title: KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors.
abstract: Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. This begins to establish how copy number changes could originate during tumorigenesis and demonstrates that transient overexpression of specific chromatin modulators could promote these events.
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, 13th Street, Charlestown, MA 02129, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.forename: Amity L
authors.initials: AL
authors.lastname: Manning
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.forename: Brendon
authors.initials: B
authors.lastname: Ladd
authors.forename: Juok
authors.initials: J
authors.lastname: Cho
authors.forename: Cristiana M
authors.initials: CM
authors.lastname: Pineda
authors.forename: Nancy
authors.initials: N
authors.lastname: Murphy
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D002843:Chromatin / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1; D004261:DNA Replication; D018628:Gene Dosage; D042822:Genomic Instability; D057809:HEK293 Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016196:S Phase
chemical_list: D002843:Chromatin; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human