Summary
This project aims to identify and target 3D regulatory nodes, specifically hyperconnected enhancer hubs, that maintain glioblastoma (GBM) programs, to understand and disrupt the core regulatory logic driving GBM's phenotypic plasticity and oncogenic behavior.
What they want
The project will investigate core regulatory modules critical for GBM programs, focusing on 3D enhancer-promoter interaction networks in patient-derived glioma stem-like cells (GSCs) and normal neuronal stem cells. The interdisciplinary team will combine advanced chromatin topology assays, computational modeling, network analysis, epigenetic engineering, proteomics, and functional assays. Specific aims include: (i) characterizing inter-patient and intra-tumoral heterogeneity of 3D regulatory networks and identifying conserved structures; (ii) predicting and targeting candidate central hubs and interrogating their molecular and functional consequences; and (iii) uncovering critical players of hub organization and unique vulnerabilities. The goal is to provide insights into enhancer-based reprogramming of cancer fate and establish a paradigm for therapeutic targeting of GBM.
Deliverables
- Insights into enhancer-based reprogramming of cancer fate
- New avenues for therapeutic targeting of GBM
- A paradigm for identifying and prioritizing key enhancers and regulatory factors in oncogenic programs
- Characterization of inter-patient and intra-tumoral heterogeneity of 3D regulatory networks
- Identification of conserved structures across patients and states
- Prediction and targeting of candidate central hubs
- Interrogation of molecular and functional consequences of targeting hubs
- Uncovering critical players of hub organization and unique vulnerabilities
Technical requirements
- Advanced chromatin topology assays
- Computational modeling
- Network analysis
- State-of-the-art epigenetic engineering tools
- Proteomics tools
- Ex vivo functional assays
- In vivo functional assays
- Construction of 3D enhancer-promoter interaction networks
- Epigenetic perturbation techniques
