Babaei Sepideh, Akhtar Waseem, de Jong Johann, Reinders Marcel, de Ridder Jeroen
Delft Bioinformatics Lab, Faculty of Electrical Engineering Mathematics and Computer Science, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands.
Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Nat Commun. 2015 Feb 27;6:6381. doi: 10.1038/ncomms7381.
Genomically distal mutations can contribute to the deregulation of cancer genes by engaging in chromatin interactions. To study this, we overlay viral cancer-causing insertions obtained in a murine retroviral insertional mutagenesis screen with genome-wide chromatin conformation capture data. Here we find that insertions tend to cluster in 3D hotspots within the nucleus. The identified hotspots are significantly enriched for known cancer genes, and bear the expected characteristics of bona fide regulatory interactions, such as enrichment for transcription factor-binding sites. In addition, we observe a striking pattern of mutual exclusive integration. This is an indication that insertions in these loci target the same gene, either in their linear genomic vicinity or in their 3D spatial vicinity. Our findings shed new light on the repertoire of targets obtained from insertional mutagenesis screening and underline the importance of considering the genome as a 3D structure when studying effects of genomic perturbations.
基因组远端突变可通过参与染色质相互作用导致癌症基因的失调。为了研究这一现象，我们将在小鼠逆转录病毒插入诱变筛选中获得的病毒致癌插入与全基因组染色质构象捕获数据进行叠加。在此，我们发现插入倾向于聚集在细胞核内的三维热点区域。所确定的热点区域显著富集了已知的癌症基因，并具有真正调控相互作用的预期特征，如转录因子结合位点的富集。此外，我们观察到一种显著的相互排斥整合模式。这表明这些位点的插入靶向同一个基因，无论是在其线性基因组附近还是三维空间附近。我们的研究结果为从插入诱变筛选中获得的靶标库提供了新的见解，并强调了在研究基因组扰动的影响时将基因组视为三维结构的重要性。
