Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications.
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Abstract | Acquired chromosomal DNA amplifications are features of many tumors. Although overexpression and stabilization of the histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A generates transient site-specific copy number gains (TSSGs), additional mechanisms directly controlling site-specific DNA copy gains are not well defined. In this study, we uncover a collection of H3K4-modifying chromatin regulators that function with H3K9 and H3K36 regulators to orchestrate TSSGs. Specifically, the H3K4 tri-demethylase KDM5A and specific COMPASS/KMT2 H3K4 methyltransferases modulate different TSSG loci through H3K4 methylation states and KDM4A recruitment. Furthermore, a distinct chromatin modifier network, MLL1-KDM4B-KDM5B, controls copy number regulation at a specific genomic locus in a KDM4A-independent manner. These pathways comprise an epigenetic addressing system for defining site-specific DNA rereplication and amplifications. |
Year of Publication | 2018
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Journal | Cell
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Volume | 174
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Issue | 4
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Pages | 803-817.e16
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Date Published | 2018 08 09
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ISSN | 1097-4172
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DOI | 10.1016/j.cell.2018.06.018
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PubMed ID | 30057114
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PubMed Central ID | PMC6212369
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Grant list | R01 GM097360 / GM / NIGMS NIH HHS / United States
UL1 TR001102 / TR / NCATS NIH HHS / United States
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