Global Reorganization of the Nuclear Landscape in Senescent Cells

Tamir Chandra, Philip Andrew Ewels, Stefan Schoenfelder, Mayra Furlan-Magaril, Steven William Wingett, Kristina Kirschner, Jean-Yves Thuret, Simon Andrews, Peter Fraser, Wolf Reik

Research output: Contribution to journalArticlepeer-review

Abstract

Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria. We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. In addition, we observe a senescence-specific spatial clustering of heterochromatic regions, suggesting a unique second step required for SAHF formation. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.

Original languageEnglish
Pages (from-to)471-483
Number of pages13
JournalCell Reports
Volume10
Issue number4
Early online date29 Jan 2015
DOIs
Publication statusPublished - 3 Feb 2015

Keywords

  • Cell Aging
  • Cell Line
  • Cell Proliferation
  • Chromatin
  • Chromatin Assembly and Disassembly
  • Heterochromatin
  • Humans
  • In Situ Hybridization, Fluorescence

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