An integrative ENCODE resource for cancer genomics.

Area of Science:

• Genomics
• Cancer Biology
• Systems Biology

Background:

• The Encyclopedia of DNA Elements (ENCODE) provides extensive functional genomics data for universal genome interpretation.
• Customized annotations are beneficial for specific research applications, enhancing genome analysis.
• Understanding complex diseases like cancer requires detailed regulatory network information.

Purpose of the Study:

• To develop a custom genome annotation using advanced functional genomics assays (eCLIP, Hi-C, STARR-seq) in ENCODE cell types.
• To build comprehensive, experimentally derived networks of transcription factors (TFs) and RNA-binding proteins (RBPs).
• To apply this network-based annotation to cancer research, focusing on regulatory hierarchies and network rewiring during oncogenesis.

Main Methods:

• Leveraging eCLIP, Hi-C, and whole-genome STARR-seq assays on ENCODE cell types.
• Constructing experimentally derived networks of TFs and RBPs, including TF-RBP crosstalk.
• Analyzing regulatory network changes during oncogenesis in cancer-associated cell types.
• Developing a workflow for prioritizing key genomic elements, variants, and regulators.

Main Results:

• A custom genome annotation with comprehensive TF and RBP networks was developed.
• SUB1, a novel RBP, was identified to drive aberrant tumor expression and amplify MYC oncogenic activity.
• Oncogenic transformations were mapped to a stem-like state in cell space, with opposing trends for oncogene knockdowns.
• Prioritization workflow successfully identified key elements and variants for cancer research applications.

Conclusions:

• The custom annotation and network resource provide valuable insights into cancer biology and oncogenesis.
• Identification of novel regulators like SUB1 offers potential therapeutic avenues.
• The developed workflow aids in prioritizing targets for further investigation in cancer genomics and therapeutics.