Batista Frank, Vaiman Daniel, Dausset Jean, Fellous Marc, Veitia Reiner A
Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, and Faculté de Médecine René Descartes, Université Paris V UM 3, 75014 Paris, France.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3330-5. doi: 10.1073/pnas.0611326104. Epub 2007 Feb 20.
FOXL2 is a gene encoding a forkhead transcription factor, whose mutations are responsible for the blepharophimosis-ptosis-epicanthus inversus syndrome that often involves premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. We have recently shown that the aromatase gene is a target of FOXL2, and only three other targets have been reported so far. To detect potential transcriptional targets of FOXL2, we used DNA chips and quantitative PCR to compare the transcriptomes of granulosa-like cells overexpressing, or not, FOXL2. This analysis showed that mediators of inflammation, apoptotic and transcriptional regulators, genes involved in cholesterol metabolism, and genes encoding enzymes and transcription factors involved in reactive oxygen species detoxification were up-regulated. On the other hand, FOXL2 down-regulated the transcription of several genes involved in proteolysis and signal transduction and in transcription regulation. A bioinformatic analysis was conducted to discriminate between potential target promoters activated and repressed by FOXL2. In addition, the promoters of strongly activated genes were enriched in forkhead recognition sites, suggesting that these genes might be direct FOXL2 targets. Altogether, these results provide insight into the activity of FOXL2 and may help in understanding the mechanisms of pathogenesis of FOXL2 mutations if the targets prove to be the same in the ovary.
FOXL2是一种编码叉头转录因子的基因，其突变会导致睑裂狭小-上睑下垂-内眦赘皮综合征，该综合征常伴有卵巢早衰。FOXL2是最早出现的卵巢标志物之一，它与其靶基因一起，为研究正常和病理状态下的卵巢发育及功能提供了一个绝佳模型。我们最近发现芳香化酶基因是FOXL2的一个靶基因，到目前为止仅报道了另外三个靶基因。为了检测FOXL2潜在的转录靶基因，我们使用DNA芯片和定量PCR来比较过表达或未过表达FOXL2的颗粒样细胞的转录组。该分析表明，炎症介质、凋亡和转录调节因子、参与胆固醇代谢的基因以及编码参与活性氧解毒的酶和转录因子的基因均上调。另一方面，FOXL2下调了几个参与蛋白水解、信号转导和转录调节的基因的转录。进行了生物信息学分析，以区分被FOXL2激活和抑制的潜在靶启动子。此外，强激活基因的启动子富含叉头识别位点，表明这些基因可能是FOXL2的直接靶基因。总之，这些结果为FOXL2的活性提供了深入了解，如果这些靶基因在卵巢中被证明是相同的，可能有助于理解FOXL2突变的发病机制。
