EPIGENETICS : A GATEKEEPER TO DNA AMPLIFICATION

Orateur : Jonathan R. WHETSTINE (Harvard Medical School, USA)

DNA amplifications are often associated with poor prognosis and drug resistance ; however, little is known about how these amplifications are selectively generated. Our group discovered that modulation of histone methyltransferases and demethylase and their associated chromatin states control DNA copy gains of regions associated with drug resistance. Transient site-specific copy number gains (TSSGs) occur upon overexpression or stabilization of a histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A and associate with reduced drug response. The mechanism(s) by which specific genomic loci are selected to undergo amplification and whether additional chromatin regulators are involved in generating drug resistant associated loci were not known. Using a series of unbiased genetic and chemical screens, we identified novel methyl modifying enzymes that regulate DNA copy gains. Our screen uncovered insights into both TSSG targeting and the identification of additional epigenetic factors modulating DNA amplification of drug resistant regions in the genome. These currently unpublished data will be discussed at the meeting.

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