An integrative ENCODE Resource for Cancer Genomics
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AbstractENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource. ENCODE is a resource comprising thousands of functional genomic datasets. Here, the authors present custom annotation within ENCODE for cancer, highlighting a workflow that can help prioritise key elements in oncogenesis.
All Author(s) ListJing Zhang, Donghoon Lee, Vineet Dhiman, Peng Jiang, Jie Xu, Patrick McGillivray, Hongbo Yang, Jason Liu, William Meyerson, Declan Clarke, Mengting Gu, Shantao Li, Shaoke Lou, Jinrui Xu, Lucas Lochovsky, Matthew Ung, Lijia Ma, Grace Yu, Qin Cao, Arif Harmanci, Koon-Kiu Yan, Anurag Sethi, Gamze Gürsoy, Michael Schoenberg, Joel Rozowsky, Jonathan Warrell, Prashant Emani, Flynn Chen, Yucheng Yang, Timur Galeev, Xiangmeng Kong, Shuang Liu, Xiaotong Li, Jayanth Krishnan, Yanlin Feng, Juan Carlos Rivera-Mulia, Jessika Adrian, James Broach, Michael Bolt, Jennifer Moran, Dominic Fitzgerald, Vishnu Dileep, Tingting Liu, Shenglin Mei, Takayo Sasaki, Claudia Trevilla-Garcia, Su Wang, Yanli Wang, Chongzhi Zang, Daifeng Wang, Robert Klein, Michael Snyder, David Gilbert, Kevin Yip, Chao Cheng, Feng Yue, Xiaole Liu, Kevin White, Mark Gerstein
Journal nameNature Communications
Year2020
Month7
Volume Number11
Issue Number1
PublisherNature Publishing Group
Article number3696
ISSN2041-1723
LanguagesEnglish-United States

Last updated on 2024-20-08 at 00:21