TY - JOUR
T1 - XKDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors
AU - Black, Joshua C.
AU - Manning, Amity L.
AU - Van Rechem, Capucine
AU - Kim, Jaegil
AU - Ladd, Brendon
AU - Cho, Juok
AU - Pineda, Cristiana M.
AU - Murphy, Nancy
AU - Daniels, Danette L.
AU - Montagna, Cristina
AU - Lewis, Peter W.
AU - Glass, Kimberly
AU - Allis, C. David
AU - Dyson, Nicholas J.
AU - Getz, Gad
AU - Whetstine, Johnathan R.
N1 - Funding Information:
We are grateful to Ravi Mylvaganam and the MGH Flow Cytometry core for assistance with the cell sorting. We thank Mo Motamedi for helpful comments on the manuscript. This work was supported by funding to J.R.W. from the Ellison Medical Foundation, CA059267 and R01GM097360. G.G. and J.K. are supported by NIH U24CA143845. J.C.B. was a Fellow of The Jane Coffin Childs Memorial Fund for Medical Research. This investigation has been aided by a grant from The Jane Coffin Childs Memorial Fund for Medical Research. N.J.D. is supported by R01CA155202. A.L.M. is supported by MGH ECOR Tosteson Postdoctoral Fellowship. C.M. is supported by CCSG P30CA013330.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.06.051
DO - 10.1016/j.cell.2013.06.051
M3 - Article
C2 - 23871696
AN - SCOPUS:84881154753
SN - 0092-8674
VL - 154
SP - X541-555
JO - Cell
JF - Cell
IS - 3
ER -