RT Journal
A1 Sher, Noa
A1 Bell, George W.
A1 Li, Sharon
A1 Nordman, Jared
A1 Eng, Thomas
A1 Eaton, Matthew L
A1 MacAlpine, David M
A1 Orr-Weaver, Terry L
T1 Developmental control of gene copy number by repression of replication initiation and fork progression
JF Genome Research 
JO Genome Research 
YR 2011 
FD November 16 
DO 10.1101/gr.126003.111 
SP gr.126003.111 
UL http://genome.cshlp.org/content/early/2011/11/16/gr.126003.111.abstract 
AB Precise DNA replication is crucial for genome maintenance, yet this process has been inherently difficult to study on a genome-wide level in untransformed differentiated metazoan cells.  To determine how metazoan DNA replication can be repressed, we examined regions selectively under-replicated in Drosophila polytene salivary glands and found they are transcriptionally silent and enriched for the repressive H3K27me3 mark.  In the first genome-wide analysis of binding of the Origin Recognition Complex (ORC) in a differentiated metazoan tissue, we find that ORC binding is dramatically reduced within these large domains, suggesting reduced initiation as one mechanism leading to under-replication.  Inhibition of replication fork progression by the chromatin protein SUUR is an additional repression mechanism to reduce copy number.  Although repressive histone marks are removed when SUUR is mutated and copy number restored, neither transcription nor ORC binding are reinstated.  Tethering of SUUR protein to a specific site is insufficient to block replication, however.  These results establish that developmental control of DNA replication, both at the initiation and elongation stages, is a mechanism to change gene copy number during differentiation.