Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes. Issue 12 (22nd May 2015)

• Record Type: Journal Article
• Authors: Kim, Kwoneel; Yang, Woojin; Lee, Kang Seon; Bang, Hyoeun; Jang, Kiwon; Kim, Sang Cheol; Yang, Jin Ok; Park, Seongjin; Park, Kiejung; Choi, Jung Kyoon
• Is Part Of: Nucleic acids research. Volume 43:Issue 12(2015)
• Page Start: 5716
• Page End: 5729
• Publication Date: 2015-05-22
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkv532
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: 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 effects. 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.