RT Journal
A1 Martin, Melvenia M.
A1 Ryan, Michael
A1 Kim, RyangGuk
A1 Zakas, Anna L.
A1 Fu, Haiqing
A1 Lin, Chii Mei
A1 Reinhold, William C.
A1 Davis, Sean R.
A1 Bilke, Sven
A1 Liu, Hongfang
A1 Doroshow, James H.
A1 Reimers, Mark A.
A1 Valenzuela, Manuel S.
A1 Pommier, Yves
A1 Meltzer, Paul S.
A1 Aladjem, Mirit I.
T1 Genome-wide depletion of replication initiation events in highly transcribed regions
JF Genome Research 
JO Genome Research 
YR 2011 
FD November 01 
VO 21 
IS 11 
SP 1822 
OP 1832 
DO 10.1101/gr.124644.111 
UL http://genome.cshlp.org/content/21/11/1822.abstract 
AB This report investigates the mechanisms by which mammalian cells coordinate DNA replication with transcription and chromatin assembly. In yeast, DNA replication initiates within nucleosome-free regions, but studies in mammalian cells have not revealed a similar relationship. Here, we have used genome-wide massively parallel sequencing to map replication initiation events, thereby creating a database of all replication initiation sites within nonrepetitive DNA in two human cell lines. Mining this database revealed that genomic regions transcribed at moderate levels were generally associated with high replication initiation frequency. In genomic regions with high rates of transcription, very few replication initiation events were detected. High-resolution mapping of replication initiation sites showed that replication initiation events were absent from transcription start sites but were highly enriched in adjacent, downstream sequences. Methylation of CpG sequences strongly affected the location of replication initiation events, whereas histone modifications had minimal effects. These observations suggest that high levels of transcription interfere with formation of pre-replication protein complexes. Data presented here identify replication initiation sites throughout the genome, providing a foundation for further analyses of DNA–replication dynamics and cell-cycle progression.