Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes

Kwoneel Kim, Woojin Yang, Kang Seon Lee, Hyoeun Bang, Kiwon Jang, Sang Cheol Kim, Jin Ok Yang, Seongjin Park, Kiejung Park, Jung Kyoon Choi
2015 Nucleic Acids Research  
Global network modeling of distal regulatory interactions is essential in understanding the overall architecture of gene expression programs. Here, we developed a Bayesian probabilistic model and computational method for global causal network construction with breast cancer as a model. Whereas physical regulator binding was well supported by gene expression causality in general, distal elements in intragenic regions or loci distant from the target gene exhibited particularly strong functional
more » ... fects. Modeling the action of long-range enhancers was critical in recovering true biological interactions with increased coverage and specificity overall and unraveling regulatory complexity underlying tumor subclasses and drug responses in particular. Transcriptional cancer drivers and risk genes were discovered based on the network analysis of somatic and genetic cancer-related DNA variants. Notably, we observed that the risk genes were functionally downstream of the cancer drivers and were selectively susceptible to network perturbation by tumorigenic changes in their upstream drivers. Furthermore, cancer risk alleles tended to increase the susceptibility of the transcription of their associated genes. These findings suggest that transcriptional cancer drivers selectively induce a combinatorial misregulation of downstream risk genes, and that genetic risk factors, mostly residing in distal regulatory regions, increase transcriptional susceptibility to upstream cancer-driving somatic changes.
doi:10.1093/nar/gkv532 pmid:26001967 pmcid:PMC4499150 fatcat:hvpbvysiwndhhhnyawxbkog65u