title: Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program.
abstract: DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains. We further demonstrate that Rif1 defines and restricts the interactions between replication-timing domains during the G1 phase, thereby revealing a function of Rif1 as organizer of nuclear architecture. Rif1 loss affects both number and replication-timing specificity of the interactions between replication-timing domains. In addition, during the S phase, Rif1 ensures that replication of interacting domains is temporally coordinated. In summary, our study identifies Rif1 as the molecular link between nuclear architecture and replication-timing establishment in mammals.
authors.affiliation: Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Foti
authors.affiliation: Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gnan
authors.affiliation: Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cornacchia
authors.affiliation: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Dileep
authors.affiliation: Max Planck Institute of Immunbiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany.
authors.forename: Aydan
authors.initials: A
authors.lastname: Bulut-Karslioglu
authors.affiliation: Max Planck Institute of Immunbiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Diehl
authors.affiliation: Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy.
authors.forename: Andreas
authors.initials: A
authors.lastname: Buness
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Felix A
authors.initials: FA
authors.lastname: Klein
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Johnstone
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Remco
authors.initials: R
authors.lastname: Loos
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK; Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.affiliation: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Gilbert
authors.affiliation: Max Planck Institute of Immunbiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.affiliation: Max Planck Institute of Immunbiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.affiliation: Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy. Electronic address: sara.buonomo@ed.ac.uk.
authors.forename: Sara C B
authors.initials: SC
authors.lastname: Buonomo
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D042522:DNA Replication Timing; D016193:G1 Phase; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034501:Telomere-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D002843:Chromatin; C492748:Rif1 protein, mouse; D034501:Telomere-Binding Proteins