Global reorganization of the nuclear landscape in senescent cells

Cell Rep. 2015 Feb 3;10(4):471-83. doi: 10.1016/j.celrep.2014.12.055. Epub 2015 Jan 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cellular Senescence / genetics*
  • Cellular Senescence / physiology*
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / genetics
  • Chromatin Assembly and Disassembly / physiology
  • Heterochromatin / genetics
  • Heterochromatin / metabolism*
  • Humans
  • In Situ Hybridization, Fluorescence

Substances

  • Chromatin
  • Heterochromatin