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.
Original language | English |
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Pages (from-to) | 803-817.e16 |
Journal | Cell |
Volume | 174 |
Issue number | 4 |
DOIs | |
State | Published - Aug 9 2018 |
Keywords
- 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