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Developmental control of gene copy number by repression of replication initiation and fork progression.

Authors :
Sher N
Bell GW
Li S
Nordman J
Eng T
Eaton ML
Macalpine DM
Orr-Weaver TL
Source :
Genome research [Genome Res] 2012 Jan; Vol. 22 (1), pp. 64-75. Date of Electronic Publication: 2011 Nov 16.
Publication Year :
2012

Abstract

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 is reinstated. Tethering of the SUUR protein to a specific site is insufficient to block replication, however. These results establish that developmental control of DNA replication, at both the initiation and elongation stages, is a mechanism to change gene copy number during differentiation.

Details

Language :
English
ISSN :
1549-5469
Volume :
22
Issue :
1
Database :
MEDLINE
Journal :
Genome research
Publication Type :
Academic Journal
Accession number :
22090375
Full Text :
https://doi.org/10.1101/gr.126003.111