An integrative ENCODE resource for cancer genomics

Jing 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, Shan Yu, Qin Cao, Arif Harmanci, Koon-Kiu Yan, Anurag Sethi, Gamze Gürsoy, Michael Rutenberg Schoenberg, Joel Rozowsky, Jonathan Warrell, Prashant Emani, Yucheng T. Yang, Timur Galeev, Xiangmeng Kong, Shuang Liu, Xiaotong Li, Jayanth Krishnan, Yanlin Feng, Juan Carlos Rivera-Mulia, Jessica Adrian, James R 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 J. Klein, Michael Snyder, David M. Gilbert, Kevin Yip, Chao Cheng, Feng Yue (), X. Shirley Liu (), Kevin P. White () and Mark Gerstein ()
Additional contact information
Jing Zhang: Yale University
Donghoon Lee: Yale University
Vineet Dhiman: University of Chicago
Peng Jiang: Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health
Jie Xu: Northwestern University
Patrick McGillivray: Yale University
Hongbo Yang: Northwestern University
Jason Liu: Yale University
William Meyerson: Yale University
Declan Clarke: Yale University
Mengting Gu: Yale University
Shantao Li: Yale University
Shaoke Lou: Yale University
Jinrui Xu: Yale University
Lucas Lochovsky: Yale University
Matthew Ung: Geisel School of Medicine at Dartmouth
Lijia Ma: University of Chicago
Shan Yu: University of Chicago
Qin Cao: The Chinese University of Hong Kong
Arif Harmanci: University of Texas Health Science Center at Houston
Koon-Kiu Yan: Yale University
Anurag Sethi: Yale University
Gamze Gürsoy: Yale University
Michael Rutenberg Schoenberg: Yale University
Joel Rozowsky: Yale University
Jonathan Warrell: Yale University
Prashant Emani: Yale University
Yucheng T. Yang: Yale University
Timur Galeev: Yale University
Xiangmeng Kong: Yale University
Shuang Liu: Yale University
Xiaotong Li: Yale University
Jayanth Krishnan: Yale University
Yanlin Feng: Yale University
Juan Carlos Rivera-Mulia: Florida State University
Jessica Adrian: Stanford University
James R Broach: The Pennsylvania State University
Michael Bolt: University of Chicago
Jennifer Moran: University of Chicago
Dominic Fitzgerald: University of Chicago
Vishnu Dileep: Florida State University
Tingting Liu: Northwestern University
Shenglin Mei: Harvard Medical School
Takayo Sasaki: Florida State University
Claudia Trevilla-Garcia: Florida State University
Su Wang: Harvard Medical School
Yanli Wang: The Pennsylvania State University
Chongzhi Zang: University of Virginia
Daifeng Wang: University of Wisconsin-Madison
Robert J. Klein: Icahn School of Medicine at Mount Sinai
Michael Snyder: Stanford University
David M. Gilbert: Florida State University
Kevin Yip: The Chinese University of Hong Kong
Chao Cheng: Geisel School of Medicine at Dartmouth
Feng Yue: Northwestern University
X. Shirley Liu: Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health
Kevin P. White: University of Chicago
Mark Gerstein: Yale University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract ENCODE 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.

Date: 2020
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Citations: View citations in EconPapers (10)

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DOI: 10.1038/s41467-020-14743-w

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