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A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Chen, Han,Li, Chunyan,Peng, Xinxin,Zhou, Zhicheng,Weinstein, John N.,Caesar-Johnson, Samantha J.,Demchok, John A.,Felau, Ina,Kasapi, Melpomeni,Ferguson, Martin L.,Hutter, Carolyn M.,Sofia, Heidi J.,Ta Elsevier 2018 Cell Vol.173 No.2
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Summary The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Highlights <UL> <LI> Systematic analysis of enhancer expression across ∼9,000 samples of 33 cancer types </LI> <LI> Global enhancer activation positively correlates with aneuploidy but not mutations </LI> <LI> A computational method that infers causal enhancer-target-gene relationships </LI> <LI> Enhancers as key regulators of therapeutic targets, including PD-L1 </LI> </UL> Graphical Abstract [DISPLAY OMISSION]
2
lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

Wang, Zehua,Yang, Bo,Zhang, Min,Guo, Weiwei,Wu, Zhiyuan,Wang, Yue,Jia, Lin,Li, Song,Caesar-Johnson, Samantha J.,Demchok, John A.,Felau, Ina,Kasapi, Melpomeni,Ferguson, Martin L.,Hutter, Carolyn M.,Sof Cell Press 2018 Cancer Cell Vol. No.
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Summary We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129–283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo. Highlights <UL> <LI> LncRNAs show a hypomethylation phenotype, in contrast to a CIMP phenotype in cancer </LI> <LI> EPIC1 promotes breast tumorigenesis through regulating cancer cell-cycle progression </LI> <LI> EPIC1 directly interacts with MYC protein through EPIC1's 129–283 nt region </LI> <LI> EPIC1 regulates MYC targets by enhancing MYC occupancy on its target promoters </LI> </UL> Graphical Abstract [DISPLAY OMISSION]

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