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Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplification are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMT) and demethylases (KDM) in regulating transient site-specific DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance to control extrachromosomal amplification of the oncogene. This study further establishes that cellular signals (hypoxia and EGF) are able to directly promote amplification through modulation of the enzymes controlling copy gains. Moreover, we demonstrate that chemical inhibitors targeting specific KMTs and KDMs are able to promote or block extrachromosomal amplification, which identifies potential therapeutic strategies for controlling copy-number heterogeneity in cancer, and, in turn, drug response. SIGNIFICANCE: This study identifies a network of epigenetic factors and cellular signals that directly control DNA amplification. We demonstrate that chemical inhibitors targeting enzymes controlling this amplification can be used to rheostat copy number, which uncovers therapeutic opportunities for controlling DNA amplification heterogeneity and the associated drug response..