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PMID: 19360092 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transcription initiation activity sets replication origin efficiency in mammalian cells.

PLoS genetics ·Vol. 5 ·No. 4 ·2009-04-00 ·Pages e1000446

Sequeira-Mendes J, Díaz-Uriarte R, Apedaile A, Huntley D, Brockdorff N, Gómez M

Abstract

Genomic mapping of DNA replication origins (ORIs) in mammals provides a powerful means for understanding the regulatory complexity of our genome. Here we combine a genome-wide approach to identify preferential sites of DNA replication initiation at 0.4% of the mouse genome with detailed molecular analysis at distinct classes of ORIs according to their location relative to the genes. Our study reveals that 85% of the replication initiation sites in mouse embryonic stem (ES) cells are associated with transcriptional units. Nearly half of the identified ORIs map at promoter regions and, interestingly, ORI density strongly correlates with promoter density, reflecting the coordinated organisation of replication and transcription in the mouse genome. Detailed analysis of ORI activity showed that CpG island promoter-ORIs are the most efficient ORIs in ES cells and both ORI specification and firing efficiency are maintained across cell types. Remarkably, the distribution of replication initiation sites at promoter-ORIs exactly parallels that of transcription start sites (TSS), suggesting a co-evolution of the regulatory regions driving replication and transcription. Moreover, we found that promoter-ORIs are significantly enriched in CAGE tags derived from early embryos relative to all promoters. This association implies that transcription initiation early in development sets the probability of ORI activation, unveiling a new hallmark in ORI efficiency regulation in mammalian cells.

MeSH Terms
Animals Cell Line CpG Islands Embryonic Stem Cells/cytology Mammals/genetics Mice Promoter Regions, Genetic Replication Origin Transcription, Genetic
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Sequeira-Mendes Joana
Edificio Departamental, Instituto de Microbiología Bioquímica, CSIC/Universidad de Salamanca, Salamanca, Spain.
Díaz-Uriarte Ramón
Apedaile Anwyn
Huntley Derek
Brockdorff Neil
Gómez María
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000446
Published
2009-04-00
Epub
2009-00-10
Pages
e1000446
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2661365
Subset
IM
Grants
Wellcome Trust · 081385 · United Kingdom
Wellcome Trust · 103768 · United Kingdom
External Links
PubMed source DOI: 10.1371/journal.pgen.1000446 PMC Full Text View journal details
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