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 Lemaitre; Giacomo Cavalli

doi:10.1016/j.molcel.2020.03.007

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

Biochemistry, Molecular Biology, and Biophysics (TMED)

Research output: Contribution to journal › Article › peer-review

77 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 language	English (US)
Pages (from-to)	522-538.e9
Journal	Molecular Cell
Volume	78
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2020.03.007
State	Published - 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 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 ).

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). 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.

Publisher Copyright:
© 2020 The Authors

Keywords

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

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.molcel.2020.03.007

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Sati, S., Bonev, B., Szabo, Q., Jost, D., Bensadoun, P., Serra, F., Loubiere, V., Papadopoulos, G. L., Rivera-Mulia, J. C., Fritsch, L., Bouret, P., Castillo, D., Gelpi, J. L., Orozco, M., Vaillant, C., Pellestor, F., Bantignies, F., Marti-Renom, M. A., Gilbert, D. M., ... Cavalli, G. (2020). 4D Genome Rewiring during Oncogene-Induced and Replicative Senescence. Molecular Cell, 78(3), 522-538.e9. https://doi.org/10.1016/j.molcel.2020.03.007

Sati, S, Bonev, B, Szabo, Q, Jost, D, Bensadoun, P, Serra, F, Loubiere, V, Papadopoulos, GL, Rivera-Mulia, JC, Fritsch, L, Bouret, P, Castillo, D, Gelpi, JL, Orozco, M, Vaillant, C, Pellestor, F, Bantignies, F, Marti-Renom, MA, Gilbert, DM, Lemaitre, JM & Cavalli, G 2020, '4D Genome Rewiring during Oncogene-Induced and Replicative Senescence', Molecular Cell, vol. 78, no. 3, pp. 522-538.e9. https://doi.org/10.1016/j.molcel.2020.03.007

@article{87aa15cabebb4bb2b71cda8bdc2c9e2d,

title = "4D Genome Rewiring during Oncogene-Induced and Replicative Senescence",

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.",

keywords = "3D genome architecture, DNMT1, Hi-C, chromatin compartments, gene regulation, oncogene-induced senescence, replicative senescence, senescence",

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

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{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement No 676556 (MuG), the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}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{\'e}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{\'e}), the French National Cancer Institute (INCa Project N. PLBIO12-103 ), and by grant from Ligue National Centre le Contre le cancer “Equipe Labellis{\'e}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{\'e} , Agence Nationale de la Recherche ( ANR-15-CE12-006-03 ) and the Fondation pour la Recherche M{\'e}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{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement 676556 ), the Ministry of Economy and Competitiveness ( BFU2017-85926-P ), and the Ag{\`e}ncia de Gesti{\'o} 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{\'i}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 ). 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{\l}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{\'e}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{\'e}), the French National Cancer Institute (INCa Project N. PLBIO12-103), and by grant from Ligue National Centre le Contre le cancer “Equipe Labellis{\'e}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{\'e}, Agence Nationale de la Recherche (ANR-15-CE12-006-03) and the Fondation pour la Recherche M{\'e}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{\`e}ncia de Gesti{\'o} 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{\'i}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. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = may,

day = "7",

doi = "10.1016/j.molcel.2020.03.007",

language = "English (US)",

volume = "78",

pages = "522--538.e9",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - 4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

AU - Sati, Satish

AU - Bonev, Boyan

AU - Szabo, Quentin

AU - Jost, Daniel

AU - Bensadoun, Paul

AU - Serra, Francois

AU - Loubiere, Vincent

AU - Papadopoulos, Giorgio Lucio

AU - Rivera-Mulia, Juan Carlos

AU - Fritsch, Lauriane

AU - Bouret, Pauline

AU - Castillo, David

AU - Gelpi, Josep Ll

AU - Orozco, Modesto

AU - Vaillant, Cedric

AU - Pellestor, Franck

AU - Bantignies, Frederic

AU - Marti-Renom, Marc A.

AU - Gilbert, David M.

AU - Lemaitre, Jean Marc

AU - Cavalli, Giacomo

N1 - 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 ). 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). 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. Publisher Copyright: © 2020 The Authors

PY - 2020/5/7

Y1 - 2020/5/7

N2 - 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.

AB - 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.

KW - 3D genome architecture

KW - DNMT1

KW - Hi-C

KW - chromatin compartments

KW - gene regulation

KW - oncogene-induced senescence

KW - replicative senescence

KW - senescence

UR - http://www.scopus.com/inward/record.url?scp=85083005663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85083005663&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2020.03.007

DO - 10.1016/j.molcel.2020.03.007

M3 - Article

C2 - 32220303

AN - SCOPUS:85083005663

SN - 1097-2765

VL - 78

SP - 522-538.e9

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -

4D Genome Rewiring during Oncogene-Induced and Replicative Senescence

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