Franck Pellestor, Jean-Marc Lemaitre, Quentin Szabo, Giorgio L. Papadopoulos, Juan Carlos Rivera-Mulia, Satish Sati, Pauline Bouret, Giacomo Cavalli, Daniel Jost, Modesto Orozco, Frédéric Bantignies, François Serra, Boyan B. Bonev, Lauriane Fritsch, David Castillo, David M. Gilbert, Paul Bensadoun, Josep Ll. Gelpi, Vincent Loubiere, Cédric Vaillant, Marc A. Marti-Renom, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Helmholtz Zentrum München = German Research Center for Environmental Health, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Barcelona Institute of Science and Technology (BIST), University of Minnesota Medical School, University of Minnesota System, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), University of Barcelona, Laboratoire de Physique de l'ENS Lyon (Phys-ENS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Florida State University [Tallahassee] (FSU), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting HMGA2 expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation. Work at the M.A.M.-R. lab was supported by the European Research Council under the 7th Framework Program FP7/2007-2013 (ERC grant agreement 609989), the European Union’s Horizon 2020 research and innovation programme (grant agreement 676556), the Ministry of Economy and Competitiveness (BFU2017-85926-P), and the Agència de Gestió d’Ajuts Universitaris i de Recerca, AGAUR (SGR468). Work at CRG, BIST, and UPF was in part funded by the Spanish Ministry of Economy and Competitiveness, ‘‘Centro de Excelencia Severo Ochoa 2013-2017’’ (SEV-2012-0208), and ‘‘Centro de Excelencia María de Maeztu 2016-2019.’’ This article/publication is based upon work from COST Action CA18127, supported by COST (European Cooperation in Science and Technology)