An integrative ENCODE resource for cancer genomics.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 07 2020
29 07 2020
Historique:
received:
18
07
2019
accepted:
20
01
2020
entrez:
31
7
2020
pubmed:
31
7
2020
medline:
9
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32728046
doi: 10.1038/s41467-020-14743-w
pii: 10.1038/s41467-020-14743-w
pmc: PMC7391744
doi:
Substances chimiques
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3696Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007033
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009906
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA200060
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG009446
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM083337
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124820
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA218900
Pays : United States
Organisme : NIDDK NIH HHS
ID : R24 DK106766
Pays : United States
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