Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence

Genes Dev. 2013 Aug 15;27(16):1800-8. doi: 10.1101/gad.217281.113.

Abstract

Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression.

Keywords: Lamin B1; epigenetics; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Chromatin Assembly and Disassembly / genetics*
  • Gene Expression Regulation
  • Heterochromatin / chemistry
  • Heterochromatin / metabolism*
  • Histones / metabolism
  • Lamin Type B / genetics
  • Lamin Type B / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary

Substances

  • Heterochromatin
  • Histones
  • Lamin Type B
  • lamin B1