title: The chromatin environment shapes DNA replication origin organization and defines origin classes.
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.
authors.affiliation: Institute of Human Genetics, CNRS, 34396 Montpellier, France;
authors.forename: Christelle
authors.initials: C
authors.lastname: Cayrou
authors.affiliation: INSERM, U1090 TAGC, Marseille F-13288, France; Aix Marseille University, U1090 TAGC, Marseille F-13288, France;
authors.forename: Benoit
authors.initials: B
authors.lastname: Ballester
authors.affiliation: Institute of Human Genetics, CNRS, 34396 Montpellier, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Peiffer
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), 13009 Marseille, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Fenouil
authors.affiliation: Institute of Human Genetics, CNRS, 34396 Montpellier, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Coulombe
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), 13009 Marseille, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Andrau
authors.affiliation: INSERM, U1090 TAGC, Marseille F-13288, France; Aix Marseille University, U1090 TAGC, Marseille F-13288, France;
authors.forename: Jacques
authors.initials: J
authors.lastname: van Helden
authors.affiliation: Institute of Human Genetics, CNRS, 34396 Montpellier, France;
authors.forename: Marcel
authors.initials: M
authors.lastname: Méchali
mesh_terms: D000818:Animals; D001482:Base Composition; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D002874:Chromosome Mapping; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D004261:DNA Replication; D053595:Embryonic Stem Cells; D016678:Genome; D023281:Genomics; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones; D006801:Humans; D051379:Mice; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D051738:Origin Recognition Complex; D018741:Replication Origin; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D009707:Nucleosomes; D051738:Origin Recognition Complex