The chromatin environment shapes DNA replication origin organization and defines origin classes
Christelle Cayrou 1,5,8, Benoit Ballester 2,3,5, Isabelle Peiffer 1, Romain Fenouil 4,6, Philippe Coulombe 1, Jean-Christophe Andrau 4,7, Jacques van Helden 2,3 and Marcel Méchali 1
1Institute of Human Genetics, CNRS, 34396 Montpellier, France;
2INSERM, U1090 TAGC, Marseille F-13288, France;
3Aix Marseille University, U1090 TAGC, Marseille F-13288, France;
4Centre d'Immunologie de Marseille-Luminy (CIML), 13009 Marseille, France
Corresponding authors: mechali{at}igh.cnrs.fr, Jacques.van-Helden{at}univ-amu.fr
↵5 These authors contributed equally to this work.
↵Present addresses: 6Mount Sinai Hospital, New York, NY 10029-6574, USA; 7Institute of Molecular Genetics, CNRS-UMR 5535, 34293 Montpellier, France; 8Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS UMR 7284, 06107 Nice, France
Credit/Crédito: Adrien Méchali
Abstract
To unveil the still-elusive nature of metazoan replication origins, we identified them genome-wide and at unprecedented high-resolution in mouse ES cells. This allowed initiation sites (IS) and initiation zones (IZ) to be differentiated. We then characterized their genetic signatures and organization and integrated these data with 43 chromatin marks and factors. Our results reveal that replication origins can be grouped into three main classes with distinct organization, chromatin environment, and sequence motifs. Class 1 contains relatively isolated, low-efficiency origins that are poor in epigenetic marks and are enriched in an asymmetric AC repeat at the initiation site. Late origins are mainly found in this class. Class 2 origins are particularly rich in enhancer elements. Class 3 origins are the most efficient and are associated with open chromatin and polycomb protein-enriched regions. The presence of Origin G-rich Repeated elements (OGRE) potentially forming G-quadruplexes (G4) was confirmed at most origins. These coincide with nucleosome-depleted regions located upstream of the initiation sites, which are associated with a labile nucleosome containing H3K64ac. These data demonstrate that specific chromatin landscapes and combinations of specific signatures regulate origin localization. They explain the frequently observed links between DNA replication and transcription. They also emphasize the plasticity of metazoan replication origins and suggest that in multicellular eukaryotes, the combination of distinct genetic features and chromatin configurations act in synergy to define and adapt the origin profile.
Footnotes
[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.192799.115.
Received April 4, 2015.
Accepted October 14, 2015.
© 2015 Cayrou et al.; Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
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Professores, pesquisadores e alunos de universidades públicas e privadas com acesso ao Portal de Periódicos CAPES/MEC podem ler gratuitamente este artigo da Genome Research e de mais 30.000 publicações científicas.
