Involvement of condensin in cellular senescence through gene regulation and compartmental reorganization

Senescence is induced by various stimuli such as oncogene expression and telomere shortening, referred to as oncogene-induced senescence (OIS) and replicative senescence (RS), respectively, and accompanied by global transcriptional alterations and 3D genome reorganization. Here, we demonstrate that the human condensin II complex participates in senescence via gene regulation and reorganization of euchromatic A and heterochromatic B compartments. Both OIS and RS are accompanied by A-to-B and B-to-A compartmental transitions, the latter of which occur more frequently and are undergone by 14% (430 Mb) of the human genome. Mechanistically, condensin is enriched in A compartments and implicated in B-to-A transitions. The full activation of senescence genes (SASP genes and p53 targets) requires condensin; its depletion impairs senescence markers. This study describes that condensin reinforces euchromatic A compartments and promotes B-to-A transitions, both of which are coupled to optimal expression of senescence genes, thereby allowing condensin to contribute to senescent processes.

[1]  Adrian A Canutescu,et al.  Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. , 2005, Developmental cell.

[2]  Rugang Zhang,et al.  A novel role for the condensin II complex in cellular senescence , 2015, Cell cycle.

[3]  Philip A. Ewels,et al.  Global Reorganization of the Nuclear Landscape in Senescent Cells , 2015, Cell reports.

[4]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[5]  Jeffrey N. McKnight,et al.  Condensin-Dependent Chromatin Compaction Represses Transcription Globally during Quiescence. , 2019, Molecular cell.

[6]  L. Mirny,et al.  Iterative Correction of Hi-C Data Reveals Hallmarks of Chromosome Organization , 2012, Nature Methods.

[7]  O. Bensaude,et al.  Inhibiting eukaryotic transcription. Which compound to choose? How to evaluate its activity? , 2011, Transcription.

[8]  M. Yanagida,et al.  RNA pol II transcript abundance controls condensin accumulation at mitotically up-regulated and heat-shock-inducible genes in fission yeast , 2015, Genes to cells : devoted to molecular & cellular mechanisms.

[9]  Zhaohui S. Qin,et al.  Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing. , 2015, Molecular cell.

[10]  David A. Orlando,et al.  Supplemental Information Multiple Structural Maintenance of Chromosome Complexes at Transcriptional Regulatory Elements , 2013 .

[11]  William Stafford Noble,et al.  HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient , 2017, bioRxiv.

[12]  A. G. Chatterjee,et al.  Epigenetic regulation of condensin-mediated genome organization during the cell cycle and upon DNA damage through histone H3 lysine 56 acetylation. , 2012, Molecular cell.

[13]  Rachel Patton McCord,et al.  Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome , 2013, Genome research.

[14]  A. Papantonis,et al.  Transcription as a force partitioning the eukaryotic genome , 2014, Biological chemistry.

[15]  E. Skordalakes,et al.  Interaction between TBP and Condensin Drives the Organization and Faithful Segregation of Mitotic Chromosomes. , 2015, Molecular cell.

[16]  Yanli Wang,et al.  Topologically associating domains are stable units of replication-timing regulation , 2014, Nature.

[17]  Jonathan M. Cairns,et al.  Phenotype Specific Analyses Reveal Distinct Regulatory Mechanism for Chronically Activated p53 , 2015, PLoS genetics.

[18]  John J. Cole,et al.  HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia , 2014, Genes & development.

[19]  Neva C. Durand,et al.  Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. , 2016, Cell systems.

[20]  Osamu Iwasaki,et al.  Transcription factors mediate condensin recruitment and global chromosomal organization in fission yeast , 2016, Nature Genetics.

[21]  Holger Erfle,et al.  Super-Resolution Microscopy , 2017, Methods in Molecular Biology.

[22]  Alexander van Oudenaarden,et al.  Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins , 2013, Proceedings of the National Academy of Sciences.

[23]  J. Lawrence,et al.  Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence , 2013, The Journal of cell biology.

[24]  J. Dekker,et al.  Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation , 2015, Nature.

[25]  M. Narita,et al.  Cellular senescence and its effector programs , 2014, Genes & development.

[26]  Erez Lieberman Aiden,et al.  Cohesin Loss Eliminates All Loop Domains , 2017, Cell.

[27]  K. Noma.  The Yeast Genomes in Three Dimensions: Mechanisms and Functions. , 2017, Annual review of genetics.

[28]  Manuel Serrano,et al.  Cellular senescence: from physiology to pathology , 2014, Nature Reviews Molecular Cell Biology.

[29]  O. Iwasaki,et al.  Involvement of condensin-directed gene associations in the organization and regulation of chromosome territories during the cell cycle , 2015, Nucleic acids research.

[30]  K. Shirahige,et al.  Condensin targets and reduces unwound DNA structures associated with transcription in mitotic chromosome condensation , 2015, Nature Communications.

