Johnathan R. Whetstine

Fox Chase Cancer Center, USA

Title: Epigenetics: A Gatekeeper to extrachromosomal DNA Amplification and Drug Response

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Biography

For two decades, Dr. Whetstine has studied how chromatin factors control gene expression and genome stability. These studies initially focused on a specific class of chromatin regulators, JmjC-containing histone demethylases, that he discovered. His laboratory uncovered a role for demethylases and methyltransferases in regulating DNA amplification.  In fact, his group discovered the first enzyme responsible for generating extrachromosomal transient site-specific DNA copy gains.  His group is addressing the molecular features that are responsible for increasing the propensity of regions to amplify so that the defining principles controlling selective amplification and the associated plasticity can be identified and modulated.  His laboratory leverages these insights in order to identify biomarkers and therapeutic targets to target genetic heterogeneity.  Dr. Whetstine is a Professor, the Jack Schultz Basic Science Endowed Chair, the founding director of the Cancer Epigenetics Institute and co-leader of the Cancer Signaling and Epigenetics program at Fox Chase Cancer Center.

Abstract

Acquired chromosomal DNA amplifications are features of many tumors. However, mechanisms directly controlling site-specific extrachromosomal DNA copy gains are not well defined.  We previously discovered that transient site-specific copy number gains (TSSGs) occur upon overexpression and stabilization of the histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A. We have now expanded the collection of epigenetic regulators involved in DNA amplification to more than eight enzymes.  In fact, there are a compendium of H3K4/9/27/36 modifying chromatin regulators that orchestrate TSSG formation for oncogenes and drug-resistant associated oncogenes. Our studies have illustrated that there are epigenetic addressing systems for defining site-specific DNA rereplication and amplifications in the genome. The regulation of lysine methylation balance by histone methyltransferases and demethylases is key to these events. We have begun to address the impact that methylation states have on DNA amplification through biochemical, genomic and cytological approaches.  We have further uncovered additional novel relationships between methylation balance and DNA amplification as well as the orchestration of replication throughout the genome.  These studies emphasize the critical interplay between direct chromatin modulation, replication dynamics and DNA amplification.  Recent data related to these findings will be presented at the meeting.