Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications

Sweta Mishra, Capucine Van Rechem, Sangita Pal, Thomas L. Clarke, Damayanti Chakraborty, Sarah D. Mahan, Joshua C. Black, Sedona E. Murphy, Michael S. Lawrence, Danette L. Daniels, Jonathan R. Whetstine

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish
Pages (from-to)803-817.e16
Issue number4
StatePublished - Aug 9 2018


  • KDM5
  • rereplication
  • KDM4
  • SETD1B
  • MLL
  • chromatin
  • H3K36
  • epigenetics
  • amplification
  • KMT
  • TSSG
  • H3K4
  • KDM
  • H3K9
  • histone
  • K36M
  • JmjC
  • Lysine/metabolism
  • Humans
  • Histones/metabolism
  • DNA Copy Number Variations
  • DNA Methylation
  • HEK293 Cells
  • Retinoblastoma-Binding Protein 2/genetics
  • Chromatin/metabolism
  • Cell Cycle


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