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

Mahito Sadaie, Rafik Salama, Thomas Carroll, Kosuke Tomimatsu, Tamir Chandra, Andrew R.J. Young, Masako Narita, Pedro A. Pérez-Mancera, Dorothy C. Bennett, Heung Chong, Hiroshi Kimura, Masashi Narita

Research output: Contribution to journalArticlepeer-review

140 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1800-1808
Number of pages9
JournalGenes and Development
Volume27
Issue number16
DOIs
Publication statusPublished - Aug 15 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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