TY - JOUR
T1 - An integrative ENCODE resource for cancer genomics
AU - ENCODE Project Consortium
AU - Zhang, Jing
AU - Lee, Donghoon
AU - Dhiman, Vineet
AU - Jiang, Peng
AU - Xu, Jie
AU - McGillivray, Patrick
AU - Yang, Hongbo
AU - Liu, Jason
AU - Meyerson, William
AU - Clarke, Declan
AU - Gu, Mengting
AU - Li, Shantao
AU - Lou, Shaoke
AU - Xu, Jinrui
AU - Lochovsky, Lucas
AU - Ung, Matthew
AU - Ma, Lijia
AU - Yu, Shan
AU - Cao, Qin
AU - Harmanci, Arif
AU - Yan, Koon-Kiu
AU - Sethi, Anurag
AU - Gürsoy, Gamze
AU - Schoenberg, Michael Rutenberg
AU - Rozowsky, Joel
AU - Warrell, Jonathan
AU - Emani, Prashant
AU - Yang, Yucheng T
AU - Galeev, Timur
AU - Kong, Xiangmeng
AU - Liu, Shuang
AU - Li, Xiaotong
AU - Krishnan, Jayanth
AU - Feng, Yanlin
AU - Rivera-Mulia, Juan Carlos
AU - Adrian, Jessica
AU - Broach, James R
AU - Bolt, Michael
AU - Moran, Jennifer
AU - Fitzgerald, Dominic
AU - Dileep, Vishnu
AU - Liu, Tingting
AU - Mei, Shenglin
AU - Sasaki, Takayo
AU - Trevilla-Garcia, Claudia
AU - Wang, Su
AU - Wang, Yanli
AU - Zang, Chongzhi
AU - Wang, Daifeng
AU - Gilbert, David M
PY - 2020/7/29
Y1 - 2020/7/29
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-020-14743-w
DO - 10.1038/s41467-020-14743-w
M3 - Article
C2 - 32728046
SN - 2041-1723
VL - 11
SP - 3696
JO - Nature communications
JF - Nature communications
IS - 1
ER -