4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

Satish Sati, Boyan Bonev, Quentin Szabo, Daniel Jost, Paul Bensadoun, Francois Serra, Vincent Loubiere, Giorgio Lucio Papadopoulos, Juan Carlos Rivera-Mulia, Lauriane Fritsch, Pauline Bouret, David Castillo, Josep Ll Gelpi, Modesto Orozco, Cedric Vaillant, Franck Pellestor, Frederic Bantignies, Marc A. Marti-Renom, David M. Gilbert, Jean Marc LemaitreGiacomo Cavalli

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)522-538.e9
JournalMolecular Cell
Volume78
Issue number3
DOIs
StatePublished - May 7 2020

Bibliographical note

Funding Information:
We thank Dr. Carl Mann for generously providing the WI-38-RAF and BJ-RAF cells used in this study, Genotoul facility for providing high computing resources, and MRI-IGH for microscopy support. We thank Dr. Guy Nir and Ting Wu for their support in designing oligopaints used in the study. We thank Max James Fritz for proofreading our manuscript. S.S. was supported by LabEx EPIGENMED postdoctoral fellowship and MuG project. Research in the laboratory of G.C. was supported by the CNRS, the University of Montpellier, and by grants from the European Research Council (ERC-2008-AdG No 232947), the European Union's Horizon 2020 research and innovation programme under grant agreement No 676556 (MuG), the European Union's Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No 813327 (ChromDesign), the Agence Nationale de la Recherche (N. ANR-15-CE12-006-01), the Fondation pour la Recherche M?dicale (Grant N. DEI20151234396), the French National Cancer Institute (INCa, Projects N. PLBIO16-222 and PLBIO18-362), the Laboratory of Excellence EpiGenMed (N. ANR-10-LABX-12), and the MSD Grant ?GENE-IGH.? Research in the laboratory of J.M.-L. was supported by INSERM, the University of Montpellier, the CHRU Montpellier/SAFE-iPSC facility (INGESTEM consortium Infrastructure en Biology Sant?), the French National Cancer Institute (INCa Project N. PLBIO12-103), and by grant from Ligue National Centre le Contre le cancer ?Equipe Labellis?e (2015?2019).? F.B. was supported by CNRS. Q.S. was supported by the French Ministry of Higher Education and Research and La Ligue Nationale Contre le Cancer. D.J. was supported by CNRS Mission Interdisciplinarit?, Agence Nationale de la Recherche (ANR-15-CE12-006-03) and the Fondation pour la Recherche M?dicale (DEI20151234396) and acknowledges computational resources from CIMENT infrastructure (supported by the Rhone-Alpes region, Grant CPER07 13 CIRA). 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 Ag?ncia de Gesti? 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 Mar?a de Maeztu 2016-2019.? This article/publication is based upon work from COST Action CA18127, supported by COST (European Cooperation in Science and Technology). Conceptualization, S.S. J.-M.L. and G.C.; Methodology, S.S.; Investigation, S.S. P. Bensadoun, P. Bouret, L.F. F.P. and J.-C.R.-M.; Software, S.S. B.B. Q.S. D.J. F.S. G.L.P. C.V. and V.L.; Resources, D.M.G. M.A.M.-R. J.L.G. M.O. and F.B.; Review and Editing, S.S. J.-M.L. and G.C.; Supervision, J.-M.L. and G.C. The authors declare no competing interests.

Funding Information:
We thank Dr. Carl Mann for generously providing the WI-38-RAF and BJ-RAF cells used in this study, Genotoul facility for providing high computing resources, and MRI-IGH for microscopy support. We thank Dr. Guy Nir and Ting Wu for their support in designing oligopaints used in the study. We thank Max James Fritz for proofreading our manuscript. S.S. was supported by LabEx EPIGENMED postdoctoral fellowship and MuG project . Research in the laboratory of G.C. was supported by the CNRS , the University of Montpellier , and by grants from the European Research Council ( ERC-2008-AdG No 232947 ), the European Union’s Horizon 2020 research and innovation programme under grant agreement No 676556 (MuG), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813327 (ChromDesign), the Agence Nationale de la Recherche ( N. ANR-15-CE12-006-01 ), the Fondation pour la Recherche Médicale (Grant N. DEI20151234396 ), the French National Cancer Institute (INCa, Projects N. PLBIO16-222 and PLBIO18-362 ), the Laboratory of Excellence EpiGenMed ( N. ANR-10-LABX-12 ), and the MSD Grant “GENE-IGH.” Research in the laboratory of J.M.-L. was supported by INSERM , the University of Montpellier , the CHRU Montpellier/SAFE-iPSC facility (INGESTEM consortium Infrastructure en Biology Santé), the French National Cancer Institute (INCa Project N. PLBIO12-103 ), and by grant from Ligue National Centre le Contre le cancer “Equipe Labellisée ( 2015 – 2019 ).” F.B. was supported by CNRS . Q.S. was supported by the French Ministry of Higher Education and Research and La Ligue Nationale Contre le Cancer . D.J. was supported by CNRS Mission Interdisciplinarité , Agence Nationale de la Recherche ( ANR-15-CE12-006-03 ) and the Fondation pour la Recherche Médicale ( DEI20151234396 ) and acknowledges computational resources from CIMENT infrastructure (supported by the Rhone-Alpes region, Grant CPER07 13 CIRA ). 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 ).

Publisher Copyright:
© 2020 The Authors

Keywords

  • 3D genome architecture
  • DNMT1
  • Hi-C
  • chromatin compartments
  • gene regulation
  • oncogene-induced senescence
  • replicative senescence
  • senescence

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