title: Reorganization of chromosome architecture in replicative cellular senescence.
abstract: Replicative cellular senescence is a fundamental biological process characterized by an irreversible arrest of proliferation. Senescent cells accumulate a variety of epigenetic changes, but the three-dimensional (3D) organization of their chromatin is not known. We applied a combination of whole-genome chromosome conformation capture (Hi-C), fluorescence in situ hybridization, and in silico modeling methods to characterize the 3D architecture of interphase chromosomes in proliferating, quiescent, and senescent cells. Although the overall organization of the chromatin into active (A) and repressive (B) compartments and topologically associated domains (TADs) is conserved between the three conditions, a subset of TADs switches between compartments. On a global level, the Hi-C interaction matrices of senescent cells are characterized by a relative loss of long-range and gain of short-range interactions within chromosomes. Direct measurements of distances between genetic loci, chromosome volumes, and chromatin accessibility suggest that the Hi-C interaction changes are caused by a significant reduction of the volumes occupied by individual chromosome arms. In contrast, centromeres oppose this overall compaction trend and increase in volume. The structural model arising from our study provides a unique high-resolution view of the complex chromosomal architecture in senescent cells.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Criscione
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: De Cecco
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Benjamin
authors.identifier: 0000-0002-4935-8172
authors.initials: B
authors.lastname: Siranosian
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Yue
authors.identifier: 0000-0001-6533-5563
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Kreiling
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: John M
authors.identifier: 0000-0001-9363-4253
authors.initials: JM
authors.lastname: Sedivy
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.; Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Neretti
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D020223:Chromosome Painting; D002877:Chromosomes, Human / Q000235:genetics* / Q000648:ultrastructure*; D003198:Computer Simulation; D004276:DNA, Satellite / Q000737:chemistry / Q000235:genetics; D006801:Humans; D021621:Imaging, Three-Dimensional; D017404:In Situ Hybridization, Fluorescence; D008957:Models, Genetic; D008958:Models, Molecular
chemical_list: D002843:Chromatin; D004276:DNA, Satellite
keywords: DNA FISH; Hi-C; cellular senescence; centromere; chromatin; chromosome architecture; chromosome conformation capture; genome organization; long-range interactions; telomere