Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks.
Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks.
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DOI：
10.1093/nar/gkw523
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发表时间：
2016-07-27
影响因子：
14.9
通讯作者：
DeCaprio JA
中科院分区：
文献类型：
--
作者：
Fischer M;Grossmann P;Padi M;DeCaprio JA
细胞周期（CC）和TP 53调控网络在癌症中经常失调。虽然已经进行了许多TP 53和CC调节基因的全基因组研究，但研究之间的显著差异使得难以评估任何给定的感兴趣基因的调节。为了克服单个研究的局限性，我们开发了一种荟萃分析方法来识别高置信度的靶基因，这些基因反映了它们在独立数据集中的识别频率。通过比较TP 53和CC调节基因的差异表达与TP 53、RB 1、E2 F、DREAM、B-MYB、FOXM 1和MuvB的染色质免疫沉淀研究来产生基因调控网络。来自p21缺失细胞的RNA-seq数据显示，TP 53的基因下调通常需要p21（CDKN 1A）。被TP 53下调的基因也被鉴定为被DREAM复合物结合的CC基因。转录因子RB、E2 F1和E2 F7与DREAM靶基因的一个子集结合，这些靶基因在CC的G1/S中起作用，而B-MYB、FOXM 1和MuvB控制G2/M基因表达。我们的方法产生了TP 53，DREAM，MMB-FOXM 1和RB-E2 F的高置信度排名的靶基因图谱，并能够预测和区分CC调控。www.targetgenereg.org上的网络图谱可以评估任何感兴趣的人类基因的调控。
Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.