Department of Functional Genomics and Cancer, Université de Strasbourg, F_67404 Illkirch Cedex, France.
J Biol Chem. 2011 Sep 23;286(38):33322-34. doi: 10.1074/jbc.M111.263681. Epub 2011 Jul 29.
The nuclear retinoic acid receptors interact with specific retinoic acid (RA) response elements (RAREs) located in the promoters of target genes to orchestrate transcriptional networks involved in cell growth and differentiation. Here we describe a genome-wide in silico analysis of consensus DR5 RAREs based on the recurrent RGKTSA motifs. More than 15,000 DR5 RAREs were identified and analyzed for their localization and conservation in vertebrates. We selected 138 elements located ±10 kb from transcription start sites and gene ends and conserved across more than 6 species. We also validated the functionality of these RAREs by analyzing their ability to bind retinoic acid receptors (ChIP sequencing experiments) as well as the RA regulation of the corresponding genes (RNA sequencing and quantitative real time PCR experiments). Such a strategy provided a global set of high confidence RAREs expanding the known experimentally validated RAREs repertoire associated to a series of new genes involved in cell signaling, development, and tumor suppression. Finally, the present work provides a valuable knowledge base for the analysis of a wider range of RA-target genes in different species.
核视黄酸受体与特定的视黄酸（RA）反应元件（RARE）相互作用，这些元件位于靶基因的启动子中，以协调参与细胞生长和分化的转录网络。在这里，我们根据反复出现的 RGKTSA 基序，对基于共识 DR5 RARE 的全基因组计算机分析进行了描述。确定并分析了超过 15000 个 DR5 RARE，以确定它们在脊椎动物中的定位和保守性。我们选择了 138 个位于转录起始位点和基因末端 ±10 kb 处的元件，并在 6 个以上物种中保守。我们还通过分析它们与视黄酸受体的结合能力（ChIP 测序实验）以及相应基因的 RA 调节（RNA 测序和定量实时 PCR 实验）来验证这些 RARE 的功能。这种策略提供了一组全局高可信度 RARE，扩展了与一系列新基因相关的已知经过实验验证的 RARE repertoire，这些新基因涉及细胞信号转导、发育和肿瘤抑制。最后，本工作为在不同物种中分析更广泛范围的 RA 靶基因提供了有价值的知识库。
