Nucleic Acids Research Advance Access originally published online on August 10, 2009
Nucleic Acids Research 2009 37(18):6064-6075; doi:10.1093/nar/gkp631
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Nucleic Acids Research, 2009, Vol. 37, No. 18 6064-6075
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genomics |
Open chromatin encoded in DNA sequence is the signature of ‘master’ replication origins in human cells
1Université de Lyon, F-69000 Lyon, 2Laboratoire Joliot-Curie and Laboratoire de Physique, CNRS, Ecole Normale Supérieure de Lyon, F-69007 Lyon and 3Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France
*To whom correspondence should be addressed. Tel: +33 4 7272 8757; Fax: +33 4 7272 8080; Email: alain.arneodo{at}ens-lyon.fr
Received June 16, 2009. Revised July 10, 2009. Accepted July 14, 2009.
For years, progress in elucidating the mechanisms underlying replication initiation and its coupling to transcriptional activities and to local chromatin structure has been hampered by the small number (approximately 30) of well-established origins in the human genome and more generally in mammalian genomes. Recent in silico studies of compositional strand asymmetries revealed a high level of organization of human genes around 1000 putative replication origins. Here, by comparing with recently experimentally identified replication origins, we provide further support that these putative origins are active in vivo. We show that regions 
300-kb wide surrounding most of these putative replication origins that replicate early in the S phase are hypersensitive to DNase I cleavage, hypomethylated and present a significant enrichment in genomic energy barriers that impair nucleosome formation (nucleosome-free regions). This suggests that these putative replication origins are specified by an open chromatin structure favored by the DNA sequence. We discuss how this distinctive attribute makes these origins, further qualified as ‘master’ replication origins, priviledged loci for future research to decipher the human spatio-temporal replication program. Finally, we argue that these ‘master’ origins are likely to play a key role in genome dynamics during evolution and in pathological situations.