Abstract CN07-02: Epigenetics: A gatekeeper to DNA amplification

Abstract

Abstract DNA copy gains and amplifications are often associated with tumorigenesis, poor prognosis, and drug resistance. However, little is known about how these regions of the genome are selected for amplification. Our group discovered that modulation of epigenetic factors and their associated chromatin states controls DNA copy gains of drug-resistant regions. In fact, transient site-specific copy number gains occur in both normal and cancer cells upon manipulation of a histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A. However, the mechanism by which KDM4A is targeted to specific genomic regions and whether additional chromatin regulators are involved in this process were unknown. To begin addressing these questions, we performed a series of unbiased genetic screens against all the histone lysine-modifying enzymes and followed their ability to generate copy gains of regions using DNA fluorescence in situ hybridization. Our screen uncovered insights about how KDM4A targeting influences DNA amplification in the human genome. We also demonstrated that specific epigenetic factors are working as a network to modulate DNA amplification of drug-resistant regions of the genome. Furthermore, we uncovered KDM4A-independent DNA amplifications, which established that additional regions are undergoing epigenetic control for amplification. These data will be discussed at the meeting. Citation Format: Johnathan R. Whetstine. Epigenetics: A gatekeeper to DNA amplification [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN07-02.