[31]  Ozlem Yildirim.  Isolation of Nascent Transcripts with Click Chemistry , 2015, Current protocols in molecular biology.

[32]  Hiroshi Kimura,et al.  Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. , 2012, Molecular cell.

[33]  Simon Tavaré,et al.  Autophagy mediates the mitotic senescence transition. , 2009, Genes & development.

[34]  L. Mirny,et al.  Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization , 2017, Cell.

[35]  Hideki Tanizawa,et al.  Architectural alterations of the fission yeast genome during the cell cycle , 2017, Nature Structural & Molecular Biology.

[36]  S. Ogura,et al.  Proteome analysis of human nuclear insoluble fractions , 2009, Genes to cells : devoted to molecular & cellular mechanisms.

[37]  S. Lowe,et al.  Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence , 2003, Cell.

[38]  Zhaohui S. Qin,et al.  Insulator function and topological domain border strength scale with architectural protein occupancy , 2014, Genome Biology.

[39]  J. Mallm,et al.  HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types. , 2018, Molecular cell.

[40]  Andrew S. Belmont,et al.  Large-scale chromatin organization: the good, the surprising, and the still perplexing. , 2014, Current opinion in cell biology.

[41]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[42]  P. Meister,et al.  From single genes to entire genomes: the search for a function of nuclear organization , 2016, Development.

[43]  Nicola Neretti,et al.  Reorganization of chromosome architecture in replicative cellular senescence , 2016, Science Advances.

[44]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[45]  J. Campisi,et al.  The senescence-associated secretory phenotype: the dark side of tumor suppression. , 2010, Annual review of pathology.

[46]  Brian J. Beliveau,et al.  Spatial organization of chromatin domains and compartments in single chromosomes , 2016, Science.

[47]  J. Campisi,et al.  Cellular senescence: when bad things happen to good cells , 2007, Nature Reviews Molecular Cell Biology.

[48]  J. Ellenberg,et al.  Distinct functions of condensin I and II in mitotic chromosome assembly , 2004, Journal of Cell Science.

[49]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[50]  Jill M Dowen,et al.  Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes , 2014, Cell.

[51]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Misteli,et al.  Long-Range Chromatin Interactions. , 2015, Cold Spring Harbor perspectives in biology.

[53]  L. Steinmetz,et al.  Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcription , 2018, bioRxiv.

[54]  Yuda Fang,et al.  Spatial and temporal regulation of Condensins I and II in mitotic chromosome assembly in human cells. , 2004, Molecular biology of the cell.

[55]  Adrian Salic,et al.  Exploring RNA transcription and turnover in vivo by using click chemistry , 2008, Proceedings of the National Academy of Sciences.

[56]  G. C. Rogers,et al.  SCFSlimb ubiquitin ligase suppresses condensin II–mediated nuclear reorganization by degrading Cap-H2 , 2013, The Journal of cell biology.

[57]  G. C. Rogers,et al.  Condensin II Regulates Interphase Chromatin Organization Through the Mrg-Binding Motif of Cap-H2 , 2015, G3: Genes, Genomes, Genetics.

[58]  F. Uhlmann.  SMC complexes: from DNA to chromosomes , 2016, Nature Reviews Molecular Cell Biology.

[59]  T. Misteli.  Beyond the Sequence: Cellular Organization of Genome Function , 2011 .

[60]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[61]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Xiaoping Zhou,et al.  Condensin I and II Complexes License Full Estrogen Receptor α-Dependent Enhancer Activation. , 2015, Molecular cell.

[63]  Sigal Shachar,et al.  3D Chromosome Regulatory Landscape of Human Pluripotent Cells. , 2016, Cell stem cell.

[64]  J. Bartek,et al.  Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16ink4a , 2011, Cell cycle.

[65]  Benjamin G. Bitler,et al.  HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci , 2016, The Journal of cell biology.

[66]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[67]  D. Engelke,et al.  Clustering of yeast tRNA genes is mediated by specific association of condensin with tRNA gene transcription complexes. , 2008, Genes & development.

[68]  P. A. Pérez-Mancera,et al.  Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence , 2013, Genes & development.

[69]  Peter D. Adams,et al.  Senescent cells harbour features of the cancer epigenome , 2013, Nature Cell Biology.

[70]  Dariusz M Plewczynski,et al.  CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription , 2015, Cell.

[71]  Darjus F. Tschaharganeh,et al.  BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. , 2016, Cancer discovery.

[72]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[73]  David A. Orlando,et al.  Mediator and Cohesin Connect Gene Expression and Chromatin Architecture , 2010, Nature.

[74]  R. Guthke,et al.  Similarities in Gene Expression Profiles during In Vitro Aging of Primary Human Embryonic Lung and Foreskin Fibroblasts , 2015, BioMed research international.

[75]  Jessie C. Jeyapalan,et al.  A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging , 2014, AGE.