Cross-talk between lysine-modifying enzymes controls site-specific DNA amplifications

• Sweta Mishra ^[1] ; Capucine Van Rechem ^[1] ; Sangita Pal ^[1]
  1. [1] Harvard Medical School

     Harvard Medical School

     City of Boston, Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 4, 2018, págs. 803-817
• Idioma: inglés
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• Resumen

  • 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.