Potier Delphine, Davie Kristofer, Hulselmans Gert, Naval Sanchez Marina, Haagen Lotte, Huynh-Thu Vân Anh, Koldere Duygu, Celik Arzu, Geurts Pierre, Christiaens Valerie, Aerts Stein
Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, Leuven 3000, Belgium.
Department of Electrical Engineering and Computer Science and GIGA-R, University of Liège, Liège 4000, Belgium.
Cell Rep. 2014 Dec 24;9(6):2290-303. doi: 10.1016/j.celrep.2014.11.038. Epub 2014 Dec 18.
Genome control is operated by transcription factors (TFs) controlling their target genes by binding to promoters and enhancers. Conceptually, the interactions between TFs, their binding sites, and their functional targets are represented by gene regulatory networks (GRNs). Deciphering in vivo GRNs underlying organ development in an unbiased genome-wide setting involves identifying both functional TF-gene interactions and physical TF-DNA interactions. To reverse engineer the GRNs of eye development in Drosophila, we performed RNA-seq across 72 genetic perturbations and sorted cell types and inferred a coexpression network. Next, we derived direct TF-DNA interactions using computational motif inference, ultimately connecting 241 TFs to 5,632 direct target genes through 24,926 enhancers. Using this network, we found network motifs, cis-regulatory codes, and regulators of eye development. We validate the predicted target regions of Grainyhead by ChIP-seq and identify this factor as a general cofactor in the eye network, being bound to thousands of nucleosome-free regions.
基因组控制由转录因子（TFs）通过与启动子和增强子结合来控制其靶基因。从概念上讲，TFs、它们的结合位点及其功能靶标之间的相互作用由基因调控网络（GRNs）表示。在无偏差的全基因组环境中解析器官发育背后的体内GRNs涉及识别功能性TF-基因相互作用和物理TF-DNA相互作用。为了反向构建果蝇眼睛发育的GRNs，我们对72种基因扰动和分选的细胞类型进行了RNA测序，并推断出一个共表达网络。接下来，我们使用计算基序推断得出直接的TF-DNA相互作用，最终通过24,926个增强子将241个TFs与5,632个直接靶基因连接起来。利用这个网络，我们发现了网络基序、顺式调控密码以及眼睛发育的调节因子。我们通过ChIP-seq验证了颗粒头蛋白的预测靶区域，并将该因子鉴定为眼睛网络中的一个通用辅因子，它与数千个无核小体区域结合。
