Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program

  • Mol Cell. 2016 Jan 21;61(2):260-73. doi: 10.1016/j.molcel.2015.12.001.
Rossana Foti  1 ,  Stefano Gnan  1 ,  Daniela Cornacchia  1 ,  Vishnu Dileep  2 ,  Aydan Bulut-Karslioglu  3 ,  Sarah Diehl  3 ,  Andreas Buness  1 ,  Felix A Klein  4 ,  Wolfgang Huber  4 ,  Ewan Johnstone  5 ,  Remco Loos  5 ,  Paul Bertone  6 ,  David M Gilbert  2 ,  Thomas Manke  3 ,  Thomas Jenuwein  3 ,  Sara C B Buonomo  7
Affiliations
  • 1. Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy.
  • 2. Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
  • 3. Max Planck Institute of Immunbiology and Epigenetics, Stubeweg 51, 79108 Freiburg, Germany.
  • 4. Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 5. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
  • 6. 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.
  • 7. Mouse Biology Unit, EMBL Monterotondo, Via Ramarini 32, 00015 Monterotondo, Italy. Electronic address: [email protected].
PMID: 26725008 DOI: 10.1016/j.molcel.2015.12.001
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.