Wednesday, April 2, 2025
4/2/2025
Targeting Epstein-Barr Virus Super-Enhancer - Epstein-Barr Virus (EBV) causes infectious mononucleosis, lymphomas and lymphoproliferative diseases in HIV infected and immune suppressed people and is linked to autoimmune diseases. EBV converts Resting B Lymphocytes (RBLs) to continuously proliferating Lymphoblasts Cell Lines (LCLs) by expressing EBV nuclear antigens (ENBAs) and latent membrane protein 1 (LMP1) that activates NF-kB. Since LCLs express that same EBV proteins as some EBV cancers, EBV conversion of RBLs to LCLs is therefore a relevant model that can be genetically manipulated to investigate EBV's role in growth transformation. LCL growth depends on EBNA2, EBNALP, EBNA3A, EBNA3C and LMP1. Recently, we found that all the essential EBNAs and LMP1 activated NF-kB subunits converge to EBV super-enhancers (ESE) that have extraordinary H3K27ac signals. ESEs govern the expression of key oncogenes that drive LCL growth and are more sensitive to perturbations that average enhancers. To further characterize the molecular composition and their functional roles in ESEs, we will (1) Determine the mechanisms through which ESEs loop to their target genes, (2) Determine the ESE proteomic composition and identify proteins that determine ESE formation, and (3) Determine the functional roles of ESE enhancer RNA (eRNA). We will use Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based assays to identify the DNA elements essential for ESE to loop to their direct target genes and proteins essential for ESE activity. We will test the effect of eRNA knock down on host transcription and looping factor DNA binding. The experiments here in use integrative approaches to elucidate the molecular mechanism by which ESEs activate key oncogenic divers. These studies will identify opportunities for therapeutic intervention.
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