Expressomal approach for comprehensive analysis and visualization of ligand sensitivities of xenoestrogen responsive genes.
Expressomal approach for comprehensive analysis and visualization of ligand sensitivities of xenoestrogen responsive genes.
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用于综合分析和可视化异雌激素反应基因的配体敏感性的表达方法。
DOI：
10.1073/pnas.1315929110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Isselbacher,KurtJ
中科院分区：
文献类型：
--
作者：
Shioda,Toshi;Rosenthal,NoelF;Coser,KathrynR;Suto,Mizuki;Phatak,Mukta;Medvedovic,Mario;Carey,VincentJ;Isselbacher,KurtJ
虽然内分泌干扰物（EDCs）的生物学效应经常在意外低剂量下观察到，偶尔出现非单调的剂量-反应特征，但EDC反应基因的敏感性或剂量依赖性行为的转录组范围内的概况仍未探索。在这里，我们描述了表达体分析的剂量依赖性基因反应的全面检查和它的应用，以表征雌激素反应基因在MCF-7细胞。MCF-7细胞的转录组暴露于不同浓度的代表性天然和外源性雌激素48小时，通过微阵列测定，并用于计算平均分布在对数空间中的300个剂量的估计转录组的内插近似值。这些估计的转录组，指定为expressome的整个集合，提供了独特的机会来配置文件的化学特定的配体敏感性分布的大量雌激素反应基因，揭示在低浓度雌激素一般倾向于抑制，而不是激活转录。基因本体分析表明，高敏感性和低敏感性雌激素反应基因之间存在明显的功能富集，这支持了单一EDC化学品在不同剂量下可引起定性不同生物反应的观点。双酚A诱导型基因的剂量依赖性诱导的表达体热图可视化显示，除了在100 nM及以上的主要强基因活化峰外，在极低浓度范围（约0.1 nM）也有弱基因活化峰。因此，expressome分析是一个强大的方法来了解EDC剂量依赖性的动态变化，在转录组水平的基因表达，提供重要的信息配体的敏感性和非单调响应的整体概况。
Although biological effects of endocrine disrupting chemicals (EDCs) are often observed at unexpectedly low doses with occasional nonmonotonic dose–response characteristics, transcriptome-wide profiles of sensitivities or dose-dependent behaviors of the EDC responsive genes have remained unexplored. Here, we describe expressome analysis for the comprehensive examination of dose-dependent gene responses and its applications to characterize estrogen responsive genes in MCF-7 cells. Transcriptomes of MCF-7 cells exposed to varying concentrations of representative natural and xenobiotic estrogens for 48 h were determined by microarray and used for computational calculation of interpolated approximations of estimated transcriptomes for 300 doses uniformly distributed in log space for each chemical. The entire collection of these estimated transcriptomes, designated as the expressome, has provided unique opportunities to profile chemical-specific distributions of ligand sensitivities for large numbers of estrogen responsive genes, revealing that at low concentrations estrogens generally tended to suppress rather than to activate transcription. Gene ontology analysis demonstrated distinct functional enrichment between high- and low-sensitivity estrogen responsive genes, supporting the notion that a single EDC chemical can cause qualitatively distinct biological responses at different doses. Expressomal heatmap visualization of dose-dependent induction of Bisphenol A inducible genes showed a weak gene activation peak at a very low concentration range (ca.0.1 nM) in addition to the main, strong gene activation peak at and above 100 nM. Thus, expressome analysis is a powerful approach to understanding the EDC dose-dependent dynamic changes in gene expression at the transcriptomal level, providing important information on the overall profiles of ligand sensitivities and nonmonotonic responses.