Glioblastoma is the most common primary intrinsic brain tumor and universally lethal. Like many other cancers, glioblastomas have recurrent focal amplifications of oncogenes that promote cancer growth. It is not known to what extent other constituents of these amplicons support tumor formation. Cis-regulatory elements, including enhancers, are vital to the transcriptional regulation of many genes and may be an underappreciated part of these amplicons. I now propose to study the role of cis-regulatory elements in the regulation of EGFR, a very commonly amplified oncogene in glioblastoma. To accomplish this goal, I will use a CRISPR interference (CRISPRi) strategy to selectively repress putative enhancers at the EGFR locus and assess their role in EGFR regulation and overall cancer cell growth phenotype. Secondly, I will use chromosome conformation capture strategies to uncover how the looping of cis-regulatory elements in focal amplifications contributes to EGFR expression. Collectively, these proposed studies will provide a more general basis for how the cis-regulatory landscape is utilized by oncogenes in focal amplifications.
Glioblastoma is a common and highly lethal brain tumor, and even the newest therapies extend life only several months. Amplification of the oncogene EGFR is a very common step in glioblastoma carcinogenesis, but the role of the epigenome in regulating EGFR before and after amplification is poorly understood. This study aims to understand how EGFR expression is regulated in glioblastoma, with the ultimate goal of using this knowledge for therapeutics.
