association with most of the CYPs/TFs analyzed suggesting that STAT5A and STAT5b have potentially different and distinct roles in regulating expression of hepatic drug response genes. Further studies are needed to elucidate the potential roles of STAT5A and 5b in regulation of CYPs/TFs and the potential implications of these findings.
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DOI：
10.1016/j.bbrc.2014.02.024
发表时间：
2014-03-07
影响因子：
3.1
作者：
Lamba, V.;Ghodke, Y.;Guan, W.;Tracy, T. S.
通讯作者：
Tracy, T. S.
影响因子：
4.7
作者：
Angus, WGR;Larsen, MC;Jefcoate, CR
通讯作者：
Jefcoate, CR
影响因子：
4.6
作者：
Clodfelter, Karl H.;Miles, Gregory D.;Waxman, David J.
通讯作者：
Waxman, David J.
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE
影响因子：
4.8
作者：
Park, SH;Liu, XW;Waxman, DJ
通讯作者：
Waxman, DJ