title: Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes.
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.
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Kwoneel
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Woojin
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Kang Seon
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Hyoeun
authors.initials: H
authors.lastname: Bang
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Kiwon
authors.initials: K
authors.lastname: Jang
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 135-710, Republic of Korea.
authors.forename: Sang Cheol
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Korean Bioinformation Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Jin Ok
authors.initials: JO
authors.lastname: Yang
authors.affiliation: Korean Bioinformation Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Seongjin
authors.initials: S
authors.lastname: Park
authors.affiliation: Korean Bioinformation Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Kiejung
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea jungkyoon@kaist.ac.kr.
authors.forename: Jung Kyoon
authors.initials: JK
authors.lastname: Choi
mesh_terms: D001499:Bayes Theorem; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D006801:Humans; D061986:MCF-7 Cells; D012306:Risk; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors