O'Lone Raegan, Frith Martin C, Karlsson Elinor K, Hansen Ulla
Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215, USA.
Mol Endocrinol. 2004 Aug;18(8):1859-75. doi: 10.1210/me.2003-0044. Epub 2004 Mar 18.
Estrogen influences the physiology of many target tissues in both women and men. The long-term effects of estrogen are mediated predominantly by nuclear estrogen receptors (ERs) functioning as DNA-binding transcription factors. Tissue-specific responses to estrogen therefore result from regulation of different sets of genes. However, it remains perplexing as to what regulatory sequence contexts specify distinct genomic responses. First, this review classifies estrogen response sequences in mammalian target genes. Of note, around one third of known human target genes associate only indirectly with ER, through intermediary transcription factor(s). Then, computational approaches are presented both for refining direct ER-binding sites and for formulating hypotheses regarding the overall genomic expression pattern. Surprisingly, limited evolutionary conservation of specific estrogen-responsive sites is observed between human and mouse. Finally, consideration of the cellular functions of regulated human genes suggests links between particular biological roles and specific types of estrogen response elements, although with the important caveat that only a restricted set of target genes is available. These analyses support the view that specific, hormone-driven gene expression programs can result from the interplay of environmental and cellular cues with the distinct types of estrogen-response sequences.
雌激素对女性和男性的许多靶组织的生理机能均有影响。雌激素的长期作用主要由作为DNA结合转录因子的核雌激素受体（ERs）介导。因此，组织对雌激素的特异性反应源于对不同基因集的调控。然而，究竟是何种调控序列背景决定了不同的基因组反应，这一点仍令人困惑。首先，本综述对哺乳动物靶基因中的雌激素反应序列进行了分类。值得注意的是，约三分之一的已知人类靶基因仅通过中间转录因子与ER间接相关。然后，介绍了用于优化直接ER结合位点以及针对整体基因组表达模式提出假设的计算方法。令人惊讶的是，人类和小鼠之间特定雌激素反应位点的进化保守性有限。最后，对受调控的人类基因的细胞功能进行考量，发现特定生物学作用与特定类型的雌激素反应元件之间存在联系，不过重要的是，仅有有限的一组靶基因可供研究。这些分析支持了这样一种观点，即特定的、激素驱动的基因表达程序可能源于环境和细胞信号与不同类型雌激素反应序列之间的相互作用。
