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

Cell. 2018 Aug 9;174(4):803-817.e16. doi: 10.1016/j.cell.2018.06.018. Epub 2018 Jul 26.

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.

Keywords: H3K36; H3K4; H3K9; JmjC; K36M; KDM; KDM4; KDM5; KMT; MLL; SETD1B; TSSG; amplification; chromatin; epigenetics; histone; rereplication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Chromatin / metabolism*
  • DNA Copy Number Variations*
  • DNA Methylation*
  • HEK293 Cells
  • Histones / metabolism*
  • Humans
  • Lysine / metabolism*
  • Retinoblastoma-Binding Protein 2 / genetics
  • Retinoblastoma-Binding Protein 2 / metabolism*

Substances

  • Chromatin
  • Histones
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2
  • Lysine